Synthesis of substituted resorcinol monomethyl ethers from 2-bromo-3-methoxycyclohex-2-en-1-ones

Article abstract of DOI:10.1021/acs.joc.5b00192

2-Bromo-3-methoxycyclohex-2-en-1-ones are readily alkylated at C-6 with reactive halides, and then treatment with DBU (2 equiv) in PhMe at room temperature results in smooth loss of bromide and aromatization to resorcinol monomethyl ethers of defined substitution pattern.

Full text of DOI:10.1021/acs.joc.5b00192

Article
pubs.acs.org/joc
Synthesis of Substituted Resorcinol Monomethyl Ethers from
2‑Bromo-3-methoxycyclohex-2-en-1-ones
Wenjie Shao and Derrick L. J. Clive*
Chemistry Department, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
S
* Supporting Information
ABSTRACT: 2-Bromo-3-methoxycyclohex-2-en-1-ones are readily
alkylated at C-6 with reactive halides, and then treatment with
DBU (2 equiv) in PhMe at room temperature results in smooth
loss of bromide and aromatization to resorcinol monomethyl ethers
of defined substitution pattern.
significant extent using the bases we tried [LDA, (Me3Si)2NK,
INTRODUCTION
■
(Me3Si)2NLi, NaH], and we suspect that the preferred
conformation is such that the α-hydrogen at C-6 is not
collinear with the p-orbital of the adjacent carbonyl group, so
that deprotonation is difficult. Attempts to epimerize cis-2 by
heating in PhMe at 70 °C with 1 equiv of DBU2 led cleanly to
4.
The transformation 2 → 4 represents a regiocontrolled
method for making alkylated monomethyl ethers of resorcinol
and we have refined it to a general procedure.
There are several corresponding methods described in the
literature. The use of DDQ in refluxing dioxane for
dehydrogenation of 3-alkoxycyclohex-2-en-1-ones appears to
give poor yields (29−38%)3 and sometimes fails altogether.4
Likewise, dehydrogenation with Pd-black in refluxing cymene is
also not reliable,4 but use of Hg(OAc)2 in refluxing acetic acid
did work well (e.g., 84% yield) in a case where experiments
with DDQ and Pd-black were unsuccessful.4,5 Treatment of the
silyl ether 5 with I2 in refluxing MeOH gave the silyl ether 6 in
84% yield (Scheme 2).6 In principle, one would expect
desilylation of 6 to be easy, so this method should also provide
a route to resorcinol monomethyl ethers.
During synthetic work related to coleophomone B1 we
alkylated the bromide 1 with prenyl bromide (1 → 2, Scheme
1) under standard conditions (LDA, THF, −78 °C) and then
tried to carry out a second alkylation at C-6 with a different
allylic halide (2 → 3), again using LDA at a low temperature.
However, we found that very little alkylation occurred unless
the temperature was raised to 0 °C, at which point we did
obtain a somewhat larger proportion of the desired product (3)
as a mixture of diastereoisomers, together with a small amount
of the monomethyl ether 4.
Scheme 1. Dialkylation Studies on 2-Bromo-3-methoxy-5-
methylcyclohex-2-en-1-one
Scheme 2. An Iodine-Mediated Aromatization
In attempting to improve the second alkylation step (2 → 3),
we tried to generate the required enolate with (Me3Si)2NK in
THF at −78 °C, and after an arbitrary period of 30 min, we
quenched the mixture with very dilute hydrochloric acid,
hoping to establishthrough recovery of 2that the desired
enolate was stable at a low temperature. However, very little of
2 was recovered and 4 was the major isolable product.
Further experiments showed that the trans isomer of 2
(trans-2), whose structure was verified by single crystal X-ray
analysis, could be alkylated (trans-2 → 3) in 28% yield (71%
corrected for recovered 2, which was now a 10:1 cis−trans
mixture). In contrast, cis-2 could not be alkylated to any
In certain highly specific cases, in the presence of Rh3+, a
pendant double bond has been isomerized into a six-membered
ring to effect aromatization to a mixture (ca. 1:1, 81% yield) of
mono- and dimethyl ethers (7 → 8 + 9), with the ratio being
sensitive to the experimental conditions (Scheme 3).7
Finally, bromination8,9 (e.g., 10 → 11) or corresponding
selenation10,11 (e.g., 12 → 13) have also been used (Scheme 4).
Received: January 27, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00192
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a
Scheme 3. A Rhodium-Mediated Aromatization
Table 1. Yields for Alkylation and Aromatization
Scheme 4. Bromination and Selenenylation Methods for
Aromatization
RESULTS AND DISCUSSION
■
The present method is experimentally straightforward: One
alkylates a 2-bromo-3-methoxycyclohex-2-en-1-one (e.g., 1 →
2) and adds 2 equiv of DBU to a room temperature solution of
the alkylation product in PhMe. Using as a test case compound
18 (see Table 1), the only one whose aromatization we
monitored, we found that the reaction is over within 5 h at 50
°C, but it is more convenient to carry out the aromatizations at
room temperature for an overnight period. The reactions are all
very clean, and Table 1 lists our results.
The starting 2-bromo-3-methoxycyclohex-2-en-1-one (1) is
easily prepared by bromination12 (NBS, 91% yield) of 3-
methoxy-5-methylcyclohex-2-en-1-one, itself available by the
classical procedure of Michael addition of ethyl acetoacetate to
methyl crotonate in the presence of EtONa (54%), followed by
heating with acid at pH 113 and O-methylation with
(MeO)3CH (91%).14 This synthetic route is general,15 and
compound 27 was made analogously from methyl (E)-pent-2-
enoate.16
The alkylation step to attach the C-6 chain (LDA, alkyl
halide, THF, −78 °C) gave the yields indicated in Table 1. All
the alkylations were done with an alkyl bromide, except for the
preparation of 18, where methyl iodide was used.
The last entry in the Table (27 → 28) shows that, as
expected, the method is not limited to methyl substitution at C-
5.
