A Family of Routes to Substituted Phenols, Including Meta-Substituted Phenols

Article abstract of DOI:10.1021/acs.joc.5b02187

A new family of routes to substituted phenols has been developed. 2-Bromo-3-methoxycyclohex-2-en-1-ones are readily deprotonated at C-6, and the resulting anions react smoothly with a variety of electrophiles; treatment with DBU in PhMe at room temperature then results in efficient aromatization to benzene derivatives of a regiochemically defined substitution pattern. This sequence affords phenolic azides (ArN₃), sulfides (ArSR, ArSAr′), selenides (ArSePh), alcohols [ArCH(OH)R], amino derivatives [ArCH(NHSO₂Ar′)R), and 1,2-benzenediols. A complementary set of substitution patterns is obtained by DIBAL-H reduction or reaction with a Grignard reagent before aromatization; the latter process gives compounds in which the newly introduced substituent is meta to the phenolic hydroxyl.

Full text of DOI:10.1021/acs.joc.5b02187

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Article
A Family of Routes to Substituted Phenols,
including meta-Substituted Phenols
Wenjie Shao, and Derrick L. J. Clive
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02187 • Publication Date (Web): 20 Nov 2015
Downloaded from http://pubs.acs.org on November 24, 2015
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A Family of Routes to Substituted Phenols, including meta-Substituted
Phenols
Wenjie Shao and Derrick. L. J. Clive*
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Chemistry Department, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
derrick.clive@ualberta.ca
ABSTRACT: A new family of routes to substituted phenols has been developed. 2-Bromo-3-
methoxycyclohex-2-en-1-ones are readily deprotonated at C-6 and the resulting anions react
smoothly with a variety of electrophiles; treatment with DBU in PhMe at room temperature then
results in efficient aromatization to benzene derivatives of regiochemically defined substitution
pattern. This sequence affords phenolic azides (ArN ), sulfides (ArSR, ArSAr'), selenides
3
(
ArSePh), alcohols [ArCH(OH)R], amino derivatives [ArCH(NHSO Ar')R), and 1,2-
2
benzenediols. A complementary set of substitution patterns is obtained by DIBAL-H reduction
or reaction with a Grignard reagent before aromatization; the latter process gives compounds in
which the newly-introduced substituent is meta to the phenolic hydroxyl.
INTRODUCTION
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A recent report from this laboratory described how attempts to alkylate the bromoketone
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(Scheme 1) led to the unexpected formation of phenol 3 rather than the desired dialkylated
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product 4. The formation of 3 was then developed into a general procedure (Scheme 2, R = Me,
Et) that affords alkyl-substituted resorcinol monomethyl ethers (5→6→7) under very
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SCHEME 1. Discovery of the aromatization process.
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straightforward conditions—simple C-6 alkylation of a bromoketone of type 5 (R = Me, Et),
followed by treatment with DBU in PhMe at room temperature. The yields in the alkylation step
(
5→6) were in the range 70-91% (average 74.8%) and for the aromatization (6→7) the yields
were 82-92%.
SCHEME 2. Routes to alkyl-substituted phenols.
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R = H, Me, Et; R = allyl, propargyl, benzyl, Me, CH CO Bu-t.
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RESULTS AND DISCUSSION
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Our experiments were limited to alkylation and we found that only reactive halides such
allylic, benzylic and propargylic halides, α-halo esters and methyl iodide were suitable.
However, we have since examined the possibility of using other electrophiles and we find that
the alkylations shown generically in Scheme 2 represent only one type of example of a new
family of routes to phenols; the generation of this family is summarized in Scheme 3 where E
denotes a wide variety of groups easily installed with electrophilic reagents. So far, we have
1
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examined compounds of type 8 in which R is MeO or H, and R is H or Me.
SCHEME 3. General family of routes to substituted phenols.
1
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R = H, OMe; R = H, Me, E = N , SMe, SPh, SPmb, SePh, OH, OTHP, CH(OH)Ph,
3
CH(NHSO Tol)Ar, CH(OH)R, F. Pmb = p-methoxybenzyl.
2
The closest precedents we can find for the aromatization step are the reports summarized
in Scheme 4, which shows that aromatization of a bromoenone (11→12) was induced with 40%
2
, 3
HBr-AcOH in CH Cl . There is also the incidental observation, made during studies on the
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preparation of (benzoyloxy)enones, that treatment of iodoenone 13 with Bu NHSO in refluxing
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THF (4 h) gives phenol 14.
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SCHEME 4. Acid-mediated aromatization of α-haloenones.
We have applied the principle expressed in Scheme 3 to the preparation of a number of
phenols. Our results are listed in Table 1 which also includes the outcome of a modification
(
entry 6) that extends the approach to 1,2-benzenediols. The significance of the overall process
is that it directly links the ability to functionalize a cyclohexenone-like structure α to the
carbonyl on the one hand with the correspondingly substituted benzene ring, and does this
reliably and in good yield under mild conditions.
Table 1. Aromatization products and yields.
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a
b
Yield corrected for recovered starting 3-methoxybromoenone. Yield deliberately suppressed;
the compound is a byproduct when using only 1.05 equiv of fluorinating agent.
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The starting bromoenones such as 8 are readily made by bromination of 3-
methoxycyclohexenones or cyclohexenones, which are themselves available by several
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straightforward classical procedures.
Sulfenylation of 2-bromo-3-methoxycyclohex-2-en-1-one (entries 2—4) is easily
achieved by deprotonation of the parent carbonyl compound (1, LDA) and quenching with a
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reagent of the type RSSO Tol (R = Me, Ph, Pmb).
Likewise, phenylselenation is
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straightforward (LDA, PhSeCl). All of the enone sulfur derivatives, irrespective of whether the
substituent on the chalcogen is aromatic or aliphatic, undergo efficient aromatization (yields 82-
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1%) on treatment with DBU in PhMe at room temperature. For selenium we have examined
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only a phenyl substituent. These reactions are quite fast, being complete within 20 min to 2 h.
In contrast, the azide 15 (entry 1), which is readily prepared by treating the appropriate enolate
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(generated with LDA) with 2,4,6-tri-isopropylbenzensulfonyl azide requires about 5 h.
