Proximity- and chelation-induced SNAr 1,4-aromatic ortho-substitution of ortho-methoxyphenyl 2-alkyl ketones

Article abstract of DOI:10.1055/s-0034-1379992

The direct displacement of an o-methoxy group in o-methoxyaryl ketones with aryl, alkyl, and alkenyl Grignard reagents to provide a series of o-substituted ketones is described. Application of this reaction to the synthesis of a C-methyl analogue of a cyc

Full text of DOI:10.1055/s-0034-1379992

SYNTHESIS
0
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3
9
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1
4
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7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1091–1100
paper
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Proximity- and Chelation-Induced SNAr 1,4-Aromatic ortho-Sub-
stitution of ortho-Methoxyphenyl 2-Alkyl Ketones
Gwendal Grelier
Etienne Chénard
Martin Büschleb
Stephen Hanessian*
OMe
O
R2
O
R2MgBr
R1
R1
X = H, OMe, Br, Cl
R1 = alkyl, cycloalkyl
13 examples
68–99%
R
2 = alkyl, alkenyl, aryl
X
X
Department of Chemistry, Université de Montréal, Station
Centre-Ville, C. P. 6128, Montréal, Quebec H3C 3J7, Canada
stephen.hanessian@umontreal.ca
Received: 20.11.2014
Accepted after revision: 22.12.2014
Published online: 12.02.2015
We were initially surprised to find that the biaryl ad-
duct 3a was formed in 59% yield, in addition to the expect-
ed alcohol 2a (30%). In this reaction, we had effectively re-
placed the o-methoxy group with an aryl group. Intrigued
by this result, we were led through a literature search to the
pioneering work by Fuson and Speck, who in 1942 had re-
ported that o-methoxybenzoylmesitylene reacted with
phenylmagnesium bromide in refluxing benzene to afford
2-phenylbenzoylmesitylene in 35% yield.2 The reaction was
extended to o-methoxynaphthoylmesitylene with higher
yields (Scheme 2). Further examples included the direct o-
arylation of hindered aromatic ketones and esters in what
amounts to a replacement of an aromatic C–H with an aryl
moiety provided by the Grignard reagent.3 Since then, sev-
eral examples of SNAr displacement of o-methoxy groups
with Grignard reagents in aromatic esters4 and oxazolines5
have been reported. In 2011, Shaw and co-workers6 revisit-
DOI: 10.1055/s-0034-1379992; Art ID: ss-2014-m0711-op
Abstract The direct displacement of an o-methoxy group in o-me-
thoxyaryl ketones with aryl, alkyl, and alkenyl Grignard reagents to pro-
vide a series of o-substituted ketones is described. Application of this
reaction to the synthesis of a C-methyl analogue of a cyclooxygenase
inhibitor is shown. The scope and limitations are discussed.
Key words aromatic substitution, biaryls, Grignard reaction in aryl ke-
tones, steric hindrance, transition-metal-free reactions
In the course of our synthetic studies on the diastereo-
selective arylation of 2-alkylbenzylic alcohols,1 ketone 1a
was treated with p-methoxyphenylmagnesium bromide
with the intention of obtaining the corresponding benzylic
tertiary alcohol 2a (Scheme 1).
OMe
OMe
OMe
OH
MgBr
MeO
OMe
O
(2 equiv)
2a (30%)
Et2O, 0 °C
+
OMe
MeO
1a
O
MeO
3a (59%)
Scheme 1 Unexpected 1,4-aromatic substitution of o-methoxyaryl alkyl ketones
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ed the Fuson chemistry with a detailed study of the direct
displacement of o-methoxy groups in o-methoxynaphtha-
lene methyl esters and ketones (Scheme 2).
N
O
O
Fuson 1942
CO2H
R2
O
OMe
O
t-Bu
R2MgBr
F
O
R1
R1 = Me, H
R1
MeO
4 (activates G-receptor
coupled receptor)
5 (in vivo flexor
reflex inhibition)
R
2 = Ph, Et, 2-MeOC6H4
(18–47%)
O
MeO2S
R
O
OMe
O
O
O
O
O
RMgBr
HO
MeO
O
MeO
R = Me, Et, n-Bu, Ph, Naph
MeO
Schizanrin N (7)
(56–80%)
6 (cyclooxygenase
Shaw 2011
OMe
inhibitor)
(cytotoxic, anti-HIV)
R2
O
Figure 1 Bioactive compounds featuring an o-biaryl ketone motif
O
R2MgBr
R1
R1
Herein, we report an extension of the original Fuson3,4a
and more recent Shaw and Houk6,7 1,4-aromatic substitu-
tion reaction of o-methoxyaryl alkyl ketones. As shown in
Scheme 1, the reaction of enantiomerically enriched 1-
(2′,4′-dimethoxyphenyl)-2-isopropylpent-4-en-1-one (1a)
(80% ee)13 with 2 equivalents of p-methoxyphenylmagne-
sium bromide resulted in a 59:30 ratio for the ketone 3a as
the 1,4-substitution product over the tertiary alcohol 2a
(Scheme 1, Table 1, entry 1). Remarkably no erosion of en-
antiopurity was observed in the product 3a. Optimization
of this reaction with the racemic ketone 1a revealed a ratio
of 3a/2a = 84:16 using dichloromethane as solvent instead
of diethyl ether. Although lowering the temperature to
–78 °C did not improve the ratio (entry 2), changing the sol-
vent to dichloromethane (entry 3) had a positive effect, and
decreasing the concentration to 0.01 M showed a further
improvement to 87:10 in favor of the 1,4-displacement
product 3a (entry 4). Additionally, the effect of Lewis acids
as additives was investigated and showed an improved se-
lectivity [3a/2a = 93:7 using equimolar CuI, but incomplete
conversion (80%), entry 5]. Therefore, the scope of the reac-
tion was investigated without the use of any additive under
the optimized conditions [2 equiv of Grignard reagent, di-
chloromethane (0.01 M), r.t., 45 min].14
R1 = Me, n-Bu
2 = i-Pr, n-Bu
(52–90%)
R
Scheme 2 Previous work towards the 1,4-aromatic substitution reac-
tion of o-methoxynaphthyl 2-ketones with Grignard reagents
Remarkably, the corresponding tosylate esters were un-
reactive, indicating the possible intermediacy of a magne-
sium chelate between the carbonyl group of the ester and
the o-methoxy group in the naphthalene moiety. That the
reaction was energetically feasible in spite of the disruption
of aromaticity of the naphthalene moiety was contrasted
with its failure in the case of isopropyl o-methoxybenzo-
ate.4e The mechanism of this unique, albeit long neglected,
transformation was recently reported by Houk and Shaw,7
and clarified based on theoretical calculations. Indeed, they
showed that an inner sphere attack of nucleophilic groups
from the reagent involved magnesium chelates. Although
the reaction is not catalytic in nature, it is an attractive al-
ternative to a transition-metal-catalyzed transformation
with applications in pharmaceutical synthetic processes.8
The biphenyl moiety is a prevalent subunit in a number of
bioactive compounds such as pivaloylbiaryl 4,9 biphenyl ke-
tone 5,10 cyclohexyl biaryl ketone 611 as well as natural
products such as schizanrin N (7), a member of the diben-
zocyclooctadiene-type lignan family12 (Figure 1).