Allylic, propargylic, and benzylic bromides are suitable
alkylating agents, and we have also used an α-bromo ester
(to prepare 25). Attempts to use butyl bromide or iodide for
the alkylation step were unsuccessful, but all the activated
bromides we used and methyl iodide worked satisfactorily,
giving yields of at least 70% without any attempt at
optimization.
a
Yields in the first column are for alkylation of the parent 2-bromo-5-
methyl-(or ethyl)-3-methoxycyclohex-2-en-1-one. All aromatizations-
were done overnight at room temperature. Stereochemistry not
determined. Yield for bromination of 3-methoxy-5-methylcyclohex-2-
en-1-one.
b
c
pure aromatization products were isolated in high yield
(average yield 87% for nine examples).
The alkyl bromides used are all known compounds, except
for that needed to make 14; it was prepared by the method
summarized in Scheme 5.
With the exception of 18 and 21, the alkylation products (see
Table 1) were inconsequential mixtures of chromatographically
inseparable diastereoisomers, with one predominating, and it
was sometimes difficult to decide if some of the minor signals in
the NMR spectra represented the minor isomer or an impurity.
If the latter, the amount must have been very small, because the
We assume that the mechanism involves migration of the
initial double bond, as summarized in Scheme 6. Besides DBU,
we examined the use of pyridine and triethylamine with
compound 2, but these two bases were ineffective, at least at
room temperature, and the bromide starting material remained
unchanged.
For comparison purposes, compound 39 was subjected to
the action of I2 in refluxing MeOH,6 but we obtained a complex
1
mixture and very little, if any (by H NMR), of the desired
B
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studied. Our control experiments with the model substrates 39
and 40 show that the present method has a number of
advantages over existing procedures.
Scheme 5. Preparation of Bromide 34
EXPERIMENTAL SECTION
■
General Procedures. Solvents used for chromatography were
distilled before use. Commercial thin-layer chromatography plates
(silica gel, Merck 60F-254) were used. Silica gel for flash
chromatography was Merck type 60 (230−400 mesh). Dry solvents
were prepared under an inert atmosphere and transferred by syringe or
cannula. The symbols s, d, t, and q used for 13C NMR spectra indicate
zero, one, two, or three attached hydrogens, respectively, the
assignments being made from APT spectra. Solutions were evaporated
under water pump vacuum, and the residue was then kept under oil
pump vacuum. High-resolution electrospray mass spectrometric
analyses were done with an orthogonal time-of-flight analyzer, and
electron ionization mass spectra were measured with a double-focusing
sector mass spectrometer.
2-Bromo-3-methoxy-5-methylcyclohex-2-en-1-one (1). NBS
(4.35 g, 24.4 mmol) was added in one portion to a stirred and cooled
(0 °C) solution of 3-methoxy-5-methycyclohex-2-en-1-one13,14 (2.85
g, 20.3 mmol) in CH2Cl2 (14 mL). Stirring at 0 °C was continued for
2 h with protection from light. The reaction mixture was diluted with
saturated aqueous NaHCO3 and extracted with CH2Cl2. The
combined organic extracts were washed with brine, dried (MgSO4),
and evaporated. Crystallization of the residue from MeOH gave 1
(4.05 g, 91%) as a white solid: 97−100 °C; FTIR (CDCl3, cast) 1653,
1615 cm−1; 1H NMR (CDCl3, 500 MHz) δ 1.17 (d, J = 6.5 Hz, 3 H),
2.21−2.33 (m, 3 H), 2.65−2.69 (m, 1 H), 2.78−2.85 (m, 1 H), 3.97
(s, 3 H); 13C NMR (CDCl3, 125 MHz) δ 20.8 (q), 28.1 (d), 34.7 (t),
44.8 (t), 56.3 (q), 102.7 (s), 172.1 (s), 190.9 (s); exact mass (electron
ionization) m/z calcd for C8H1179BrO2 (M)+ 217.9942, found
217.9941.
2-Bromo-3-methoxy-5-methyl-6-(3-methylbut-2-en-1-yl)-
cyclohex-2-en-1-one (2). n-BuLi (2.50 M in hexanes, 2.60 mL, 6.50
mmol) was added dropwise to a stirred and cooled (−78 °C) solution
of i-Pr2NH (0.93 mL, 6.64 mmol) in THF (10 mL). Stirring at −78
°C was continued for 30 min and then a solution of 1 (1.10 g, 5.02
mmol) in THF (5 mL) was added dropwise. The cold bath was not
recharged, so the temperature rose to 0 °C over 2 h. The mixture was
then recooled to −78 °C and a solution of prenyl bromide (2.24 mL,
19.4 mmol) in THF (5 mL) was added dropwise. The cold bath was
left in place, but not recharged, and stirring was continued for 6 h. The
reaction mixture was diluted with saturated aqueous NH4Cl and
extracted with EtOAc. The combined organic extracts were washed
with brine, dried (MgSO4), and evaporated. Flash chromatography of
the residue over silica gel (3 × 15 cm), using 1:4 EtOAc−hexanes,
gave 2 (1.14 g, 79%) as a pale yellow solid: FTIR (CDCl3, cast) 1659,
1592 cm−1; 1H NMR (CDCl3, 500 MHz) δ (major isomer) 1.13 (d, J
= 6.5 Hz, 3 H), 1.65 (s, 3 H), 1.69 (s, 3 H), 2.17−2.27 (m, 2 H),
2.32−2.41 (m, 2 H), 2.48−2.59 (m, 1 H), 2.83 (dd, J = 17.5, 5.0 Hz, 1
H), 3.95 (s, 3 H) 5.02−5.06 (m, 1 H); 13C NMR (CDCl3, 125 MHz)
δ (major isomer) 17.8 (q), 17.9 (q), 25.8 (q), 27.0 (t), 30.1 (d), 33.0
(t), 52.6 (d), 56.1 (q), 102.2 (s), 120.7 (d), 133.5 (s), 170.3 (s), 192.6
(s); exact mass (electrospray) m/z calcd for C13H1979BrNaO2 (M +
Na)+ 309.0461, found 309.0457.
Scheme 6. Suggested Mechanism
4,5
dimethoxy product 40. Similarly, the use of Hg(OAc)2 was
shown to be incompatible with the presence of a triple bond, as
1
compound 41 gave none (by H NMR) of the desired 42,
either at reflux temperature4,5 or at room temperature. While
the first of these experiments (I2/MeOH) was expected to
produce a bis-ether, instead of a mono ether, as in our method,
both experiments serve the purpose of showing that certain
side-chain functionality is incompatible with the I2/MeOH or
Hg(OAc)2/AcOH reagent systems, both of which appear from
the literature to be the best of the prior methods.