It is noteworthy that the aldol products (entries 8 and 10) do not suffer dehydration. In
the case of the benzaldehyde adduct 30, it is evident that base-induced dehydration, which would
be facilitated by the presence of conjugation in the resulting product, is not a significant
pathway, if it occurs at all, so that entry 8 represents the result of a demanding test for the
intrusion of this undesired reaction.
The sulfonamide 32 (entry 9), easily made by enolate condensation with N-
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toluenesulfonyl)benzaldimine is also aromatized smoothly, but slowly; it was generated in an
overnight reaction period in 84% yield.
Where the substituent introduced at the beginning is an oxygen atom [Table 1, entries 6
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and 7; use of 2-(4-methylbenzenesulfonyl)-3-phenyloxaziridine) ] we found that for the simple
enone 28 aromatization proceeded normally, but for the 3-methoxyenone (25) protection of the
hydroxyl is required, and a THP ether was found to be suitable.
+
When E (see Scheme 3) is a heteroatom there is the potential for elimination within the
six-membered ring (Scheme 5, 9→42→43). Fortunately, for all the sulfur, selenium and oxygen
SCHEME 5. Potential side reaction.
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substituents we have examined, such elimination does not occur; however, it does occur with
bromine (E = Br), but not with fluorine. Surprisingly, the fluoro compound 38 (entry 12) was
aromatized rather slowly and was best generated by overnight exposure to DBU (PhMe, room
temperature). We noticed that the difluoro compound 40 was always formed as a byproduct in
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the generation of 38 but the amount could be suppressed to a level of 8% by using no more
than 1.05 equiv of the commercial fluorinating reagent [FN(SO Ph) ] and, with this
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stoichiometry, the yield of the monofluoride 38 was 75%. The use of a very slight excess of the
fluorinating reagent, rather than exactly 1 equiv, gives a better result.
The substitution pattern of the final aromatic product can easily be modified by DIBAL-
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H reduction of the penultimate bromoenone. For example, bromoenone 21 was reduced (1
equiv DIBAL-H in PhMe at 0 °C, <5 min), treated briefly (<5 min) with 3 M hydrochloric acid
at 0 °C and, after product isolation, exposed to the action of DBU in PhMe. These operations
served to convert 21 into 46 (Scheme 6). 3-Alkoxy-2-halocyclohex-2-en-1-ones do not appear to
have been reduced before with hydride reagents, and we find that DIBAL-H in PhMe gives a
much better result than DIBAL-H in CH Cl or LiAlH in Et O. The example shown in Scheme
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6 was chosen as a demanding test because there again exists the potential for elimination of the
PmbS group but, in the event, this does not occur and the overall transformation is extremely
efficient in removing the methoxy group and affording a different regiochemical pattern to that
resulting directly from 21 itself.
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As illustrated by entries 7 and 11, the presence of the C-3 methoxy group is not required
for the aromatization but it does play a subtle role in the first step (cf 5→6) because, in its
absence, that first step does not work if there is a substituent at C-5.
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SCHEME 6. Modification of the substitution pattern.
Pmb = p-methoxybenzyl.
In a process analogous to the conversion of 21 to 46, reaction of 17 with a Grignard
reagent (we used vinylmagnesium bromide), mild acid hydrolysis and aromatization with DBU
generates phenol 49 (Scheme 7), in which the noteworthy feature is that the new substituent has
been introduced meta to the hydroxyl—an orientation that is complementary to that provided by
classical electrophilic substitution of phenol derivatives.
SCHEME 7. Introduction of a meta substituent.
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The probable mechanism for the aromatization is shown in Scheme 8 and, on that basis,
all of these transformations depend on the ability of the 2-bromocyclohex-2-en-1-one unit to
undergo deconjugation (see 9→52, Scheme 8) in the presence of DBU, so that elimination of
HBr (52→10) can then take place. The process must involve initial removal of a C-4 hydrogen
from a non-enolized enone system (9), and so the relative acidity of the C-4 and C-6 hydrogens,
as well as the pK of the base (and, possibly, its steric requirements) are critical for the successful
a
outcome. The choice of DBU was not arbitrary; when we tried pyridine with 1 there was no
reaction and the compound was equally inert to Et N. The deconjugation is evidently easy, as
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the aromatization proceeds at room temperature in good yield (80-92%).
SCHEME 8. Mechanism of the aromatization.
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CONCLUSION
The possibility of using both kinetic enolization of bromoenone systems and more
attractive conditions than those of Scheme 4 for aromatization have not been appreciated
before—neither of the precedents in Scheme 4 made use of functionalization α to the carbonyl
but, as shown here, such an enolate-based approach opens a simple and general route to an
extensive range of aromatics.
Our results establish that deprotonation of 2-bromocyclohex-2-en-1-one systems and
quenching with various azido, carbonyl, fluorine, oxygen, sulfur, selenium, N-(sulfonyl)aldimine
1
and alkyl electrophiles gives the expected α-substituted adducts which, in turn, undergo
efficient aromatization on exposure to the action of DBU in PhMe at room temperature. The
regiochemistry of the final products is established in the initial reaction α to the carbonyl and is
highly regiocontrolled, while the aromatic products themselves are functionalized in a way that
allows further manipulation. The process is clearly general and is based on a previously
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unrecognized characteristic of the 2-bromocyclohex-2-en-1-one structure—the ability to effect
irreversible kinetic deprotonation at C-6 with LDA and then to deprotonate the system reversibly
at C-4 with DBU. The overall procedure constitutes a new family of routes to phenolic
compounds that have been functionalized in a regiocontrolled manner, and gives direct and
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efficient access to a wide range of phenols.
If the initial product before aromatization is
reduced with DIBAL-H or treated with a Grignard reagent then the scope is enlarged to a further
range of substitution patterns. When a Grignard reagent RMgX is used a noteworthy result is
that the R group is meta to the phenolic hydroxyl in the final product. For some purposes the
transition metal-free nature of the process will be an important advantage.
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). The specified solvents were the same as
those used for tlc monitoring of the reactions. Dry solvents were prepared under an inert
1
3
atmosphere and transferred by syringe or cannula. The symbols s, d, t and q used for C 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.