A less electron-rich aromatic substrate lacking the 4-
methoxy substituent showed decreased selectivity (3b/2b =
54:14) and yield (Table 2, entry 1). Increasing the steric
bulk of the alkyl side chain to tert-butyl resulted in the ex-
clusive formation of the biaryl ketone 3c in excellent yield,
although five equivalents of p-methoxyphenylmagnesium
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Table 1 Grignard Reactions Using o-Methoxyaryl 2-Ketone 1a
OMe
OMe
OMe
MgBr
(2 equiv)
OMe
O
OMe
O
OH
+
MeO
MeO
MeO
1a
2a
3a
Entry
Solvent (c)
Temp
Yield (%)a of 2a
Yield (%)a of 3a
1b
2
Et2O (0.1 M)
0 °C to r.t.
30
40c
16c
10
7c
59
Et2O (0.03 M)
CH2Cl2 (0.03 M)
CH2Cl2 (0.01 M)
CH2Cl2 (0.01 M)
–78 °C to r.t.
60c
84c
87
3
r.t.
r.t.
r.t.
4
5d
93c
a Isolated yield, if not otherwise indicated.
b Enantiomeric excess: 1a, 80%; 3a, 78%.
c Crude 1H NMR ratio.
d CuI (2 equiv), 80% conversion.
bromide were necessary for full conversion in this case (en-
try 2). The cyclopentyl group is large enough to yield the
1,4-product 3d exclusively (entry 3), while the smaller cy-
clopropyl group enabled the 1,4-displacement reaction giv-
ing the major product in a ratio of 3e/2e = 55:26 (entry 4). A
methyl group or aryl substituent gave exclusively the tertia-
ry alcohol 2f and 2g in good to excellent yields (entries 5,
6).
The scope of the Grignard reagent was investigated us-
ing
1-(2′,4′-dimethoxyphenyl)-2-tert-butylpent-4-en-1-
one (1c) as the starting material, which can be prepared in
two steps from 1,3-dimethoxybenzene (8) (Scheme 3).14,15
Table 2 Grignard Reactions Using o-Methoxyaryl 2-Ketones 1
OMe
OMe
OMe
OMe
O
OMe
O
MgBr
(2 equiv)
OH
R
R
R
+
X
X
X
1
2
3
Entry
Ketone
R
X
Yield (%)a of 2
Yield (%)a of 3
1b
2b,c
3b
4b
5e
1b
1c
1d
1e
1f
i-Pr
H
2a, 14
2cd
3b, 54
3c, 99
3d, 87
3e, 55
3fd
t-Bu
OMe
OMe
OMe
OMe
OMe
cyclopentyl
cyclopropyl
Me
2dd
2e, 26
2f, 92
2g, 97
6b
1g
Ph
3gd
a Isolated yield.
b Optimized conditions (0.01 M in CH2Cl2, r.t., 45 min).
c Grignard reagent used: 5 equiv.
d Not observed.
e Et2O (0.1 M), 0 °C to r.t.
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Thus, halogenated aryls such as 1-(4′-bromo-2′-methoxy-
phenyl)-2-tert-butylpent-4-en-1-one (1h) and 1-(4′-
chloro-2′-methoxyphenyl)-2-tert-butylpent-4-en-1-one
(1i) are well tolerated, affording the 1,4-displacement prod-
ucts 3h and 3i in good to excellent yields. This shows as
well that for 2′-methoxy-4′-halophenyl 2-alkyl ketones, the
addition-elimination reaction is faster than a metal ex-
change and it enables the subsequent functionalization of
these halides. Simple alkyl and alkenyl Grignard reagents
could be utilized in very good to excellent yields to provide
3j–l. Less electron-rich Grignard reagents like PhMgBr al-
lowed the exclusive formation of the o-biaryl 2-alkyl ke-
tones 3m and 3n. However, substrates bearing o,o-dime-
thoxy groups in the aromatic core were recovered un-
changed, presumably due to an additional chelation
opportunity with the two vicinal methoxy groups.16 Also,
electron-poor aryl Grignard reagents were not reactive
enough (3-pyridinyl and 3-furanyl, results not shown).
O
O
MeO
9
O
Cl
97%
MgBr
SnCl4, CH2Cl2
–15 °C, 1 h
SMe
CH2Cl2, r.t., 2 h
OH
O
O
O
O
59% (3.5 equiv)
52% (2.0 equiv)
O
MeS
MeO
10
11
1) KHMDS, THF
–78 °C, 30 min
2) MeI, 18 h
R2MgBr (5.0 equiv)
MgBr
70%
OMe
O
R2
O
CH2Cl2 (0.01 M)
r.t.
R1
R1
–78 °C to r.t.
X
X
SMe
(3 equiv)
1
3
O
CH2Cl2, r.t., 21 h
1)
O
O
O
OMe
O
O
67%
Cl
AlCl3, CH2Cl2, r.t.
2) KHMDS, THF
–78 °C
CH2R1
O
MeO
MeS
O
3) allyl iodide, r.t.
12
13
Scheme 4 Synthesis of C-methyl cyclooxygenase precursor 13
OMe
X
3h: X = Br 99%
3i: X = Cl 68%
X
Sesamol was methylated to its methyl ether 9, which
was acylated in a Friedel–Crafts reaction with tin(IV) chlo-
ride and cyclohexylcarbonyl chloride to give ketone 10 in
excellent yield. Surprisingly, the attempted aromatic substi-
tution with p-methylthiophenylmagnesium bromide gave
exclusively the tertiary alcohol 11, probably due to a lack of
sufficient steric bulk by the cyclohexyl moiety. However,
the α-methyl cyclohexyl ketone 12, easily prepared by eno-
late methylation, gave the expected 1,4-displacement prod-
uct 13, a C-methylated analogue of the cyclooxygenase in-
hibitor 6, in excellent yield. Additionally, this reaction was
monitored by 1H NMR experiments. While addition of 1
equivalent Grignard reagent gave no conversion after 24
hours, the reaction with 2 equivalents led to full conversion
overnight. The reaction profile suggests second order kinet-
ics (Grignard reagent) in agreement with an addition/elimi-
nation mechanism. Following the computational studies by
Houk and co-workers with o-methoxynaphthyl esters and
ketones,7 the more bulky ketone 12 requires at least a sec-
8
R2
O
O
MeO
3j: R2
R1
=
87%
MeO
3k: R2
3l: R2
=
95%
83%
3m: R1 = i-Pr 82%
3n: R1 = t-Bu 68%
=
Scheme 3 Scope of the nucleophiles
Finally, this 1,4-aromatic substitution method was ap-
plied to the synthesis of a C-methyl analogue of the cycloo-
xygenase inhibitor 6 (Scheme 4).11
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ond equivalent of Grignard reagent to deliver the nucleo-
phile while the first equivalent chelates the carbonyl and
methoxy oxygens.
Grignard Reactions; General Procedure 3 (GP3)
To a solution of o-methoxyaryl alkyl ketone 1 (1.0 equiv) [either with
or without a Lewis acid (1.0 equiv)] in anhydrous CH2Cl2 (0.01 M) was
added a solution of the Grignard reagent (2.0 equiv) in one portion at
r.t. After stirring for 45 min, the reaction mixture was quenched by
the addition of sat. aq NH4Cl. The aqueous layer was extracted with
CH2Cl2 (2 ×), the organic layers were combined and washed with
brine (2 ×), dried (MgSO4), filtered, and concentrated.