5-Methoxy-3-methyl-2-(3-methylbut-2-en-1-yl)phenol (4).1b
DBU (304 mg, 2.00 mmol) was added to a stirred solution of 2 (287
mg, 1.00 mmol) in PhMe (2 mL). Stirring was continued overnight
and the mixture was diluted with hydrochloric acid (5%) and extracted
thoroughly with EtOAc. The combined organic extracts were washed
with brine, dried (MgSO4), and evaporated. Flash chromatography of
the residue over silica gel (1.8 × 10 cm), using 1:3 EtOAc−hexanes,
gave 4 (175 mg, 85%) as a thick oil: FTIR (CDCl3, cast) 3419, 1614,
CONCLUSION
■
Our procedure for making differentially protected resorcinol
derivatives is very simple. It accommodates functionality in the
side chain that is added in the first step; this functionality
renders the final products readily amenable to further
manipulation. The alkylation yields are ≥70%, provided that
the alkylating agent is activated (the halide should be allylic,
propargylic, or benzylic, in the form of an α-halo ester, or
methyl iodide), and the aromatization occurs at room
temperature in yields of 82−92% for the examples we have
1
1590 cm−1; H NMR (CDCl3, 500 MHz) δ 1.74 (s, 3 H), 1.81 (s, 3
H), 2.27 (s, 3 H), 3.30 (d, J = 8.5 Hz, 2 H), 3.75 (s, 3 H), 5.12 (s, 1
H), 5.13−5.17 (m, 1 H), 6.28 (d, J = 3.0 Hz, 1 H), 6.35 (d, J = 3.0 Hz,
1 H); 13C NMR (CDCl3, 125 MHz) δ 17.8 (q), 20.3 (q), 25.2 (t),
25.7 (q), 55.2 (q), 99.5 (d), 108.5 (d), 117.8 (s), 122.1 (d), 133.8 (s),
C
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138.1 (s), 155.2 (s), 158.4 (s); exact mass (electron ionization) m/z
calcd for C13H18O2 (M)+ 206.1306, found 206.1304.
up. Flash chromatography of the residue over silica gel (1.8 × 13 cm),
using 1:5 EtOAc−hexanes, gave 18 (243 mg, 73%) as a white solid:
FTIR (CDCl3, cast) 1654, 1590 cm−1; 1H NMR (CDCl3, 500 MHz) δ
(major isomer) 1.17 (d, J = 6.5 Hz, 3 H), 1.24 (d, J = 7.0 Hz, 3 H),
1.92−1.98 (m, 1 H), 2.12−2.18 (m, 1 H), 2.36 (dd, J = 17.5, 10.0 Hz,
1 H), 2.83 (dd, J = 17.5, 9.5 Hz, 1 H), 3.95 (s, 3 H); 13C NMR
(CDCl3, 125 MHz) δ (major isomer) 13.4 (q), 19.7 (q), 34.0 (d), 34.4
(t), 47.4 (d), 56.1 (q), 102.3 (s), 170.7 (s), 193.1 (s); exact mass
(electron ionization) m/z calcd for C9H1379BrO2 (M)+ 232.0098,
found 232.0097.
2-Bromo-3-methoxy-6-[(2E)-4-[4(methoxyphenyl)methoxy]-
2-methylbut-2-en-1-yl]-5-methylcyclohex-2-en-1-one (14). The
procedure for compound 2 was followed, using n-BuLi (2.50 M in
hexanes, 0.28 mL, 0.70 mmol), i-Pr2NH (0.12 mL, 0.85 mmol) in
THF (2 mL), a solution of 1 (138 mg, 0.63 mmol) in THF (2 mL),
and a solution of 34 (468 mg, 1.64 mmol) in THF (2 mL). The
mixture was left overnight after the addition of 34 and then worked up.
Flash chromatography of the residue over silica gel (1.8 × 10 cm),
using 1:4 EtOAc−hexanes, gave 14 (205 mg, 77%) as a colorless oil:
5-Methoxy-2,3-dimethylphenol (19).18 The procedure for 4
was followed, using DBU (330 mg, 2.17 mmol) and a solution of 18
(241 mg, 1.03 mmol) in PhMe (2 mL). Workup and flash
chromatography of the residue over silica gel (1.8 × 10 cm), using
1:5 EtOAc−hexanes, gave 19 (141 mg, 90%) as a white solid: mp 94−
95 °C (lit.18 mp 93−93.5 °C); 1H NMR (CDCl3, 500 MHz) δ 2.08 (s,
3 H), 2.24 (s, 3 H), 3.74 (s, 3 H), 4.64 (s, 1 H), 6.25 (d, J = 2.5 Hz, 1
H), 6.35 (d, J = 2.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 10.8
(q), 20.4 (q), 55.2 (q), 98.9 (d), 108.0 (d), 114.3 (s), 138.8 (s), 154.2
(s), 157.9 (s).
1
FTIR (CDCl3, cast) 1659, 1611, 1589 cm−1; H NMR (CDCl3, 500
MHz) δ (major isomer) 1.11 (d, J = 7.0 Hz, 3 H), 1.63 (s, 3 H), 2.14−
2.26 (m, 1 H), 2.29−2.47 (m, 4 H), 2.84 (dd, J = 18, 5.5 Hz, 1 H),
3.80 (s, 3 H), 3.93 (s, 3 H), 4.01 (s, 2 H) 4.42 (s, 2 H), 5.40−5.43 (m,
1 H), 6.87 (d, J = 9.0 Hz, 2 H), 7.26 (d, J = 8.5 Hz, 2 H); 13C NMR
(CDCl3, 125 MHz) δ (major isomer) 16.1 (q), 20.0 (q), 29.1 (d), 31.2
(t), 40.1 (t), 50.5 (d), 55.2 (q), 56.2 (q), 66.2 (t), 71.9 (t), 101.2 (s),
113.7 (d), 124.2 (d), 129.4 (d), 130.4 (s), 137.0 (s), 159.2 (s), 169.7
(s), 192.9 (s); exact mass (electrospray) m/z calcd for C21H2879BrO4
(M + H)+ 423.1165, found 423.1166.