6
-Azido-2-bromo-3-methoxy-5-methylcyclohexe-2-en-1-one (15). n-BuLi (2.5 M in
hexanes, 0.13 mL, 0.325 mmol) was added dropwise to a stirred and cooled (–78 °C) solution of
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i-Pr NH (0.05 mL, 0.357 mmol) in THF (1.5 mL). Stirring at –78 °C was continued for 30 min
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and then a solution of 1 (65 mg, 0.297 mmol) in THF (1.5 mL) was added dropwise over < 1 min.
The cold bath was left in place, but not recharged, so that the temperature rose to 0 °C over 2 h.
The mixture was then recooled to –78 °C and a solution of 2,4,6-triisopropylbenzenesulfonyl
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azide (180 mg, 0.582 mmol) in THF (1.5 mL) was added dropwise over < 1 min. The cold bath
was left in place, but not recharged, and stirring was continued for 1 h, by which point the
temperature had risen to –20 °C. A solution of AcOH in THF (1 N, 0.33 mL) was added and the
solvent was evaporated. Flash chromatography of the residue over silica gel (1 × 15 cm), using
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:3 EtOAc–hexanes, gave 15 (59.5 mg, 77%) as a pale yellow oil: FTIR (CDCl , cast) 2104,
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–
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1668 cm ; H NMR (CDCl , 500 MHz) δ (major isomer) 1.15 (d, J = 7.0 Hz, 3 H), 2.34–2.40
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m, 1 H), 2.50–2.55 (m, 1 H), 2.62–2.90 (m, 1 H), 3.97 (s, 3 H), 4.04–4.05 (m, 1 H); C NMR
(
CDCl , 125 MHz) δ (major isomer) 15.9 (q), 31.0 (t), 33.0 (d), 56.7 (d), 66.7 (q), 100.0 (s),
3
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+
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72.8 (s), 186.6 (s); exact mass (electron ionization) m/z calcd for C H O BrN (M) 258.9956,
8 10 2 3
found 258.9951.
2-Azido-5-methoxy-3-methylphenol (16). DBU (67 mg, 0.44 mmol) was added to a
stirred solution of 15 (56.1 mg, 0.215 mmol) in PhMe (1 mL). Stirring was continued for 1 h
and the reaction mixture was diluted with 5% hydrochloric acid and extracted with EtOAc. The
combined organic extracts were washed with brine, dried (MgSO ) and evaporated. Flash
4
chromatography of the residue over silica gel (1 × 15 cm), using 1:5 EtOAc-hexanes, gave 16
–
1 1
(32.1 mg, 83%) as a pale yellow, thick oil: FTIR (CDCl , cast) 3366, 2115, 1614 cm ; H NMR
3
(
CDCl , 500 MHz) δ 2.34 (s, 3 H), 3.74 (s, 3 H), 5.40 (br s, 1 H), 6.29 (d, J = 3.0 Hz, 1 H), 6.34
3
1
3
(d, J = 3.0 Hz, 1 H); C NMR (CDCl , 125 MHz) δ 17.1 (q), 56.3 (q), 99.3 (d), 108.6 (d), 127.7
3
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–
(
s), 163.2 (s), 172.0 (s); exact mass (electrospray) m/z calcd for C H O N (M–H) 178.0622,
8 8 2 3
found 178.0621.
2
-Bromo-3-methoxy-5-methyl-6-(methylsulfanyl)cyclohex-2-en-1-one (17). n-BuLi
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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33
34
35
36
37
38
39
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
2.5 M in hexanes, 0.13 mL, 0.325 mmol) was added dropwise to a stirred and cooled (–78 °C)
solution of i-Pr NH (0.05 mL, 0.357 mmol) in THF (2.0 mL). Stirring at –78 °C was continued
2
for 30 min and then a solution of 1 (65 mg, 0.297 mmol) in THF (2.0 mL) was added dropwise
over < 1 min. The cold bath was left in place, but not recharged, so that the temperature rose to
8b
0 °C over 2.5 h. The mixture was then recooled to –78 °C and a solution of TolSO SMe (132
2
mg, 0.653 mmol) in THF (2.0 mL) was added dropwise over < 1 min. The cold bath was left in
place, but not recharged, and stirring was continued for 4 h, during which the mixture reached
room temperature.
The reaction mixture was diluted with saturated aqueous NH Cl and
4
extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4)
and evaporated. Flash chromatography of the residue over silica gel (1 × 15 cm), using 1:3
–1
EtOAc–hexanes, gave 17 (58.2 mg, 74%) as a pale yellow oil: FTIR (CDCl , cast) 1655 cm ;
3
1
H NMR (CDCl , 500 MHz) δ (major isomer) 1.20 (d, J = 7.0 Hz, 3 H), 2.15 (s, 3 H), 2.42–3.05
3
1
3
(
(
(
m, 3 H), 3.25–3.34 (m, 1 H), 3.93 (s, 3 H); C NMR (CDCl , 125 MHz) δ (major isomer) 14.2
3
q), 19.6 (q), 31.0 (t), 31.5 (d), 54.5 (d), 56.3 (q), 99.7 (s), 169.0 (s), 187.3 (s); exact mass
7
2
9
+
electron ionization) m/z calcd for C H O BrS (M) 263.9819, found 263.9813.
9
13
5
-Methoxy-3-methyl-2-(methylsulfanyl)phenol (18). DBU (35.6 mg, 0.234 mmol) was
added to a stirred solution of 17 (31 mg, 0.117 mmol) in PhMe (1 mL). Stirring was continued
for 1 h and the reaction mixture was diluted with 5% hydrochloric acid and extracted with
EtOAc. The combined organic extracts were washed with brine, dried (MgSO ) and evaporated.
4
Flash chromatography of the residue over silica gel (1 × 15 cm), using 1:4 EtOAc-hexanes, gave
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5
6
–1
1
1
8 (19.6 mg, 91%) as a colorless oil: FTIR (CDCl , cast) 3374, 1608 cm ; H NMR (CDCl ,
3
3
500 MHz) δ 2.16 (s, 3 H), 2.48 (s, 3 H), 3.77 (s, 3 H), 6.40 (d, J = 3.0 Hz, 1 H), 6.43 (d, J = 3.0
13
Hz, 1 H), 7.14 (s, 1 H); C NMR (CDCl , 125 MHz) δ 18.7 (q), 20.9 (q), 55.2 (q), 97.3 (d),
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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8
9
0
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
08.7 (d), 111.4 (s), 144.1 (s), 158.2 (s), 161.2 (s); exact mass (electrospray) m/z calcd for
–
C H O S (M–H) 183.0485, found 183.0488.