In conclusion, based on the pioneering work of Fuson
and co-workers3,4a and the latest results by Shaw and Houk7
who explored o-methoxynaphthalene core alkyl ketones,
we were able to expand the scope of this very mild and
practical 1,4-aromatic substitution reaction of o-methoxy-
phenyl 2-alkyl ketones to include different aryl, alkenyl,
and alkyl appendages at the site originally occupied by the
o-methoxyaryl group. The 1,4-aromatic substitution of o-
methoxyphenyl 2-alkyl ketones at room temperature, gives
direct transition-metal-free access17 to biaryl 2-alkyl ke-
tones of which just a few examples are described in the lit-
erature and can complement ruthenium- and palladium-
catalyzed cross-couplings18 or decarboxylative cross-cou-
plings between aryl carboxylic acids.19 Utilizing this meth-
od, a C-methyl analogue 13 of the cyclooxygenase inhibitor
6 was synthesized in three steps from O-methyl sesamol in
45% overall yield.
1′-(4′′,5′-Dimethoxybiphenyl-2′-yl)-2-isopropylpent-4-en-1-one
(3a) and 1-(2′,4′-Dimethoxyphenyl)-2-isopropyl-1-(4′′-methoxy-
phenyl)pent-4-en-1-ol (2a) (racemic)
The reaction was performed according to the GP3 using 1-(2′,4′-di-
methoxyphenyl)-2-isopropylpent-4-en-1-one (1a; 10 mg, 0.038
mmol), 4-methoxyphenylmagnesium bromide (151 μL, 0.5 M in THF,
0.076 mmol), and anhydrous CH2Cl2 (4.00 mL). The residue was puri-
fied by flash chromatography (n-hexane–EtOAc, 9:1) to yield 3a
(11 mg, 0.033 mmol, 87%) as a yellow oil and 2a (1.4 mg, 0.005 mmol,
10%) as a colorless oil.
3a
Rf = 0.38 (n-hexane–EtOAc, 4:1).
IR (ATR): 2959, 1673, 1599, 1578, 1515, 1499, 1440, 1247, 1175, 1024
cm–1
.
All nonaqueous reactions were run in flame-dried glassware under a
positive pressure of argon with exclusion of moisture from reagents
and glassware using standard techniques for manipulating air-sensi-
tive compounds. Anhydrous solvents were obtained using standard
drying techniques. Unless stated otherwise, commercial grade re-
agents were used without further purification. Reactions were moni-
tored by analytical TLC performed on pre-coated, glass-backed silica
gel plates. Visualization of the developed chromatogram was per-
formed by UV absorbance, aq cerium ammonium molybdate, or aq
potassium permanganate. Flash chromatography was performed on
230–400 mesh silica gel with the indicated solvent systems. Melting
points are uncorrected. Routine NMR spectra were recorded on an
AV-300, AV-400, or AV-500 spectrometer. Chemical shifts for 1H NMR
spectra are given in parts per million from TMS with the solvent reso-
nance as the internal standard (CDCl3, δ = 7.27). Data are reported as
follows: chemical shift, multiplicity (standard abbreviations), cou-
pling constant in Hz, and integration. Chemical shifts for 13C NMR
spectra are given in parts per million from TMS using the central peak
of the solvent resonance as the internal standard (CDCl3, δ = 77.16).
All spectra were obtained with complete proton decoupling. Optical
rotations were determined with a polarimeter at 589 nm, using a 1
dm cell as well as 1 mL CHCl3 at r.t. and are reported in units of
deg·cm3·g–1·dm–1. IR spectra were recorded on a FT-IR spectrometer
equipped with an integrated ATR unit and are reported in cm–1. High-
resolution mass spectra were performed on a LC-TOF instrument us-
ing electrospray ionization (ESI) techniques. Analytical chiral SFC
traces were obtained from a UV detector, with wavelengths set at 254
or 220 nm and the SFC separation conditions are described as follows:
gradient, column, flow, column temperature, back pressure (BP, psi),
retention time (tR), ratio. Analytical chiral HPLC were performed with
a chiralcel OD-H column. The column size was 4.6 mm diameter × 250
mm height. HPLC traces were obtained from a UV detector, with
wavelengths set at 254 and/or 210 nm. The HPLC separation condi-
tions and results are described as follows: gradient, column, flow, re-
tention time (tR), ratio.
1H NMR (400 MHz, CDCl3): δ = 7.49 (d, J = 8.6 Hz, 1 H), 7.24–7.18 (m, 2
H), 6.96–6.91 (m, 2 H), 6.89 (dd, J = 8.6, 2.6 Hz, 1 H), 6.81 (d, J = 2.6 Hz,
1 H), 5.45 (ddt, J = 17.1, 10.1, 7.1 Hz, 1 H), 4.92–4.84 (m, 2 H), 3.86 (s,
3 H), 3.84 (s, 3 H), 2.47 (dt, J = 8.0, 5.2 Hz, 1 H), 2.29 (ddd, J = 12.4, 9.6,
5.2 Hz, 1 H), 2.01–1.92 (m, 1 H), 1.82–1.72 (m, 1 H), 0.74 (d, J = 6.9 Hz,
3 H), 0.63 (d, J = 6.9 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 207.3, 161.0, 159.4, 142.6, 136.9,
133.8, 133.6, 130.8, 130.1, 115.9, 115.8, 114.0, 112.5, 55.4, 55.4, 55.4,
31.0, 29.2, 20.5, 18.7.
HRMS (ESI): m/z calcd for C22H26O3 [M + H]+: 339.19547; found:
339.19558.
2a
Rf = 0.20 (n-hexane–EtOAc. 4:1).
IR (ATR): 3521, 2954, 2871, 1609, 1582, 1505, 1463, 1249, 1208, 1173,
1036 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.38 (d, J = 8.6 Hz, 1 H), 7.22 (d, J = 8.8
Hz, 2 H), 6.74 (d, J = 8.8 Hz, 2 H), 6.54 (dd, J = 8.6, 2.5 Hz, 1 H), 6.39 (d,
J = 2.5 Hz, 1 H), 5.45–5.33 (m, 1 H), 4.84–4.77 (m, 1 H), 4.74–4.69 (m,
1 H), 3.79 (s, 3 H), 3.75 (s, 3 H), 3.60 (s, 3 H), 2.47–2.37 (m, 1 H), 2.30–
2.17 (m, 2 H), 2.08–2.00 (m, 1 H), 1.04 (t, J = 6.7 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ = 159.5, 158.3, 157.7, 140.8, 140.3,
127.8, 127.4, 127.0, 113.7, 112.7, 104.2, 100.5, 83.0, 55.8, 55.3, 55.2,
50.6, 29.8, 29.0, 24.6, 18.5.
HRMS (ESI): m/z calcd for C23H30O4 + Na [M + Na]+: 393.20363; found:
393.20410.