5-Methoxy-2-[(2E)-4-[(4-methoxyphenyl)methoxy]-2-meth-
ylbut-2-en-1-yl]-3-methylphenol (15). The procedure for 4 was
followed, using DBU (151 mg, 0.993 mmol) and a solution of 14 (200
mg, 0.473 mmol) in PhMe (1.5 mL). Workup and flash
chromatography of the residue over silica gel (1.8 × 10 cm), using
1:3 EtOAc−hexanes, gave 15 (133 mg, 82%) as a thick oil: FTIR
(CDCl3, cast) 3353, 1613, 1589 cm−1; 1H NMR (CDCl3, 500 MHz) δ
1.67 (s, 3 H), 2.23 (s, 3 H), 3.32 (s, 2 H), 3.74 (s, 3 H), 3.80 (s, 3 H),
4.01 (d, J = 3.0 Hz, 2 H), 4.40 (s, 2 H), 5.13 (s, 1 H), 5.32−5.36 (m, 1
H), 6.26 (d, J = 3.0 Hz, 1 H), 6.35 (d, J = 3.0 Hz, 1 H), 6.86 (d, J = 6.0
Hz, 2 H), 7.24 (d, J = 6.0 Hz, 2 H); 13C NMR (CDCl3, 125 MHz) δ
16.7 (q), 20.2 (q), 35.5 (t), 55.1 (q), 55.2 (q), 66.1 (t), 71.7 (t), 99.5
(d), 108.5 (d), 113.7 (d), 115.6 (s), 121.7 (d), 129.4 (d), 130.4 (s),
138.6 (s), 139.1 (s), 155.5 (s), 158.7 (s), 159.1 (s); exact mass
(electrospray) m/z calcd for C21H25O4 (M − H)− 341.1758, found
341.1761.
3-Methoxy-5-methylphenol (20).19 The procedure for 4 was
followed, using DBU (114 mg, 0.75 mmol) and a solution of 1 (77.2
mg, 0.357 mmol) in PhMe (1 mL). Workup and flash chromatography
of the residue over silica gel (1 × 8 cm), using 1:3 EtOAc−hexanes,
gave 20 (43.4 mg, 90%) as a thick oil: 1H NMR (CDCl3, 500 MHz) δ
2.28 (s, 3 H), 3.77 (s, 3 H), 5.16 (br s, 1 H), 6.25 (dd, J = 2.5 Hz, 1
H), 6.28 (s, 1 H), 6.34 (s, 1 H); 13C NMR (CDCl3, 125 MHz) δ 21.5
(q), 55.2 (q), 98.6 (d), 107.3 (d), 108.6 (d), 140.6 (s), 156.5 (s),
160.8 (s).
2-Bromo-3-methoxy-5-methyl-6-[3-(trimethylsilyl)prop-2-
yn-1-yl]cyclohex-2-en-1-one (21). The procedure for compound 2
was followed, using n-BuLi (2.50 M in hexanes, 0.51 mL, 1.27 mmol),
i-Pr2NH (0.20 mL, 1.43 mmol) in THF (3 mL), a solution of 1 (257
mg, 1.17 mmol) in THF (3 mL), and a solution of propargylic
bromide (750 mg, 3.93 mmol) in THF (3 mL). The mixture was left
overnight after the addition of propargylic bromide and then worked
up. Flash chromatography of the residue over silica gel (1.8 × 13 cm),
using 1:4 EtOAc−hexanes, gave 21 (270 mg, 70%) as a white solid:
2-Bromo-3-methoxy-5-methyl-6-(prop-2-en-1-yl)cyclohex-
2-en-1-one (16). The procedure for compound 2 was followed, using
n-BuLi (2.50 M in hexanes, 0.60 mL, 1.50 mmol), i-Pr2NH (0.25 mL,
1.78 mmol) in THF (6 mL), a solution of 1 (293 mg, 1.35 mmol) in
THF (3 mL), and a solution of allyl bromide (0.40 mL, 4.63 mmol) in
THF (3 mL). The mixture was left overnight after the addition of the
allyl bromide and then worked up. Flash chromatography of the
residue over silica gel (1.8 × 13 cm), using 1:5 EtOAc−hexanes, gave
16 (249 mg, 72%) as a thick oil: FTIR (CDCl3, cast) 3076, 1649, 1587
cm−1; 1H NMR (CDCl3, 500 MHz) δ (major isomer) 1.13 (d, J = 6.5
Hz, 3 H), 2.17−2.27 (m, 2 H), 2.33−2.39 (m, 2 H), 2.66−2.70 (m, 1
H), 2.82 (dd, J = 17.5, 5.0 Hz, 1 H), 3.93 (s, 3 H), 5.02−5.10 (m, 2
H), 5.67−5.75 (m, 1 H); 13C NMR (CDCl3, 125 MHz) δ (major
isomer) 19.4 (q), 30.0 (d), 32.4 (t), 33.3 (t), 51.7 (d), 56.1 (q), 102.3
(s), 117.2 (t), 135.0 (d), 170.5 (s), 192.0 (s); exact mass (electron
ionization) m/z calcd for C11H1579BrO2 (M)+ 258.0255, found
258.0257.
1
FTIR (CDCl3, cast) 2169, 1649, 1582 cm−1; H NMR (CDCl3, 500
MHz) δ (major isomer) 0.13 (s, 9 H), 1.23 (d, J = 6.5 Hz, 3 H), 2.22−
2.90 (m, 1 H), 2.39−2.42 (m, 2 H), 2.65 (dd, J = 17.0, 4.5 Hz, 1 H),
2.86−2.91 (m, 2 H), 3.97 (s, 3 H); 13C NMR (CDCl3, 125 MHz) δ
(major isomer) 0.1 (q), 18.8 (t), 19.5 (q), 30.9 (d), 33.8 (t), 50.9 (d),
56.2 (q), 86.5 (s), 102.2 (s), 103.5 (s), 170.9 (s), 190.3 (s); exact mass
(electron ionization) m/z calcd for C14H2179BrO2Si (M)+ 328.0494,
found 328.0487.