9
11
2
2
-Bromo-3-methoxy-5-methyl-6-(phenylsulfanyl)cyclohex-2-en-1-one (19). n-BuLi
(2.5 M in hexanes, 0.13 mL, 0.325 mmol) was added dropwise to a stirred and cooled (–78 °C)
solution of i-Pr NH (0.05 mL, 0.357 mmol) in THF (2.0 mL). Stirring at –78 °C was continued
2
for 30 min and then a solution of 1 (65 mg, 0.297 mmol) in THF (1.5 mL) was added dropwise
over < 1 min. The cold bath was left in place, but not recharged, so that the temperature rose to
8b
0
°C over 2.5 h. The mixture was then recooled to –78 °C and a solution of TolSO SPh (123
2
mg, 0.442 mmol) in THF (1.5 mL) was added dropwise over < 1 min. The cold bath was left in
place, but not recharged, and stirring was continued for 3 h, during which the mixture reached
room temperature. The reaction mixture was diluted with saturated aqueous NH Cl and
4
extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4)
and evaporated. Flash chromatography of the residue over silica gel (1 × 15 cm), using 1:5
–
1
EtOAc–hexanes, gave 19 (67.8 mg, 70%) as a pale yellow oil: FTIR (CDCl , cast) 1664 cm ;
3
1
H NMR (CDCl , 500 MHz) δ (major isomer) 1.12 (d, J = 7.0 Hz, 3 H), 2.38–2.42 (m, 1 H),
3
2
.51–2.53 (m, 1 H), 3.18–3.22 (m, 1 H), 3.96–3.72 (m, 1 H), 4.18 (s, 3 H), 7.36–7.38 (m, 3 H),
13
7.46–7.48 (m, 2 H); C NMR (CDCl , 125 MHz) δ (major isomer) 19.4 (q), 33.0 (d), 39.5 (t),
3
5
0.7 (d), 56.6 (q), 104.8 (s), 128.9 (d), 129.6 (d), 132.5 (s), 132.8 (d), 167.1 (s), 189.5 (s); exact
79
2
+
mass (electron ionization) m/z calcd for C H O BrS (M) 325.9976, found 325.9973.
1
4
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-Methoxy-3-methyl-2-(phenylsulfanyl)phenol (20). DBU (61.6 mg, 0.405 mmol) was
added to a stirred solution of 19 (60.3 mg, 0.184 mmol) in PhMe (1 mL). Stirring was continued
for 2 h and the reaction mixture was diluted with 5% hydrochloric acid and extracted with
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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35
36
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EtOAc. The combined organic extracts were washed with brine, dried (MgSO ) and evaporated.
4
Flash chromatography of the residue over silica gel (0.8 × 10 cm), using 1:4 EtOAc-hexanes,
–1
1
gave 20 (39.5 mg, 87%) as a white solid: mp 102–104 °C; FTIR (CDCl , cast) 3359 cm ; H
3
NMR (CDCl , 500 MHz) δ 2.37 (s, 3 H), 3.78 (s, 3 H), 4.83 (br s, 1 H), 6.38 (d, J = 2.5 Hz, 1 H),
3
1
3
6
.44 (d, J = 2.5 Hz, 1 H), 6.96–6.98 (m, 2 H), 7.02–7.06 (m, 1 H), 7.15–7.18 (m, 2 H); C NMR
(
CDCl , 125 MHz) δ 21.4 (q), 56.2 (q), 97.4 (d), 109.7 (d), 110.2 (s), 124.4 (d), 125.5 (d), 128.6
3
(
d), 138.6 (s), 146.6 (s), 157.6 (s), 162.2 (s); exact mass (electrospray) m/z calcd for C H O S
1
4
13
2
–
(
M–H) 245.0642, found 245.0640. Anal. Calcd for C H O S: C, 68.26; H, 5.73; S, 13.02.
14 14 2
Found: C, 68.47; H, 5.73; S, 12.88.
2
-Bromo-3-methoxy-6-{[(4-methoxyphenyl)methyl]sulfanyl}-5-methylcyclohex-2-en-
-one (21). n-BuLi (2.5 M in hexanes, 0.13 mL, 0.325 mmol) was added dropwise to a stirred
and cooled (–78 °C) solution of i-Pr NH (0.05 mL, 0.357 mmol) in THF (2.0 mL). Stirring at –
1
2
78 °C was continued for 30 min and then a solution of 1 (65 mg, 0.297 mmol) in THF (1.5 mL)
was added dropwise over < 1 min. The cold bath was left in place, but not recharged, so that the
temperature rose to 0 °C over 3.5 h. The mixture was then recooled to –78 °C and a solution of
8c
TolSO SPmb (113 mg, 0.387 mmol) in THF (1.5 mL) was added dropwise over < 1 min. The
2
cold bath was left in place, but not recharged, and stirring was continued for 1 h, by which point
the temperature had risen to –20 °C. The reaction mixture was diluted with saturated aqueous
NH Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried
4
(MgSO ) and evaporated. Flash chromatography of the residue over silica gel (1 × 15 cm), using
4
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1
:3 EtOAc–hexanes, gave 21 (84.3 mg, 80%) as a colorless oil: FTIR (CDCl , cast) 1657, 1609
3
–
1 1
cm ; H NMR (CDCl , 400 MHz) δ (major isomer) 1.12 (d, J = 6.8 Hz, 3 H), 2.32–2.57 (m, 2
3
H), 2.93–2.99 (m, 1 H), 3.21–3.28 (m, 1 H), 3.68–3.84 (m, 5 H), 3.91 (s, 3 H), 6.82–6.85 (m, 2
0
1
2
3
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5
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9
0
1
2
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4
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
H), 7.29–7.32 (m, 2 H); C NMR (CDCl , 125 MHz) δ (major isomer) 19.7 (q), 31.1 (t), 31.9 (d),
3
3
4.1 (t), 51.5 (d), 55.3 (q), 56.4 (q), 99.9 (s), 113.8 (d), 129.4 (s), 130.4 (d), 158.7 (s), 169.1 (s),
79
+
1
87.7 (s); exact mass (electrospray) m/z calcd for C H O BrS (M+H) 371.0311, found
16 20 3
371.0309.