(2S)-1′-(4′′,5′-Dimethoxybiphenyl-2′-yl)-2-isopropylpent-4-en-1-
one [(S)-3a] and (2S)-1-(2′,4′-Dimethoxyphenyl)-2-isopropyl-1-
(4′′-methoxyphenyl)pent-4-en-1-ol [(S)-2a] (enantiomerically en-
riched)
The reaction was performed according to the GP3 using (2S)-1-(2′,4′-
dimethoxyphenyl)-2-isopropylpent-4-en-1-one
[(S)-1a;
40 mg,
For the preparation of starting materials 1 (GP1 and GP2) and tertiary
alcohols 25 and 26 (GP3), see the Supporting Information.
0.15 mmol, 80% ee], 4-methoxyphenylmagnesium bromide (600 μL,
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0.5 M in THF, 0.300 mmol), and anhydrous Et2O (3.00 mL) (solvent
different from GP3). The Grignard reagent was added at 0 °C and the
solution was stirred for 20 h and slowly warmed up to r.t. The residue
was purified by flash chromatography (n-hexane–EtOAc, 9:1) to yield
(S)-3a {30 mg, 0.089 mmol, 59%, 78% ee, [α]D20 –37 (c 1.5, CDCl3)}; ee
was determined by chiral SFC (2% i-PrOH–hexanes, chiralcel OD, 1.0
mL/min, tR = 8.04 min and 9.31 min, ratio 11.6:88.4) as a yellow oil
and (S)-2a (17 mg, 0.045 mmol, 30%) as a colorless oil.
in THF, 0.560 mmol), and anhydrous CH2Cl2 (5.00 mL). The residue
was purified by flash chromatography (n-hexane–EtOAc, 95:5) to
yield 3c (39 mg, 0.11 mmol, 99%) as a colorless oil; Rf = 0.34 (n-hex-
ane–Et2O, 9:1).
IR (ATR): 2959, 1671, 1597, 1515, 1465, 1247, 1214, 1175, 1024, 834,
631 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 8.7 Hz, 1 H), 7.24–7.17 (m, 2
H), 6.96–6.84 (m, 3 H), 6.75 (d, J = 2.6 Hz, 1 H), 5.49 (ddt, J = 17.0, 10.1,
7.4 Hz, 1 H), 4.93 (dd, J = 17.0, 1.7 Hz, 1 H), 4.86 (dd, J = 10.1, 2.1 Hz, 1
H), 3.85 (s, 3 H), 3.84 (s, 3 H), 2.84 (dd, J = 9.5, 4.0 Hz, 1 H), 2.43 (ddd,
J = 9.5, 8.8, 7.4 Hz, 1 H), 2.20–2.08 (m, 1 H), 0.78 (s, 9 H).
The analytical data of enantiomerically enriched (S)-3a and (S)-2a are
in full agreement with the data of the racemic compounds.
2-Isopropyl-1-(4′′-methoxybiphenyl-2′-yl)pent-4-en-1-one (3b)
and 2-Isopropyl-1-(2′-methoxyphenyl)-1-(4′′-methoxyphe-
nyl)pent-4-en-1-ol (2b)
13C NMR (101 MHz, CDCl3): δ = 205.9, 161.1, 159.0, 143.7, 138.0,
134.4, 134.2, 131.6, 130.3, 116.8, 115.7, 113.6, 112.4, 57.4, 55.4, 55.3,
34.5, 32.8, 28.6.
The reaction was performed according to the GP3 using 1-(2′-me-
thoxyphenyl)-2-isopropylpent-4-en-1-one (1b; 50 mg, 0.22 mmol,),
4-methoxyphenylmagnesium bromide (863 μL, 0.5 M in THF,
0.431 mmol), and anhydrous CH2Cl2 (22.0 mL). The residue was puri-
fied by flash chromatography (n-hexane–EtOAc, 95:5) to yield 3b
(36 mg, 0.12 mmol, 54%) as a yellow oil and 2b (10 mg, 0.028 mmol,
14%) as a yellow oil.
HRMS (ESI): m/z calcd for C23H29O3 [M + H]+: 353.21112; found:
353.21182.
2-Cyclopentyl-1-(4′′,5′-dimethoxybiphenyl-2′-yl)pent-4-en-1-one
(3d)
The reaction was performed according to the GP3 using 1-(2′,4′-di-
methoxyphenyl)-2-cyclopentylpent-4-en-1-one
(1d;
115 mg,
0.398 mmol), 4-methoxyphenylmagnesium bromide (1.60 mL, 0.5 M
in THF, 0.800 mmol), and anhydrous CH2Cl2 (40.0 mL). The residue
was purified by flash chromatography (n-hexane–EtOAc, 9:1) to yield
3d (127 mg, 0.349 mmol, 87%) as a colorless oil. The reaction was also
carried out with a sequential addition of Grignard reagent (2 × 1.0
equiv, stirring overnight at r.t. in between); but 1H NMR analysis of
the crude product showed no conversion; Rf = 0.47 (n-hexane–EtOAc,
4:1).
3b
Rf = 0.57 (n-hexane–EtOAc, 9:1).
IR (ATR): 2949, 1677, 1609, 1514, 1472, 1242, 1178, 1035, 831, 760
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.50–7.42 (m, 2 H), 7.40–7.31 (m, 2 H),
7.25–7.19 (m, 2 H), 6.98–6.90 (m, 2 H), 5.42 (ddt, J = 17.0, 10.1, 7.1 Hz,
1 H), 4.91–4.82 (m, 2 H), 3.84 (s, 3 H), 2.45–2.38 (m, 1 H), 2.30 (dt, J =
14.4, 7.2 Hz, 1 H), 2.01–1.91 (m, 1 H), 1.83–1.71 (m, 1 H), 0.74 (d, J =
6.9 Hz, 3 H), 0.62 (d, J = 7.0 Hz, 3 H).
IR (ATR): 2946, 1673, 1599, 1513, 1246, 1215, 1175, 1029, 912, 832
cm–1
.
13C NMR (75 MHz, CDCl3): δ = 209.0, 159.4, 141.1, 139.9, 136.8, 133.2,
130.4, 130.3, 130.2, 128.4, 127.0, 115.9, 114.1, 55.9, 55.4, 30.5, 28.7,
20.5, 18.5.
HRMS (ESI): m/z calcd for C21H25O2 [M + H]+: 309.18491; found:
309.18393.
1H NMR (400 MHz, CDCl3): δ = 7.53 (d, J = 8.6 Hz, 1 H), 7.26–7.22 (m, 2
H), 6.97–6.93 (m, 2 H), 6.89 (dd, J = 8.6, 2.6 Hz, 1 H), 6.80 (d, J = 2.6 Hz,
1 H), 5.56–5.44 (m, 1 H), 4.90–4.84 (m, 2 H), 3.86 (s, 3 H), 3.84 (s, 3 H),
2.59 (td, J = 7.6, 4.7 Hz, 1 H), 2.27 (dt, J = 14.3, 7.2 Hz, 1 H), 2.10–2.01
(m, 1 H), 1.93 (tddd, J = 9.9, 7.6, 7.6, 7.6 Hz, 1 H), 1.63–1.52 (m, 3 H),
1.50–1.34 (m, 3 H), 0.99–0.84 (m, 2 H).
2b
13C NMR (101 MHz, CDCl3): δ = 207.1, 160.6, 158.9, 142.5, 135.8,
133.3, 133.1, 130.8, 129.7, 115.7, 115.6, 113.5, 112.0, 55.0, 55.0, 53.5,
41.0, 33.9, 30.3, 29.4, 24.7, 24.5.