5-Methoxy-3-methyl-2-[3-(trimethylsilyl)prop-2-yn-1-yl]-
phenol (22). The procedure for 4 was followed, using DBU (119 mg,
0.735 mmol) and a solution of 21 (121 mg, 0.368 mmol) in PhMe (1
mL). Workup and flash chromatography of the residue over silica gel
(1 × 10 cm), using 1:5 EtOAc−hexanes, gave 22 (79.3 mg, 87%) as a
thick oil: FTIR (CDCl3, cast) 3444, 2170, 1615, 1592 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 0.15 (s, 9 H), 2.28 (s, 3 H), 3.53 (s, 2 H), 3.75
(s, 3 H), 5.88 (s, 1 H), 6.34 (d, J = 2.5 Hz, 1 H), 6.37 (d, J = 2.5 Hz, 1
H); 13C NMR (CDCl3, 125 MHz) δ −0.05 (q), 17.2 (t), 20.3 (q),
55.2 (q), 87.2 (s), 100.1 (d), 103.4 (s), 108.8 (d), 113.1 (s), 138.0 (s),
155.4 (s), 159.0 (s); exact mass (electrospray) m/z calcd for
C14H19O2Si (M − H)− 247.1160, found 247.1161.
5-Methoxy-3-methyl-2-(prop-2-en-1-yl)phenol (17).17 The
procedure for 4 was followed, using DBU (100 mg, 0.658 mmol)
and a solution of 14 (81.5 mg, 0.318 mmol) in PhMe (1 mL). Workup
and flash chromatography of the residue over silica gel (1 × 10 cm),
1
using 1:3 EtOAc−hexanes, gave 17 (46.8 mg, 84%) as a thick oil: H
2-Bromo-6-[(3-bromophenyl)methyl]-3-methoxy-5-methyl-
cyclohex-2-en-1-one (23). The procedure for compound 2 was
followed, using n-BuLi (2.50 M in hexanes, 0.32 mL, 0.80 mmol), i-
Pr2NH (0.13 mL, 0.93 mmol) in THF (2 mL), a solution of 1 (161
mg, 0.735 mmol) in THF (2 mL), and a solution of 3-bromobenzyl
bromide (550 mg, 2.20 mmol) in THF (2 mL). The mixture was left
overnight after the addition of 3-bromobenzyl bromide and then
worked up. Flash chromatography of the residue over silica gel (1.8 ×
13 cm), using 1:4 EtOAc−hexanes, gave 23 (199 mg, 70%) as a white
NMR (CDCl3, 500 MHz) δ 2.26 (s, 3 H), 3.36 (d, J = 7.5 Hz, 2 H),
3.75 (s, 3 H), 5.00−5.08 (m, 2 H), 5.90−6.00 (m, 1 H), 6.28 (d, J =
3.5 Hz, 1 H), 6.37 (d, J = 3.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz)
δ 19.9 (q), 30.1 (t), 55.2 (q), 99.5 (d), 108.5 (d), 115.2 (t), 116.0 (s),
135.9 (d), 138.8 (s), 154.9 (s), 158.6 (s).
2-Bromo-3-methoxy-5,6-dimethylcyclohex-2-en-1-one (18).
The procedure for compound 2 was followed, using n-BuLi (2.50 M in
hexanes, 0.63 mL, 1.57 mmol), i-Pr2NH (0.26 mL, 1.85 mmol) in
THF (6 mL), a solution of 1 (313 mg, 1.43 mmol) in THF (3 mL),
and a solution of MeI (0.20 mL, 3.21 mmol) in THF (2 mL). The
mixture was left overnight after the addition of MeI and then worked
1
solid: FTIR (CDCl3, cast) 1659, 1590 cm−1; H NMR (CDCl3, 500
MHz) δ (major isomer) 1.12 (d, J = 7.0 Hz, 3 H), 2.03−2.07 (m, 1
H), 2.36−2.56 (m, 2 H), 2.74−3.00 (m, 3 H), 3.93 (s, 3 H), 7.15−7.16
D
DOI: 10.1021/acs.joc.5b00192
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The Journal of Organic Chemistry
Article
(m, 2 H), 7.33−7.37 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ
(major isomer) 20.0 (q), 29.6 (d), 32.6 (t), 34.4 (t), 53.8 (d), 56.3
(q), 101.9 (s), 122.4 (s), 127.9 (d), 129.4 (d), 130.0 (d), 132.1 (d),
141.6 (s), 170.4 (s), 192.0 (s); exact mass (electron ionization) m/z
calcd for C15H1679Br2O2 (M)+ 385.9516, found 385.9522.
2-[(3-Bromophenyl)methyl]-5-methoxy-3-methylphenol
(24). The procedure for 4 was followed, using DBU (150 mg, 0.987
mmol) and a solution of 23 (191 mg, 0.492 mmol) in PhMe (2 mL).
Workup and flash chromatography of the residue over silica gel (1.8 ×
10 cm), using 1:5 EtOAc−hexanes, gave 24 (139 mg, 92%) as a white
solid: mp 115−117 °C; FTIR (CDCl3, cast) 3402, 3057, 1615, 1592
cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.21 (s, 3 H), 3.77 (s, 3 H), 3.95
(s, 2 H), 4.60 (s, 1 H), 6.26 (d, J = 2.5, 1 H), 6.38 (d, J = 2.5, 1 H),
7.06−7.12 (m, 2 H), 7.28−7.30 (m, 2 H); 13C NMR (CDCl3, 125
MHz) δ 20.2 (q), 31.0 (t), 55.2 (q), 99.5 (d), 108.5 (d), 116.8 (s),
122.6 (s), 126.7 (d), 129.0 (d), 129.9 (d), 131.0 (d), 139.4 (s), 142.9
(s), 154.5 (s), 158.8 (s); exact mass (electron ionization) m/z calcd for
C15H1579BrO2 (M)+ 306.0255, found 306.0250.