5
-Methoxy-2-{[(4-methoxyphenyl)methyl]sulfanyl}-3-methylphenol (22). DBU (50.9
mg, 0.335 mmol) was added to a stirred solution of 21 (58.0 mg, 0.163 mmol) in PhMe (1 mL).
Stirring was continued for 2 h and the reaction mixture was diluted with 5% hydrochloric acid
and extracted with EtOAc. The combined organic extracts were washed with brine, dried
(
MgSO ) and evaporated. Flash chromatography of the residue over silica gel (0.8 × 10 cm),
4
using 1:4 EtOAc-hexanes, gave 22 (36.7 mg, 82%) as a white solid: mp 48–50 °C; FTIR
–
1 1
(
(
(
CDCl , cast) 3377, 1614 cm ; H NMR (CDCl , 500 MHz) δ 2.25 (s, 3 H), 3.67 (s, 2 H), 3.77
3
3
s, 3 H), 3.78 (s, 3 H), 6.35 (dd, J = 3.0, 0.5 Hz, 1 H), 6.38 (dd, J = 3.0, 0.5 Hz, 1 H), 6.77–6.78
13
m, 2 H), 6.93 (s, 1 H), 6.97–6.99 (m, 2 H); C NMR (CDCl , 125 MHz) δ 21.1 (q), 39.7 (t),
3
55.2 (q), 55.3 (q), 97.2 (d), 108.6 (d), 109.4 (s), 113.9 (d), 129.7 (s), 129.9 (d), 144.9 (s), 158.7
–
(
s), 158.9 (s), 161.4 (s); exact mass (electrospray) m/z calcd for C H O S (M–H) 289.0904,
1
6
17
3
found 289.0902.
2
-Bromo-3-methoxy-5-methyl-6-(phenylselenyl)cyclohex-2-en-1-one (23).
n-BuLi
(
2.5 M in hexanes, 0.13 mL, 0.325 mmol) was added dropwise to a stirred and cooled (–78 °C)
solution of i-Pr NH (0.05 mL, 0.357 mmol) in THF (2.0 mL). Stirring at –78 °C was continued
2
for 30 min and then a solution of 1 (65 mg, 0.297 mmol) in THF (2.0 mL) was added dropwise
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over < 1 min. The cold bath was left in place, but not recharged, so that the temperature rose to
0
°C over 2.5 h. The mixture was then recooled to –78 °C and a solution of PhSeCl (113 mg,
.590 mmol) in THF (2.0 mL) was added dropwise over < 1 min. The cold bath was left in place,
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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37
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
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58
59
60
but not recharged, and stirring was continued for 4 h, during which the mixture reached room
temperature. The reaction mixture was diluted with saturated aqueous NH Cl and extracted with
4
EtOAc. The combined organic extracts were washed with brine, dried (MgSO ) and evaporated.
4
Flash chromatography of the residue over silica gel (1 × 15 cm), using 1:3 EtOAc–hexanes, gave
23 [72.1 mg, 65%, or 82% corrected for recovered 1 (11.1 mg)]) as a pale yellow oil: FTIR
–
1 1
(
CDCl , cast) 1657 cm ; H NMR (CDCl , 500 MHz) δ (major isomer) 1.17 (d, J = 7.0 Hz, 3 H),
3
3
1
3
2.42–3.01 (m, 3 H), 3.87–3.91 (m, 4 H), 7.26–7.33 (m, 3 H), 7.59–7.61 (m, 2 H); C NMR
CDCl , 125 MHz) δ (major isomer) 19.9 (q), 31.2 (t), 32.4 (d), 52.0 (d), 56.4 (q), 100.7 (s),
(
3
127.6 (s), 128.6 (d), 129.2 (d), 135.5 (d), 171.1 (s), 187.5 (s); exact mass (electron ionization)
79
80
+
m/z calcd for C H O Br Se (M) 373.9421, found 373.9420.
1
4
15
2
5
-Methoxy-3-methyl-2-(phenylselenyl)phenol (24). DBU (45 mg, 0.296 mmol) was
added to a stirred solution of 23 (50.3 mg, 0.134 mmol) in PhMe (1 mL). Stirring was continued
for 8 h and the reaction mixture was diluted with 5% hydrochloric acid and extracted with
EtOAc. The combined organic extracts were washed with brine, dried (MgSO ) and evaporated.
4
Flash chromatography of the residue over silica gel (0.8 × 10 cm), using 1:10 EtOAc-hexanes,
–
1
gave 24 (33.3 mg, 84%) as a white solid: mp 74–76 °C; FTIR (CDCl , cast) 3384, 1602 cm ;
3
1
H NMR (CDCl , 500 MHz) δ 2.41 (s, 3 H), 3.81 (s, 3 H), 6.49 (d, J = 3.0 Hz, 1 H), 6.52 (d, J =
3
1
3
3
.0 Hz, 1 H), 6.79 (s, 1 H), 7.12–7.21 (m, 5 H); C NMR (CDCl , 125 MHz) δ 23.6 (q), 55.3 (q),
3
97.3 (d), 107.1 (s), 109.1 (d), 126.4 (d), 128.5 (d), 129.4 (d), 131.1 (s), 145.2 (s), 158.4 (s), 162.3
80
–
(
s); exact mass (electrospray) m/z calcd for C H O Se (M–H) 293.0086, found 293.0091. A
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
sample was recrystallized from hexane for combustion analysis. Anal. Calcd for C H O Se: C,
1
4
14
2
5
7.37; H, 4.81. Found: C, 57.25; H, 4.82. Another sample was crystallized from hexane-
CH Cl for X-ray analysis (see Supporting Information).