HRMS (ESI): m/z calcd for C24H29O3 [M + H]+: 365.21112; found:
365.21279.
Rf = 0.40 (n-hexane–EtOAc, 9:1).
IR (ATR): 3509, 2942, 1606, 1582, 1507, 1460, 1246, 1174, 1028, 750
cm–1
.
1H NMR (300 MHz, CDCl3): δ (rotamers) = 7.56–7.46 (m, 1 H), 7.26–
7.16 (m, 3 H), 7.06–6.97 (m, 1 H), 6.86–6.72 (m, 3 H), 5.96 (ddt,
J = 16.8, 9.9, 6.8 Hz, 0.3 H), 5.45–5.28 (m, 0.7 H), 5.06–4.64 (m, 3 H),
3.76 (s, 3 H), 3.61 (s, 3 H), 2.54–2.36 (m, 1.7 H), 2.29–2.13 (m, 1.5 H),
2.09–1.94 (m, 0.8 H), 1.08–1.02 (m, 4 H), 0.95–0.86 (m, 2 H).
2-Cyclopropyl-1-(4′′,5′-dimethoxybiphenyl-2′-yl)pent-4-en-1-one
(3e) and 2-Cyclopropyl-1-(2′,4′-dimethoxyphenyl)-1-(4′′-methoxy-
phenyl)pent-4-en-1-ol (2e)
The reaction was performed according to the GP3 using 1-(2′,4′-di-
13C NMR (76 MHz, CDCl3): δ (rotamers) = 157.9, 157.7, 157.6, 141.0,
140.9, 140.1, 139.9, 135.7, 135.3, 128.1, 128.1, 127.3, 127.2, 127.0,
126.9, 121.0, 120.9, 114.5, 113.8, 113.0, 112.9, 83.8, 83.5, 77.2, 56.0,
55.3, 55.3, 50.6, 49.8, 31.2, 29.9, 29.2, 27.9, 24.9, 24.7, 18.7, 18.6.
HRMS (ESI): m/z calcd for C22H28O3 + Na [M + Na]+: 363.19307 found:
363.19139.
methoxyphenyl)-2-cyclopropylpent-4-en-1-one
(1e;
54 mg,
0.21 mmol), 4-methoxyphenylmagnesium bromide (828 μL, 0.5 M in
THF, 0.414 mmol), and anhydrous CH2Cl2 (21.0 mL). The residue was
purified by flash chromatography (n-hexane–EtOAc, 95:5) to yield 3e
(38 mg, 0.11 mmol, 55%) and 2e (19 mg, 0.052 mmol, 26%) as color-
less oils.
2-tert-Butyl-1-(4′′,5′-dimethoxybiphenyl-2′-yl)pent-4-en-1-one
(3c)
3e
Rf = 0.40 (n-hexane–EtOAc, 4:1).
The reaction was performed according to the GP3 using 1-(2′,4′-di-
IR (ATR): 3002, 2936, 2837, 1677, 1600, 1513, 1216, 1175, 1027, 831
methoxyphenyl)-2-tert-butylpent-4-en-1-one
(1c;
31 mg,
cm–1
.
0.11 mmol), 4-methoxyphenylmagnesium bromide (1.12 mL, 0.5 M
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1H NMR (400 MHz, CDCl3): δ = 7.50 (d, J = 8.6 Hz, 1 H), 7.27–7.22 (m, 2
H), 6.98–6.94 (m, 2 H), 6.89 (dd, J = 8.6, 2.6 Hz, 1 H), 6.82 (d, J = 2.6 Hz,
1 H), 5.69–5.56 (m, 1 H), 4.94–4.87 (m, 2 H), 3.89 (s, 3 H), 3.86 (s, 2 H),
2.32 (dt, J = 13.8, 6.9 Hz, 1 H), 2.22 (dt, J = 13.8, 6.9 Hz, 1 H), 1.79 (dt,
J = 9.7, 6.6 Hz, 1 H), 0.79–0.69 (m, 1 H), 0.48–0.39 (m, 1 H), 0.33–0.25
(m, 1 H), –0.10 (td, J = 9.9, 5.0 Hz, 1 H), –0.26 (td, J = 9.9, 5.0 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 208.2, 161.1, 159.5, 142.4, 136.4,
133.9, 133.4, 130.8, 130.1, 116.2, 115.6, 114.2, 112.5, 55.6, 55.5, 55.2,
36.4, 13.7, 4.6, 3.9.
1-(2′,4′-Dimethoxyphenyl)-1-(4′′-methoxyphenyl)-2-phenylpent-
4-en-1-ol (2g)
The reaction was performed according to the GP3 using 1-(2′,4′-di-
methoxyphenyl)-2-phenylpent-4-en-1-one (1g; 75 mg, 0.25 mmol),
4-methoxyphenylmagnesium bromide (1.01 mL, 0.5 M in THF,
0.500 mmol), and anhydrous CH2Cl2 (25.0 mL). The residue was puri-
fied by flash chromatography (n-hexane–EtOAc, 9:1) to yield 2g
(98 mg, 0.24 mmol, 97%) as a yellow oil; Rf = 0.15 (n-hexane–EtOAc,
9:1).
HRMS (ESI): m/z calcd for C22H25O3 [M + H]+: 337.17982; found:
337.18039.
IR (ATR): 3488, 2928, 1606, 1502, 1249, 1205, 1161, 1025, 913, 831
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.50–7.46 (m, 2 H), 7.32–7.28 (m, 2 H),
7.20–7.07 (m, 4 H), 6.91–6.87 (m, 2 H), 6.31 (dd, J = 8.7, 2.5 Hz, 1 H),
6.20 (d, J = 2.5 Hz, 1 H), 5.55 (ddt, J = 17.0, 10.1, 6.9 Hz, 1 H), 5.03 (s, 1
H), 4.87–4.78 (m, 2 H), 3.83 (s, 3 H), 3.71 (s, 3 H), 3.69–3.62 (m, 1 H),
3.43 (s, 3 H), 2.69–2.59 (m, 1 H), 2.53–2.45 (m, 1 H), 1.28 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 158.8, 157.6, 157.2, 141.0, 138.8,
137.3, 130.0, 128.5, 127.5, 127.0, 126.7, 125.6, 114.9, 112.6, 103.7,
99.1, 81.2, 55.1, 54.8, 54.8, 53.7, 34.9.
2e
Rf = 0.30 (n-hexane–EtOAc, 4:1).
IR (ATR): 3495, 2942, 1606, 1500, 1300, 1246, 1205, 1174, 1032, 824
cm–1
.