tert-Butyl 2-(3-Bromo-4-methoxy-6-methyl-2-oxocyclohex-
3-en-1-yl)acetate (25). The procedure for compound 2 was
followed, using n-BuLi (2.50 M in hexanes, 0.30 mL, 0.75 mmol), i-
Pr2NH (0.12 mL, 0.856 mmol) in THF (2 mL), a solution of 1 (146
mg, 0.667 mmol) in THF (2 mL), and a solution of tert-butyl
bromoacetate (0.31 mL, 2.10 mmol) in THF (2 mL). The mixture was
left overnight after the addition of the tert-butyl bromoacetate and
then worked up. Flash chromatography of the residue over silica gel
(1.8 × 13 cm), using 1:3 EtOAc−hexanes, gave 25 (178 mg, 70%) as a
thick oil: FTIR (CDCl3, cast) 1726, 1664, 1593 cm−1; 1H NMR
(CDCl3, 500 MHz) δ major isomer) 1.14 (d, J = 6.5 Hz, 3 H), 1.46 (s,
9 H), 2.15−2.20 (m, 1 H), 2.37 (dd, J = 17.5, 10.5 Hz, 1 H), 2.46 (dd,
J = 11.0, 5.5, 1 H), 2.56−2.61 (m, 1 H), 2.76−2.82 (m, 1 H), 3.94 (s, 3
H); 13C NMR (CDCl3, 125 MHz) δ (major isomer) 19.4 (q), 28.0
(q), 32.3 (d), 33.9 (t), 34.8 (t), 49.3 (d), 56.2 (q), 80.6 (s), 102.1 (s),
170.9 (s), 171.6 (s), 191.1 (s); exact mass (electrospray) m/z calcd for
C14H2279BrO4 (M + H)+ 333.0696, found 333.0690.
(s); exact mass (electron ionization) m/z calcd for C9H14O2 (M)+
154.0993, found 154.0995.
b. Preparation of 2-Bromo-5-ethyl-3-methoxycyclohex-2-en-1-
one. NBS (166 mg, 0.932 mmol) was added in one portion to a stirred
and cooled (0 °C) solution of 5-ethyl-3-methoxycyclohex-2-en-1-one
(120 mg, 0.779 mmol) in CH2Cl2 (4 mL). Stirring at 0 °C was
continued for 3.5 h with protection from light and the mixture was
then diluted with saturated aqueous NaHCO3 and extracted with
CH2Cl2. The combined organic extracts were washed with brine, dried
(MgSO4), and evaporated. Flash chromatography of the residue over
silica gel (1.8 × 12 cm), using 2:3 EtOAc−hexanes, gave 2-bromo-5-
ethyl-3-methoxycyclohex-2-en-1-one (165 mg, 91%) as a white solid:
1
mp 100−103 °C; FTIR (CDCl3, cast) 1733, 1662, 1585 cm−1; H
NMR (CDCl3, 500 MHz) δ 0.98 (t, J = 7.5 Hz, 3 H), 1.48−1.52 (m, 2
H), 2.04−2.12 (m, 1 H), 2.21 (dd, J = 16.0, 12.5 Hz, 1 H), 2.32 (dd, J
= 17.0, 10.0 Hz, 1 H), 2.69−2.85 (m, 2 H), 3.97 (s, 3 H); 13C NMR
(CDCl3, 125 MHz) δ 11.1 (q), 28.0 (t), 32.7 (t), 34.5 (d), 42.6 (t),
56.3 (q), 102.6 (s), 172.4 (s), 191.0 (s); exact mass (electron
ionization) m/z calcd for C15H1579BrO2 (M)+ 306.0255, found
306.0250.
c. 2-Bromo-5-ethyl-3-methoxy-6-(prop-2-en-1-yl)cyclohex-2-en-
1-one (27). The procedure for compound 2 was followed, using n-
BuLi (2.50 M in hexanes, 0.20 mL, 0.50 mmol), i-Pr2NH (0.08 mL,
0.57 mmol) in THF (2 mL), 2-bromo-5-ethyl-3-methoxycyclohex-2-
en-1-one (103 mg, 0.442 mmol) in THF (2 mL), and allyl bromide
(267 mg, 2.20 mmol) in THF (1 mL). The mixture was left overnight
after the addition of allyl bromide and then worked up. Flash
chromatography of the residue over silica gel (1 × 12 cm), using 1:3
EtOAc−hexanes, gave 27 (85.6 mg, 71%) as a white solid, which was a
mixture of diastereoisomers: FTIR (CDCl3, cast) 3075, 1646, 1613,
1587 cm−1; 1H NMR (CDCl3, 500 MHz) δ (major isomer) 0.95 (t, J =
7.5 Hz, 3 H), 1.59−1.64 (m, 2 H), 2.01−2.04 (m, 1 H), 2.37−2.49 (m,
3 H), 2.52−2.58 (m, 1 H), 2.83 (dd, J = 17.5, 5.5, 1 H), 3.96 (s, 3 H),
5.05−5.11 (m, 2 H), 5.71−5.76 (m, 1 H); 13C NMR (CDCl3, 125
MHz) δ (major isomer) 10.9 (q), 25.3 (t), 29.2 (t), 33.2 (t), 35.7 (d),
49.8 (d), 56.1 (q), 101.7 (s), 117.2 (t), 135.2 (d), 170.4 (s), 192.5 (s);
exact mass (electron ionization) m/z calcd for C12H1779BrO2 (M)+
272.0412, found 272.0408.
tert-Butyl 2-(2-Hydroxy-4-methoxy-6-methylphenyl)acetate
(26). The procedure for 4 was followed, using DBU (155 mg, 1.02
mmol) and a solution of 25 (167 mg, 0.50 mmol) in PhMe (2 mL).
Workup and flash chromatography of the residue over silica gel (1.8 ×
10 cm), using 1:4 EtOAc−hexanes, gave 26 (111 mg, 88%) as an off-
white solid: mp 72−74 °C; FTIR (CDCl3, cast) 3411, 1732, 1702,
3-Ethyl-5-methoxy-2-(prop-2-en-1-yl)phenol (28). The proce-
dure for 4 was followed, using DBU (91.3 mg, 0.60 mmol) and 27
(82.0 mg, 0.30 mmol) in PhMe (1 mL). Workup and flash
chromatography of the residue over silica gel (1 × 10 cm), using
1:6 EtOAc−hexanes, gave 28 (49.0 mg, 85%) as a thick oil: FTIR
1
1616, 1594 cm−1; H NMR (CDCl3, 500 MHz) δ 1.45 (s, 9 H), 2.29
(s, 3 H), 3.53 (s, 2 H), 3.75 (s, 3 H), 6.35 (d, J = 2.5, 1 H), 6.40 (d, J =
2.0, 1 H), 7.44 (s, 1 H); 13C NMR (CDCl3, 125 MHz) δ 20.3 (q), 27.9
(q), 34.2 (t), 55.1 (q), 82.4 (s), 100.7 (d), 108.9 (d), 112.5 (s), 138.3
(s), 156.5 (s), 159.3 (s), 173.4 (s); exact mass (electrospray) m/z
calcd for C14H19O4 (M − H)− 251.1289, found 251.1285.