2
2
0
1
2
3
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0
2
-Bromo-6-hydroxy-3-methoxy-5-methylcyclohex-2-en-1-one (25). n-BuLi (2.5 M in
hexanes, 0.26 mL, 0.65 mmol) was added dropwise to a stirred and cooled (–78 °C) solution of i-
Pr NH (0.10 mL, 0.713 mmol) in THF (3.0 mL). Stirring at –78 °C was continued for 30 min
2
and then a solution of 1 (130 mg, 0.594 mmol) in THF (3.0 mL) was added dropwise over < 1
min. The cold bath was left in place, but not recharged, so that the temperature rose to 0 °C over
3
.5 h. The mixture was then recooled to –78 °C and a solution of 2-(4-methylbenzenesulfonyl)-
11
3
-phenyloxaziridine) (250 mg, 0.909 mmol) in THF (3.0 mL) was added dropwise over < 1
min. The cold bath was left in place, but not recharged, and stirring was continued for 4 h,
during which the mixture reached room temperature. The reaction mixture was diluted with
saturated aqueous NaHCO and extracted with EtOAc. The combined organic extracts were
3
washed with brine, dried (MgSO ) and evaporated. Flash chromatography of the residue over
4
silica gel (1 × 15 cm), using 1:1 EtOAc-hexanes, gave 25 (103.3 mg, 74%) as a colorless oil:
–1 1
FTIR (CDCl , cast) 3346, 1666 cm ; H NMR (CDCl , 500 MHz) δ 1.00 (d, J = 7.0 Hz, 3 H),
3
3
2
.71–2.75 (m, 2 H), 2.92 (dd, J = 18.0, 5.5 Hz, 1 H), 3.75 (br s, 1 H), 3.99 (s, 3 H), 4.31 (d, J =
1
3
5.0 Hz, 1 H); C NMR (CDCl , 125 MHz) δ 11.9 (q), 32.4 (d), 32.6 (t), 56.6 (q), 74.5 (d), 97.8
3
79
–
(
s), 171.1 (s), 191.9 (s); exact mass (electrospray) m/z calcd for C H O Br (M–H) 232.9819,
8 10 3
found 232.9816.
2
-Bromo-3-methoxy-5-methyl-6-(oxan-2-yloxy)cyclohex-2-en-1-one (26).
3,4-
Dihydropyran (20 mg, 0.208 mmol) and pyridinium p-toluenesulfonate (0.8 mg, 0.0032 mmol)
were added to a stirred solution of 25 (40.1 mg, 0.171 mmol) in CH Cl (2 mL). Stirring was
2
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continued for 5 h and the reaction mixture was then diluted with saturated aqueous NaHCO and
3
extracted with CH Cl . The combined organic extracts were washed with brine, dried (MgSO )
2
2
4
1
and evaporated to give 26 (55.9 mg, ca 99%) as an oil that was a mixture of isomers ( H NMR)
which was used directly in the next step.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-Methoxy-3-methyl-2-(oxan-2-yloxy)phenol (27). DBU (111 mg, 0.730 mmol) was
added to a stirred solution of 26 (55.9 mg, ca 0.171 mmol) in PhMe (1 mL). Stirring was
continued overnight and the reaction mixture was diluted with ice-cold saturated aqueous NH Cl
4
and extracted with EtOAc. The combined organic extracts were washed with brine, dried
(
MgSO ) and evaporated. Flash chromatography of the residue over silica gel (0.8 × 10 cm),
4
using 1:10 EtOAc-hexanes, gave 27 (37.9 mg, 89%) as a colorless, thick oil: FTIR (CDCl , cast)
3
–1
1
3
1
6
3
327, 1620 cm ; H NMR (CDCl , 500 MHz) δ 1.55–2.06 (m, 6 H), 2.19 (s, 3 H), 3.55–3.60 (m,
3
H), 3.73 (s, 3 H), 4.14–4.16 (m, 1 H), 4.64 (dd, J = 8.5, 2.5 Hz, 1 H), 6.24 (d, J = 2.5 Hz, 1 H),
1
3
.38 (d, J = 3.0 Hz, 1 H), 7.91 (s, 1 H); C NMR (CDCl , 125 MHz) δ 16.6 (q), 21.4 (t), 24.7 (t),
3
1.4 (t), 55.4 (q), 66.4 (t), 100.1 (d), 104.9 (d), 107.2 (d), 132.0 (s), 138.1 (s), 150.3 (s), 156.7 (s);
–
exact mass (electrospray) m/z calcd for C H O (M–H) 237.1132, found 237.1130.
1
3
17
4
2
-Bromo-6-hydroxycyclohex-2-en-1-one (28). n-BuLi (2.5 M in hexanes, 0.21 mL,
0
.525 mmol) was added dropwise to a stirred and cooled (–78 °C) solution of i-Pr NH (0.09 mL,
2
0.642 mmol) in THF (3.0 mL). Stirring at –78 °C was continued for 30 min and then a solution
6b
of 2-bromocyclohex-2-en-1-one (85.2 mg, 0.487 mmol) in THF (3.0 mL) was added dropwise
over < 1 min.
Stirring at –78 °C was continued for 1 h and oxaziridine 2-(4-
11
methylbenzenesulfonyl)-3-phenyloxaziridine) (102 mg, 0.584 mmol) in THF (3.0 mL) was
added dropwise over < 1 min. The cold bath was left in place, but not recharged, and stirring
was continued for 4 h, during which the mixture reached room temperature. The reaction
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mixture was diluted with saturated aqueous NH Cl and extracted with EtOAc. The combined
4
organic extracts were washed with ice-cold aqueous 0.1%w/v NaOH and brine, dried (MgSO4)
and evaporated. Flash chromatography of the residue over silica gel (1 × 15 cm), using 1:3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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2
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4
5
6
7
8
9
0
–
1 1
EtOAc–hexanes, gave 28 (73.4 mg, 79%) as a colorless oil: FTIR (CDCl , cast) 3482 cm ; H
3
NMR (CDCl , 500 MHz) δ 1.94–2.04 (m, 1 H), 2.40–2.46 (m, 1 H), 2.55–2.58 (m, 2 H), 3.57 (d,
3
13
J = 2.0 Hz, 1 H), 4.30 (ddd, J = 13.5, 5.5, 1.5 Hz, 1 H), 7.40–7.42 (m, 1 H); C NMR (CDCl ,
3
125 MHz) δ 26.7 (t), 30.7 (t), 73.3 (d), 120.2 (s), 152.2 (d), 193.9 (s); exact mass (electron
79
+
ionization) m/z calcd for C H O Br (M) 189.9629, found 189.9629.