1H NMR (400 MHz, CDCl3): δ (rotamers) = 7.38–7.33 (m, 1.4 H), 7.32–
7.26 (m, 1 H), 7.21–7.15 (m, 0.6 H), 6.83–6.77 (m, 1.4 H), 6.74–6.70
(m, 0.6 H), 6.53 (d, J = 2.5 Hz, 0.3 H), 6.45–6.41 (m, 1 H), 6.38 (d, J = 2.5
Hz, 0.7 H), 6.15–5.93 (m, 1 H), 5.07–4.87 (m, 2 H), 4.83 (s, 0.3 H), 4.36
(s, 0.6 H), 3.84 (s, 0.8 H), 3.82 (s, 1.8 H), 3.80 (s, 1.9 H), 3.80 (s, 0.8 H),
3.67 (s, 1.8 H), 3.62 (s, 0.8 H), 2.66–2.52 (m, 0.3 H), 2.45–2.33 (m, 1 H),
2.28–2.13 (m, 0.7 H), 2.07–1.91 (m, 0.7 H), 0.93–0.78 (m, 1.3 H), 0.50–
0.29 (m, 1 H), 0.20 (td, J = 10.0, 5.5 Hz, 0.7 H), 0.12 to –0.02 (m, 1 H),
–0.16 to –0.23 (m, 0.3 H), –0.24 to –0.33 (m, 0.7 H), –0.80 to –0.89 (m,
0.3 H).
HRMS (ESI): m/z calcd for C26H28O4 + Na [M + Na]+: 427.18798; found:
427.18905.
1-(5′-Bromo-4′′-methoxybiphenyl-2′-yl)-2-tert-butylpent-4-en-1-
one (3h)
The reaction was performed according to the GP3 using 1-(4′-bromo-
2′-methoxyphenyl)-2-tert-butylpent-4-en-1-one
(1h;
50 mg,
13C NMR (101 MHz, CDCl3): δ (rotamers) = 159.6, 159.5, 157.9, 157.9,
139.5, 139.5, 139.4, 128.5, 128.1, 128.0, 127.7, 127.1, 114.7, 112.7,
112.3, 104.0, 103.9, 99.7, 82.1, 55.9, 55.5, 55.4, 55.3, 55.2, 55.1, 51.4,
50.0, 37.5, 36.6, 12.5, 12.1, 5.0, 4.8, 3.5.
0.15 mmol), 4-methoxyphenylmagnesium bromide (1.53 mL, 0.5 M
in THF, 0.766 mmol), and anhydrous CH2Cl2 (1.50 mL). The residue
was purified by flash chromatography (n-hexane–EtOAc, 99:1 → 98:2
→ 97:3 → 96:4) to yield 3h (59 mg, 0.15 mmol, 98%) as an orange oil;
Rf = 0.59 (n-hexane–EtOAc, 95:5).
HRMS (ESI): m/z calcd for C23H28O4 + Na [M + Na]+: 391.18798; found:
IR (ATR): 2922, 1659, 1618, 1484, 1420, 1255, 1195, 1033, 1008, 934
391.18811.
cm–1
.
1-(2′,4′-Dimethoxyphenyl)-1-(4′′-methoxyphenyl)-2-methylpent-
4-en-1-ol (2f)
1H NMR (500 MHz, CDCl3): δ = 7.54 (dd, J = 8.4, 1.9 Hz, 1 H), 7.50 (d,
J = 8.4 Hz, 1 H), 7.47 (d, J = 1.9 Hz, 1 H), 7.24–7.21 (m, 2 H), 6.97–6.94
(m, 2 H), 5.43 (ddt, J = 17.0, 10.0, 7.1 Hz, 1 H), 4.93 (ddd, J = 17.0, 3.4,
1.5 Hz, 1 H), 4.90–4.86 (m, 1 H), 3.87 (s, 3 H), 2.73 (dd, J = 8.5, 4.2 Hz,
1 H), 2.41 (ddd, J = 14.5, 8.5, 4.2 Hz, 1 H), 2.20–2.13 (m, 1 H), 0.77 (s, 9
H).
13C NMR (125 MHz, CDCl3): δ = 206.9, 159.4, 142.9, 140.5, 137.7,
134.2, 132.3, 130.8, 130.5, 130.2, 127.7, 124.9, 116.0, 114.2, 113.9,
58.4, 55.4, 34.6, 32.6, 28.6.
The reaction was performed according to the GP3 using 1-(2′,4′-di-
methoxyphenyl)-2-methylpent-4-en-1-one (1f; 40 mg, 0.17 mmol),
4-methoxyphenylmagnesium bromide (678 μL, 0.5 M in THF,
0.339 mmol), and anhydrous Et2O (1.50 mL) (solvent different from
GP3). The Grignard reagent was added at 0 °C and stirred for 1 h at
0 °C (conditions different from GP3). The residue was purified by
flash chromatography (n-hexane–EtOAc, 9:1) to yield 2f (53 mg,
0.16 mmol, 92%) as a colorless oil; Rf = 0.17 (n-hexane–EtOAc, 9:1).
HRMS (ESI): m/z calcd for C22H26BrO2 [M + H]+: 401.11107; found:
IR (ATR): 3515, 2942, 1606, 1500, 1453, 1293, 1242, 1205, 1032, 821
401.11179.
cm–1
.
1H NMR (400 MHz, CDCl3): δ (rotamers) = 7.38 (d, J = 8.5 Hz, 1 H),
7.30–7.21 (m, 2 H), 6.82–6.78 (m, 2 H), 6.53 (dd, J = 8.5, 2.4 Hz, 1 H),
6.41 (d, J = 2.4 Hz, 1 H), 5.99–5.85 (m, 0.5 H), 5.78–5.65 (m, 0.5 H),
5.09–4.88 (m, 2 H), 4.70 (s, 1 H), 3.79 (s, 3 H), 3.76 (s, 3 H), 3.60 (s, 3
H), 2.61–2.38 (m, 1.5 H), 2.07–1.79 (m, 1.5 H), 1.06 (d, J = 6.6 Hz, 1.5
H), 0.74 (d, J = 6.6 Hz, 1.5 H).
13C NMR (101 MHz, CDCl3): δ (rotamers) = 159.7, 159.7, 158.7, 158.5,
157.8, 157.7, 140.1, 139.9, 138.7, 138.7, 128.0, 127.7, 127.3, 127.2,
127.0, 126.9, 115.4, 115.4, 112.9, 112.8, 104.4, 100.7, 100.5, 80.7, 80.6,
55.9, 55.9, 55.5, 55.4, 55.3, 55.2, 40.6, 40.5, 37.1, 36.0, 14.9, 13.9.
1-(5′-Chloro-4′′-methoxybiphenyl-2′-yl)-2-tert-butylpent-4-en-1-
one (3i)
The reaction was performed according to the GP3 using 1-(4′-chloro-
2′-methoxyphenyl)-2-tert-butylpent-4-en-1-one
(1i;
60 mg,
0.21 mmol), 4-methoxyphenylmagnesium bromide (2.14 mL, 0.5 M
in THF, 1.07 mmol), and anhydrous CH2Cl2 (2.10 mL). The residue was
purified by preparative TLC (n-hexane–EtOAc, 9:1) to yield 3i (52 mg,
0.15 mmol, 68%) as a colorless oil. The reaction was repeated with se-
quential addition of the Grignard reagent (4 × 1.0 equiv, stirring over-
1
night at r.t. in between additions); but H NMR analysis of the crude
product showed just the starting material 1i; Rf = 0.66 (n-hexane–
EtOAc, 9:1).
HRMS (ESI): m/z calcd for C21H26O4 + Na [M + Na]+: 365.17233; found:
365.17341.
IR (ATR): 2956, 1671, 1609, 1582, 1514, 1464, 1297, 1245, 1093, 835
cm–1
.