1
(CDCl3, cast) 3431, 3077, 3001, 1636, 1616, 1589 cm−1; H NMR
(CDCl3, 500 MHz) δ 1.18 (t, J = 9.0 Hz, 3 H), 2.59 (q, J = 7.5 Hz, 2
H), 3.37 (dt, J = 6.0, 1.5 Hz, 2 H), 3.76 (s, 3 H), 4.88 (s, 1 H), 5.03−
5.10 (m, 2 H), 5.98 (ddt, J = 17.0, 10.0, 6.0 Hz, 1 H), 6.29 (d, J = 2.5
Hz, 1 H), 6.39 (d, J = 2.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ
15.3 (q), 26.5 (t), 29.7 (t), 55.2 (q), 99.4 (d), 107.1 (d), 115.1 (s),
115.6 (s), 136.5 (d), 144.8 (s), 155.2 (s), 159.0 (s); exact mass
(electrospray) m/z calcd for C12H15O2 (M)+ 191.1078, found
191.1079.
(2E)-4-[(tert)-Butyldiphenylsilyl)oxy]-3-methylbut-2-en-1-yl
Acetate (30). DMAP (1.52 g, 12.4 mmol), Et3N (17.4 mL, 125
mmol), and t-BuPh2SiCl (10.7 mL, 41.7 mmol) were added to a
stirred solution of 2920 (6.00 g, 41.7 mmol) in CH2Cl2 (48 mL) at
room temperature. Stirring was continued for 8 h and the mixture was
diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2.
The combined organic extracts were washed with brine, dried
(MgSO4), and evaporated. Flash chromatography of the residue over
silica gel (6 × 15 cm), using 1:6 EtOAc−hexanes, gave 30 (14.0 g,
88%) as a pale yellow oil: FTIR (CDCl3, cast) 3071, 3049, 1741 cm−1;
1H NMR (CDCl3, 500 MHz) δ 1.10 (s, 9 H), 1.67 (s, 3 H), 2.09 (s, 3
2-Bromo-5-ethyl-3-methoxy-6-(prop-2-en-1-yl)cyclohex-2-
en-1-one (27). a. Preparation of 5-Ethyl-3-methoxycyclohex-2-en-
1-one. EtONa was prepared by dissolving Na (150 mg, 6.52 mmol) in
ice-cold EtOH (7 mL). Then ethyl acetoacetate (0.84 mL, 860 mg,
6.61 mmol) and methyl 2-pentenoate (846 mg, 6.61 mmol) were
added by syringe to the resulting stirred solution. The mixture was
refluxed for 6 h (N2 atmosphere) and then evaporated. The residue
was dissolved in water (4 mL), and KOH (730 mg, 13.0 mmol) was
added. The solution was refluxed for 1 h and then cooled.
Concentrated H2SO4 was added carefully to adjust the pH to 1.
The solution was refluxed for 2 h, cooled to room temperature, and
extracted thoroughly with EtOAc. The combined organic extracts were
washed with brine, dried (MgSO4), and evaporated. The residue was
dissolved in MeOH (5 mL) and (MeO)3CH (0.72 mL, 700 mg, 6.61
mmol) was added. The solution was stirred for 24 h at room
temperature and then evaporated. Flash chromatography of the
residue over silica gel (1.8 × 12 cm), using 2:3 EtOAc−hexanes, gave
5-ethyl-3-methoxycyclohex-2-en-1-one (350 mg, 41% over two steps)
as a colorless, thick oil: FTIR (CDCl3, cast) 1734, 1655, 1609 cm−1;
1H NMR (CDCl3, 400 MHz) δ 0.95 (t, J = 9.5 Hz, 3 H), 1.40−1.47
H), 4.10 (s, 2 H), 4.68 (d, J = 2.5, 2 H), 5.73−5.76 (m, 1 H), 7.39−
7.45 (m, 6 H), 7.68−7.70 (m, 4 H); 13C NMR (CDCl3, 125 MHz) δ
13.6 (q), 19.3 (s), 21.0 (q), 26.8 (q), 60.9 (t), 67.9 (t), 117.4 (d),
127.6 (d), 129.6 (d), 133.5 (s), 135.5 (d), 140.3 (s), 171.0 (s); exact
mass (electrospray) m/z calcd for C23H30NaO3Si (M + Na)+
405.1856, found 405.1850.
(m, 2 H), 2.01−2.20 (m, 3 H), 2.42−2.50 (m, 2 H), 3.70 (s, 3 H), 5.37
(d, J = 1.6 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 11.1 (q), 28.0
(t), 34.9 (t), 35.4 (d), 43.0 (t), 55.7 (q), 102.1 (s), 178.2 (s), 199.7
E
DOI: 10.1021/acs.joc.5b00192
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The Journal of Organic Chemistry
Article
(2E)-4-[(tert-Butyldiphenylsilyl)oxy]-3-methylbut-2-en-1-ol
(31).21 K2CO3 (15.2 g, 110 mmol) was added to a stirred solution of
30 (14.0 g, 36.6 mmol) in MeOH (36 mL) at room temperature and
stirring was continued for 2 h. The mixture was diluted with water and
extracted with Et2O. The combined organic extracts were washed with
brine, dried (MgSO4), and evaporated. Flash chromatography of the
residue over silica gel (6 × 15 cm), using 1:5 EtOAc−hexanes, gave 31
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Research
Council of Canada for financial support; Dr. M. J. Ferguson and
Dr. R. McDonald for the X-ray measurements; and Drs H.
Achariya, Z. Li, and H. Yang for assistance with the preparation
of 2 and 16.