6
7
2
1
5
Benzene-1,2-diol (29). DBU (120 mg, 0.789 mmol) was added to a stirred solution of
2
8 (69.9 mg, 0.366 mmol) in PhMe (1 mL). Stirring was continued overnight and the reaction
mixture was diluted with a few (5—6) drops of AcOH. The PhMe and excess of AcOH were
evaporated, and flash chromatography of the residue over silica gel (0.8 × 10 cm), using 1:1
1
EtOAc-hexanes, gave 29 (37.4 mg, 93%) as an off-white solid: mp 102–104 °C; H NMR
1
3
(CDCl , 500 MHz) δ 5.09 (s, 2 H), 6.81–6.83 (m, 2 H), 6.87–6.88 (m, 2 H); C NMR (CDCl ,
3
3
1
25 MHz) δ 115.5 (d), 121.3 (d), 143.5 (s).
2
-Bromo-6-[hydroxy(phenyl)methyl]-3-methoxy-5-methylcyclohex-2-en-1-one (30).
n-BuLi (2.5 M in hexanes, 0.26 mL, 0.650 mmol) was added dropwise to a stirred and cooled (–
8 °C) solution of i-Pr NH (0.10 mL, 0.714 mmol) in THF (3.0 mL). Stirring at –78 °C was
7
2
continued for 30 min and then a solution of 1 (131 mg, 0.598 mmol) in THF (3.0 mL) was added
dropwise over < 1 min. The cold bath was left in place, but not recharged, so that the
temperature rose to 0 °C over 3.5 h. The mixture was then recooled to –78 °C and PhCHO (0.24
mL, 2.39 mmol) was added dropwise over < 1 min. Stirring was continued for 20 min at –78 °C.
A solution of AcOH in THF (1 N, 0.65 mL) was added and the solvent was evaporated. The
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residue was partitioned between water and EtOAc and the combined organic extracts were
washed with brine, dried (MgSO ) and evaporated. Flash chromatography of the residue over
4
silica gel (1 × 15 cm), using 1:3 EtOAc–hexanes, gave 30 (143 mg, 87%) as a white solid: FTIR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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32
33
34
35
36
37
38
39
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
–
1 1
(
CDCl , cast) 3438, 1652 cm ; H NMR (CDCl , 500 MHz) δ (major isomer) 1.07 (d, J = 7.0 Hz,
3
3
3
7
H), 2.03–2.40 (m, 2 H), 2.66–2.90 (m, 2 H), 3.16 (br s, 1 H), 3.94 (s, 3 H), 4.81–5.08 (m, 1 H),
13
.26–7.37 (m, 5 H); C NMR (CDCl , 125 MHz) δ (major isomer) 20.6 (q), 28.0 (d), 31.8 (t),
3
56.4 (d), 59.5 (q), 74.7 (d), 101.4 (s), 126.5 (d), 128.1 (d), 128.7 (d), 141.7 (s), 171.2 (s), 192.6
79
+
(
s); exact mass (electron ionization) m/z calcd for C H O Br (M) 324.0361, found 324.0356.
15 17 3
2
-[Hydroxy(phenyl)methyl]-5-methoxy-3-methylphenol (31). DBU (0.10 mL, 0.696
mmol) was added to a stirred solution of 30 (113 mg, 0.348 mmol) in PhMe (1.5 mL). Stirring
was continued overnight and the reaction mixture was diluted with 5% hydrochloric acid and
extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4)
and evaporated. Flash chromatography of the residue over silica gel (1 × 10 cm), using 1:4
EtOAc-hexanes, gave 31 (74.6 mg, 88%) as a white solid: mp 113–115 °C; FTIR (CDCl , cast)
3
–1 1
3
3
7
1
319, 1623 cm ; H NMR (CDCl , 500 MHz) δ 2.15 (s, 3 H), 2.72 (d, J = 3.0 Hz, 1 H), 3.77 (s,
3
H), 6.17 (d, J = 2.5 Hz, 1 H), 6.29 (dd, J = 2.5, 1.0 Hz, 1 H), 6.38 (d, J = 2.5 Hz, 1 H), 7.30–
1
3
.37 (m, 5 H), 8.59 (s, 1 H); C NMR (CDCl , 125 MHz) δ 19.9 (q), 55.2 (q), 74.6 (d), 100.7 (d),
3
08.6 (d), 116.4 (s), 127.1 (d), 128.3 (d), 128.8 (d), 136.8 (s), 141.2 (s), 157.7 (s), 160.1 (s);
–
exact mass (electrospray) m/z calcd for C H O (M–H) 243.1027, found 243.1026. A sample
1
5
15
3
was recrystallized from hexane for combustion analysis. Anal. Calcd for C H O : C, 73.75; H,
1
5
16
3
6
.60. Found: C, 73.38; H, 6.56.
N-[(3-Bromo-4-methoxy-6-methyl-2-oxocyclohex-3-en-1-yl)(phenyl)methyl]-4-
methylbenzene-1-sulfonamide (32). n-BuLi (2.5 M in hexanes, 0.26 mL, 0.650 mmol) was
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added dropwise to a stirred and cooled (–78 °C) solution of i-Pr NH (0.10 mL, 0.714 mmol) in
2
THF (3.0 mL). Stirring at –78 °C was continued for 30 min and then a solution of 1 (130 mg,
0
.598 mmol) in THF (3.0 mL) was added dropwise over < 1 min. The cold bath was left in place,
0
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2
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4
5
6
7
8
9
0
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2
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8
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2
3
4
5
6
7
8
9
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2
3
4
5
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9
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but not recharged, so that the temperature rose to 0 °C over 3.5 h. The mixture was then
1
0
recooled to –78 °C and a solution of N-(toluenesulfonyl)benzaldimine (300 mg, 1.16 mmol) in
THF (2.0 mL) was added dropwise over < 1 min. The cold bath was left in place, but not
recharged, and stirring was continued for 1 h, by which point the temperature had risen to –20 °C.
The reaction mixture was diluted with saturated aqueous NaHCO and extracted with EtOAc.