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1H NMR (500 MHz, CDCl3): δ = 7.58 (d, J = 8.4 Hz, 1 H), 7.38 (dd, J =
8.4, 2.1 Hz, 1 H), 7.30 (d, J = 2.1 Hz, 1 H), 7.24–7.21 (m, 2 H), 6.98–6.93
(m, 2 H), 5.44 (ddt, J = 17.1, 10.1, 7.1 Hz, 1 H), 4.95–4.91 (m, 1 H), 4.88
(ddt, J = 10.1, 2.0, 1.0 Hz, 1 H), 3.87 (s, 3 H), 2.74 (dd, J = 9.0, 4.2 Hz, 1
H), 2.46–2.38 (m, 1 H), 2.20–2.14 (m, 1 H), 0.77 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 206.8, 159.4, 142.8, 140.1, 137.6,
136.4, 132.4, 131.3, 130.7, 130.5, 127.2, 116.0, 113.9, 58.3, 55.3, 34.6,
32.7, 28.6.
fied by flash chromatography (n-hexane–EtOAc, 98:2) to yield 3l
(27 mg, 0.099 mmol, 83%) as a yellow oil; Rf = 0.34 (n-hexane–EtOAc,
98:2).
IR (ATR): 2956, 1670, 1605, 1568, 1467, 1368, 1233, 1133, 1031, 919
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 8.7 Hz, 1 H), 6.79 (d, J = 2.6
Hz, 1 H), 6.73 (dd, J = 8.7, 2.6 Hz, 1 H), 5.71 (ddt, J = 17.2, 10.0, 7.2 Hz,
1 H), 5.09–4.99 (m, 1 H), 4.95–4.88 (m, 1 H), 3.84 (s, 3 H), 3.26 (dd, J =
11.5, 2.9 Hz, 1 H), 2.91 (dq, J = 14.8, 7.5 Hz, 1 H), 2.76 (dq, J = 14.8, 7.5
Hz, 1 H), 2.68–2.57 (m, 1 H), 2.32–2.22 (m, 1 H), 1.28 (t, J = 7.5 Hz, 3
H), 0.94 (s, 9 H).
HRMS (ESI): m/z calcd for C22H26ClO2 [M + H]+: 357.16276; found:
357.16158.
13C NMR (101 MHz, CDCl3): δ = 206.0, 161.6, 147.3, 137.1, 133.6,
2-tert-Butyl-1-[4′-methoxy-2′-(prop-1′′-en-2′′-yl)phenyl]pent-4-
en-1-one (3j)
131.4, 116.3, 116.1, 110.0, 57.4, 55.2, 34.5, 33.3, 28.3, 27.4, 15.8.
HRMS (ESI): m/z calcd for C18H27O2 [M + H]+: 275.20056; found;
275.20020.
The reaction was performed according to the GP3 using 1c (30 mg,
0.11 mmol), 2-propenylmagnesium bromide (1.09 mL, 0.5 M in THF,
0.554 mmol), and anhydrous CH2Cl2 (5.00 mL). The residue was puri-
fied by flash chromatography (n-hexane–EtOAc, 95:5) to yield 3j
(27 mg, 0.094 mmol, 87%) as a colorless oil; Rf = 0.65 (n-hexane–
EtOAc, 9:1).
2-Isopropyl-1-(5′-methoxybiphenyl-2′-yl)pent-4-en-1-one (3m)
The reaction was performed according to the GP3 using 1a (34 mg,
0.13 mmol), phenylmagnesium bromide (128 μL, 2 M in THF,
0.256 mmol), and anhydrous CH2Cl2 (13.0 mL). The residue was puri-
fied by flash chromatography (n-hexane–EtOAc, 95:5) to yield 3m
(32 mg, 0.10 mmol, 82%) as a yellow oil; Rf = 0.42 (n-hexane–EtOAc,
9:1).
IR (ATR): 2957, 1670, 1595, 1467, 1309, 1223, 1086, 1037, 908, 799
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 8.7 Hz, 1 H), 6.82 (dd, J = 8.7,
2.7 Hz, 1 H), 6.70 (d, J = 2.7 Hz, 1 H), 5.68 (ddt, J = 17.0, 10.1, 7.1 Hz, 1
H), 5.07–5.04 (m, 1 H), 5.01 (dd, J = 17.0, 1.5 Hz, 1 H), 4.90–4.84 (m, 1
H), 4.75–4.71 (m, 1 H), 3.85 (s, 3 H), 3.30 (dd, J = 10.7, 3.3 Hz, 1 H),
2.60 (ddd, J = 13.7, 10.7, 6.9 Hz, 1 H), 2.33–2.24 (m, 1 H), 2.12–2.08
(m, 3 H), 0.93 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 204.3, 161.9, 147.9, 147.4, 137.5,
132.2, 131.9, 116.1, 115.9, 113.3, 111.8, 56.2, 55.5, 34.6, 33.4, 28.6,
24.7.
IR (ATR): 2962, 1674, 1596, 1460, 1297, 1212, 1174, 1018, 913, 699
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.53 (d, J = 8.6 Hz, 1 H), 7.43–7.35 (m, 3
H), 7.32–7.27 (m, 2 H), 6.92 (dd, J = 8.6, 2.6 Hz, 1 H), 6.83 (d, J = 2.6 Hz,
1 H), 5.40 (ddt, J = 17.1, 10.1, 7.1 Hz, 1 H), 4.91–4.81 (m, 2 H), 3.86 (s,
3 H), 2.43 (dt, J = 7.9, 4.8 Hz, 1 H), 2.28 (ddd, J = 14.5, 7.9, 6.7 Hz, 1 H),
2.01–1.86 (m, 1 H), 1.83–1.72 (m, 1 H), 0.73 (d, J = 6.9 Hz, 3 H), 0.63
(d, J = 6.9 Hz, 3 H).
HRMS (ESI): m/z calcd for C19H27O2 [M + H]+: 287.20056; found:
287.20130.
13C NMR (101 MHz, CDCl3): δ = 207.1, 161.1, 143.2, 141.4, 136.9,
133.9, 131.0, 129.1, 128.6, 127.8, 116.1, 116.0, 113.0, 55.6, 55.5, 31.2,
29.2, 20.6, 18.9.
2-tert-Butyl-1-(2′-isopropyl-4′-methoxyphenyl)pent-4-en-1-one
(3k)
HRMS (ESI): m/z calcd for C21H24O2 + Na [M + Na]+: 331.16685; found:
The reaction was performed according to the GP3 using 1c (34 mg,
0.12 mmol), isopropylmagnesium chloride–lithium chloride complex
(472 μL, 1.3 M in THF, 0.614 mmol), and anhydrous CH2Cl2 (4.00 mL).
The residue was purified by flash chromatography (n-hexane–EtOAc,
98:2) to yield 3k (34 mg, 0.12 mmol, 95%) as a colorless oil; Rf = 0.56
(n-hexane–EtOAc, 9:1).
331.16782.
2-tert-Butyl-1-(5′-methoxybiphenyl-2′-yl)pent-4-en-1-one (3n)
The reaction was performed according to the GP3 using 1c (33 mg,
0.12 mmol), phenylmagnesium bromide (198 μL, 3 M in Et2O,
0.597 mmol), and anhydrous CH2Cl2 (5.00 mL). The residue was puri-
fied by flash chromatography (n-hexane–EtOAc, 95:5) to yield 3n
(26 mg, 0.082 mmol, 68%) as a colorless oil; Rf = 0.43 (n-hexane–
EtOAc, 9:1).