1
(11.9 g, 96%) as a colorless oil: H NMR (CDCl3, 500 MHz) δ 1.08
(s, 9 H), 1.63 (s, 3 H), 4.08 (s, 2 H), 4.21 (d, J = 2.0 Hz, 2 H), 5.73−
5.76 (m, 1 H), 7.38−7.42 (m, 6 H), 7.67−7.69 (m, 4 H); 13C NMR
(CDCl3, 125 MHz) δ 13.5 (q), 19.3 (s), 26.8 (q), 59.1 (t), 68.0 (t),
122.4 (d), 127.7 (d), 129.7 (d), 133.6 (s), 135.5 (d), 137.9 (s).
tert-Butyl({[(2E)-4-[(Methoxyphenyl)methoxy]-2-methylbut-
2-en-1-yl]oxy})diphenylsilane (32). 4-Methoxybenzyl 2,2,2-tri-
chloroacetimidate (729 mg, 2.59 mmol) in CH2Cl2 (3 mL) and p-
TsOH·H2O (41.6 mg, 0.22 mmol) were added to a stirred and cooled
(0 °C) solution of 31 (735 mg, 2.16 mmol) in CH2Cl2 (6 mL).
Stirring was continued for 4.5 h, and the mixture was diluted with
water and extracted with CH2Cl2. The combined organic extracts were
washed with brine, dried (MgSO4), and evaporated. Flash chromatog-
raphy of the residue over silica gel (3 × 15 cm), using 1:5 EtOAc−
hexanes, gave 32 (863 mg, ca. 87%) as a colorless oil, which contained
a minor impurity. The material was used directly for next step.
(2E)-4-[(4-Methoxyphenyl)methoxy]-2-methylbut-2-en-1-ol
(33).22 Bu4NF (1.0 M in THF, 2.20 mL, 2.20 mmol) was added to a
stirred and cooled (0 °C) solution of 32 (863 mg, 1.88 mmol) in THF
(10 mL). Stirring was continued for 12 h, and the mixture was diluted
with saturated aqueous NH4Cl and extracted with EtOAc. The
combined organic extracts were washed with brine, dried (MgSO4),
and evaporated. Flash chromatography of the residue over silica gel (3
× 15 cm), using 1:1 EtOAc−hexanes, gave 33 (363 mg, 76% over two
REFERENCES
■
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steps) as a colorless oil: FTIR (CDCl3, cast) 3395, 1612 cm−1; H
2871.
NMR (CDCl3, 500 MHz) δ 1.44 (br s, 1 H), 1.67 (s, 3 H), 3.80 (s, 3
H), 4.02−4.06 (m, 4 H), 4.45 (s, 2 H), 5.64−5.67 (m, 1 H), 6.88 (d, J
= 9.0 Hz, 2 H), 7.27 (d, J = 9.0 Hz, 2 H); 13C NMR (CDCl3, 125
MHz) δ 13.9 (q), 55.3 (q), 65.9 (t), 68.1 (t), 72.0 (t), 113.8 (d), 121.6
(d), 129.4 (d), 130.4 (s), 139.1 (s), 159.2 (s); exact mass
(electrospray) m/z calcd for C13H18NaO3 (M + Na)+ 245.1148,
found 245.1154.
(11) Banteli, R.; Ernst, B. Tetrahedron Lett. 1997, 38, 4059−4062.
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1992, 33, 4603−4604.
1-({[(2E)-4-Bromo-3-methylbut-2-en-1-yl]oxy}methyl)-4-me-
thoxybenzene (34).23 Ph3P (227 mg, 0.866 mmol) and CBr4 (240
mg, 0.723 mmol) were added to a stirred and cooled (0 °C) solution
of 33 (160 mg, 0.723 mmol) in CH2Cl2 (7 mL). Stirring was
continued for 3.5 h and the solvent was then evaporated. Flash
chromatography of the residue over silica gel (1.8 × 15 cm), using
1:12 EtOAc−hexanes, gave 34 (187 mg, 91%) as a colorless oil: FTIR
(15) For example, see the following: (a) Olson, G. L.; Cheung, H.-
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(prop-2-en-1-yl)phenol are formed: Biswas, B.; Sarkar, D.;
Venkateswaran, R. V. Tetrahedron 2008, 64, 3212−3216.
(18) Witty, T. R.; Remers, W. A. J. Med. Chem. 1973, 16, 1280−1284.
(19) Mirrington, R. N.; Feutrill, G. I. Organic Syntheses; Wiley: New
York, 1988; Collect. Vol. 6, pp 859−861.
1
(CDCl3, cast) 1612 cm−1; H NMR (CDCl3, 500 MHz) δ 1.78 (s, 3
H), 3.80 (s, 3 H), 3.96 (s, 2 H), 4.02 (d, J = 6.5 Hz, 2 H), 4.44 (s, 2
H), 5.78−5.80 (m, 1 H), 6.88 (d, J = 7.5 Hz, 2 H), 7.26 (d, J = 7.5 Hz,
2 H); 13C NMR (CDCl3, 125 MHz) δ 15.1 (q), 40.2 (t), 55.3 (q),
66.1 (t), 72.1 (t), 113.8 (d), 127.3 (d), 129.4 (d), 130.1 (s), 135.5 (s),
159.3 (s); exact mass (electron ionization) m/z calcd for
C13H1781BrO2 (M)+ 286.0391, found 286.0400.
(20) Mechelke, M. F.; Wiemer, D. F. J. Org. Chem. 1999, 64, 4821−
4829.
(21) Shi, L.; Lei, X.; Zhang, J.; Lin, G. Helv. Chim. Acta 2010, 93,
555−564.
(22) Nanda, S.; Scott, A. I. Tetrahedron: Asymmetry 2004, 15, 963−
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of NMR spectra of 1, 2, 4, 14−26, 28, 30, 31, 33, and
34 and an ORTEP diagram and X-ray data (CIF) for
compound trans-2. This material is available free of charge via
the Internet at http://pubs.acs.org.
970.
(23) This compound has previously been generated in situ. See ref
22.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: derrick.clive@ualberta.ca.
Notes
The authors declare no competing financial interest.
F
DOI: 10.1021/acs.joc.5b00192
J. Org. Chem. XXXX, XXX, XXX−XXX