IR (ATR): 2956, 1670, 1602, 1565, 1463, 1300, 1229, 1167, 1032, 733
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.53 (d, J = 8.7 Hz, 1 H), 6.92 (d, J = 2.6
Hz, 1 H), 6.71 (dd, J = 8.7, 2.6 Hz, 1 H), 5.73 (ddt, J = 17.1, 10.0, 7.2 Hz,
1 H), 5.06 (dd, J = 17.1, 1.7 Hz, 1 H), 4.98–4.88 (m, 1 H), 3.84 (s, 3 H),
3.49 (qq, J = 6.9, 6.7 Hz, 1 H), 3.22 (dd, J = 11.5, 2.9 Hz, 1 H), 2.74–2.52
(m, 1 H), 2.38–2.21 (m, 1 H), 1.29 (d, J = 6.7 Hz, 3 H), 1.20 (d, J = 6.9 Hz,
3 H), 0.95 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 206.9, 161.8, 151.8, 137.3, 134.3,
130.7, 116.6, 113.2, 109.7, 58.6, 55.3, 34.7, 33.4, 29.5, 28.4, 25.2, 23.8.
HRMS (ESI): m/z calcd for C19H29O2 [M + H]+: 289.21621; found:
289.21498.
IR (ATR): 2958, 1672, 1598, 1480, 1298, 1215, 1038, 1018, 913, 702
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 8.7 Hz, 1 H), 7.35–7.12 (m, 5
H), 6.81 (dd, J = 8.7, 2.7 Hz, 1 H), 6.66 (d, J = 2.7 Hz, 1 H), 5.48 (ddt,
J = 17.1, 10.0, 7.1 Hz, 1 H), 4.99–4.86 (m, 1 H), 4.76–4.71 (m, 1 H), 3.75
(s, 3 H), 2.72 (dd, J = 9.5, 3.4 Hz, 1 H), 2.42–2.22 (m, 1 H), 2.07–1.96
(m, 1 H), 0.68 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 205.6, 161.1, 144.1, 141.9, 137.9,
134.2, 131.6, 129.1, 128.1, 127.3, 116.8, 115.8, 112.6, 57.3, 55.5, 34.5,
32.9, 28.6.
2-tert-Butyl-1-(2′-ethyl-4′-methoxyphenyl)pent-4-en-1-one (3l)
HRMS (ESI): m/z calcd for C22H27O2 [M + H]+: 323.20056; found:
The reaction was performed according to the GP3 using 1c (33 mg,
0.12 mmol), ethylmagnesium bromide (199 μL, 3 M in Et2O,
0.597 mmol), and anhydrous CH2Cl2 (5.00 mL). The residue was puri-
323.20071.
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1099
G. Grelier et al.
Paper
Synthesis
Cyclohexyl(6′-methoxybenzo[d][1,3]dioxol-5′-yl)[4′′-(methyl-
thio)phenyl]methanol (11)
References
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The reaction was performed according to the GP3 using cyclohex-
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yl(6′-methoxybenzo[d][1,3]dioxol-5′-yl)methanone
(10;
56 mg,
0.21 mmol), 4-thioanisolemagnesium bromide (1.5 mL, 0.5 M in THF,
0.75 mmol), and anhydrous CH2Cl2 (11.0 mL). The residue was puri-
fied by flash chromatography (n-hexane–EtOAc, 98:2 → 97:3 → 96:4
→ 95:5) to yield 11 (49 mg, 0.13 mmol, 59%) as a colorless oil;
Rf = 0.44 (n-hexane–EtOAc, 9:1).
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IR (ATR): 3502, 2921, 1481, 1418, 1259, 1188, 1093, 1038, 824, 732
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.26–7.22 (m, 2 H), 7.17–7.13 (m, 2 H),
7.03 (s, 1 H), 6.48 (s, 1 H), 5.98–5.96 (m, 2 H), 4.86 (s, 1 H), 3.49 (s, 3
H), 2.47 (s, 3 H), 2.14–2.07 (m, 1 H), 1.97–1.91 (m, 1 H), 1.83–1.78 (m,
1 H), 1.73–1.65 (m, 2 H), 1.61–1.59 (s, 1 H), 1.46–1.27 (m, 3 H), 1.24–
1.13 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 152.8, 146.7, 145.0, 141.5, 135.3,
127.4, 127.0, 126.7, 126.3, 125.7, 107.5, 101.4, 96.9, 80.1, 57.0, 45.7,
27.8, 27.1, 27.0, 26.8, 26.6, 15.9.
MS (ESI): m/z = 369.1 [M – OH]+.
(1-Methylcyclohexyl){6′-[(4′′-methylthio)phenyl]benzo[d][1,3]di-
oxol-5′-yl}methanone (13)
The reaction was performed according to the GP3 using (6-methoxy-
benzo[d][1,3]dioxol-5-yl)(1-methylcyclohexanone)methanone (12;
24 mg, 0.088 mmol), 4-thioanisolemagnesium bromide (523 μL,
0.5 M in THF, 0.262 mmol) and anhydrous CH2Cl2 (9.00 mL). The resi-
due was purified by flash chromatography (n-hexane–EtOAc, 99.5:0.5
→ 99:1 → 98.5:1.5 → 98:2) to yield 13 (22 mg, 0.058 mmol, 67%) as a
yellow oil. [The reaction was repeated under the same conditions us-
ing 2.0 equiv and 2.5 equiv Grignard reagent, only ketone 12 could be
reisolated in both cases. This reaction was also monitored by 1H NMR
(see the Supporting Information)]; Rf = 0.51 (n-hexane–EtOAc, 9:1).
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IR (ATR): 3092, 2860, 1718, 1449, 1365, 1208, 1155, 1077, 926, 818
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.24 (s, 4 H), 6.82 (s, 1 H), 6.65 (s, 1 H),
6.04 (s, 2 H), 2.51 (s, 3 H), 1.53–1.44 (m, 3 H), 1.44–1.36 (m, 2 H),
1.36–1.26 (m, 2 H), 1.24–1.17 (m, 2 H), 1.15–1.06 (m, 1 H), 0.85 (s, 3
H).
13C NMR (125 MHz, CDCl3): δ = 215.9, 147.8, 146.3, 137.9, 137.4,
134.5, 132.1, 130.1, 126.2, 110.0, 106.4, 101.5, 48.6, 34.5, 25.6, 21.7,
21.3, 15.7.
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HRMS (ESI): m/z calcd for C22H25O3S [M + H]+: 369.15189; found:
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Acknowledgment
We thank the Natural Sciences and Engineering Research Council of
Canada (NSERC) for financial assistance.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379992.
S
u
p
p
ortioInfgrmoaitn
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ortiInfogrmoaitn
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Paper
Synthesis
J.-H.; Zhang, H.-Y.; Wen, J.; Du, X.; Chen, J.-H.; Zhang, H.-B.;
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(15) Friedel–Crafts acylation and alkylation of the potassium enolate
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1.
(16) Result not shown; addition of LiCl (3 equiv) and increased tem-
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1091–1100