3
The combined organic extracts were washed with brine, dried (MgSO ) and evaporated. Flash
4
chromatography of the residue over silica gel (1 × 15 cm), using 1:1 EtOAc–hexanes, gave 32
–
1 1
(
218.5 mg, 77%) as a colorless oil: FTIR (CDCl , cast) 3358, 1657 cm ; H NMR (CDCl , 500
3
3
MHz) δ (major isomer) 1.26 (d, J = 6.5 Hz, 3 H), 2.41–2.39 (m, 5 H), 2.57 (dd, J = 8.5, 5.0 Hz, 1
H), 2.83 (dd, J = 8.5, 5.0 Hz, 1 H), 3.94 (s, 3 H), 4.67 (dd, J = 8.0, 5.0 Hz, 1 H), 5.78 (d, J = 8.0
13
Hz, 1 H), 7.04–7.11 (m, 7 H), 7.44–7.45 (m, 2 H); C NMR (CDCl , 125 MHz) δ (major isomer)
3
19.9 (q), 21.4 (q), 29.3 (d), 33.3 (t), 56.4 (d), 56.5 (q), 58.9 (d), 101.6 (s), 126.9 (d), 127.0 (d),
1
27.1 (d), 128.2 (d), 129.2 (d), 137.6 (s), 139.5 (s), 142.9 (s), 171.4 (s), 191.4 (s); exact mass
7
9
+
(
electrospray) m/z calcd for C H O BrNS (M+H) 478.0682, found 478.0687.
22 25 4
N-[(2-hydroxy-4-methoxy-6-methylphenyl)(phenyl)methyl]-4-methylbenzene-1-
sulfonamide (33). DBU (148 mg, 0.966 mmol) was added to a stirred solution of 32 (210 mg,
.439 mmol) in PhMe (3 mL). Stirring was continued overnight and the reaction mixture was
0
diluted with 5% hydrochloric acid and extracted with EtOAc. The combined organic extracts
were washed with brine, dried (MgSO ) and evaporated. Flash chromatography of the residue
4
over silica gel (1 × 10 cm), using 1:5 EtOAc-hexanes, gave 33 (147 mg, 84%) as a white solid:
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–1
1
mp 58–60 °C; FTIR (CDCl , cast) 3326, 1614 cm ; H NMR (CDCl , 500 MHz) δ 2.11 (s, 3 H),
3
3
2.32 (s, 3 H), 3.69 (s, 3 H), 5.68 (s, 1 H), 5.76 (d, J = 9.5 Hz, 1 H), 6.00 (d, J = 2.5 Hz, 1 H), 6.17
(
d, J = 2.5 Hz, 1 H), 6.25 (d, J = 9.5 Hz, 1 H), 7.04 (d, J = 8.0 Hz, 2 H), 7.22–7.26 (m, 5 H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
7
.52–7.54 (m, 2 H); C NMR (CDCl , 125 MHz) δ 20.1 (q), 21.4 (q), 55.2 (q), 55.4 (d), 100.5
3
(
d), 108.4 (d), 117.0 (s), 126.6 (d), 126.8 (d), 127.3 (d), 128.4 (d), 129.1 (d), 137.2 (s), 138.3 (s),
1
40.1 (s), 142.9 (s), 154.3 (s), 159.6 (s); exact mass (electrospray) m/z calcd for C H NO S
2
2
22
4
–
(M–H) 396.1275, found 396.1282.
-Bromo-6-(1-hydroxyundec-10-en-1-yl)-3-methoxy-5-methylcyclohex-2-en-1-one
34). n-BuLi (2.5 M in hexanes, 0.13 mL, 0.325 mmol) was added dropwise to a stirred and
2
(
cooled (–78 °C) solution of i-Pr NH (0.05 mL, 0.357 mmol) in THF (1.5 mL). Stirring at –78 °C
2
was continued for 30 min and then a solution of 1 (65 mg, 0.298 mmol) in THF (1.5 mL) was
added dropwise over < 1 min. The cold bath was left in place, but not recharged, so that the
temperature rose to 0 °C over 4.5 h. The mixture was then recooled to –78 °C and a solution of
undec-10-enal (74.8 mg, 0.445 mmol) in THF (1.5 mL) was added dropwise over < 1 min. The
cold bath was left in place, and stirring at –78 °C was continued for 10 min. A solution of AcOH
in THF (1 N, 0.33 mL) was added and the solvent was evaporated. The residue was partitioned
between water and EtOAc and the combined organic extracts were washed with brine, dried
(MgSO ) and evaporated. Flash chromatography of the residue over silica gel (1 × 15 cm), using
4
1
:3 EtOAc–hexanes, gave 34 [79.3 mg, 69% or 92% corrected for recovered 1 (14.8 mg)] as a
–
1 1
colorless oil: FTIR (CDCl , cast) 3485, 1653 cm ; H NMR (CDCl , 500 MHz) δ 1.18 (d, J =
3
3
6
.4 Hz, 3 H), 1.25–1.79 (m, 14 H), 2.00–2.24 (m, 4 H), 2.36–2.43 (m, 2 H), 2.87–2.90 (m, 1 H),
1
3
3
.82 (br s, 1 H), 3.94 (s, 3 H), 4.90–5.00 (m, 2 H), 5.75–5.85 (m, 1 H); C NMR (CDCl , 125
3
MHz) δ 20.3 (q), 26.1 (t), 28.9 (t), 29.1 (t), 29.4 (t), 29.5 (t), 29.6 (t), 29.9 (d), 33.8 (t), 33.8 (t),
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
6.4 (t), 56.3 (d), 57.2 (q), 71.4 (d), 102.3 (s), 114.1 (t), 139.2 (d), 171.4 (s), 192.7 (s); exact
79
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+
mass (electron ionization) m/z calcd for C H O Br (M) 386.1456, found 386.1450.
19 31
2
-(1-Hydroxyundec-10-en-1-yl)-5-methoxy-3-methylphenol (35). DBU (17.8 mg,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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2
3
4
5
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7
8
9
0
0
.117 mmol) was added to a stirred solution of 34 (22.7 mg, 0.0587 mmol) in PhMe (2 mL).
Stirring was continued overnight and the reaction mixture was diluted with 5% hydrochloric acid
and extracted with EtOAc. The combined organic extracts were washed with brine, dried
(
MgSO ) and evaporated. Flash chromatography of the residue over silica gel (0.8 × 10 cm),
4
using 1:4 EtOAc-hexanes, gave 35 (14.3 mg, 80%) as a thick oil: FTIR (CDCl , cast) 3435,
3
–1 1
3
177, 1627 cm ; H NMR (CDCl , 500 MHz) δ 1.26–1.37 (m, 12 H), 1.62–1.72 (m, 1 H), 1.88–
3
2.60 (m, 3 H), 2.19 (s, 3 H), 2.36 (d, J = 3.0 Hz, 1 H), 3.75 (s, 3 H), 4.92–5.00 (m, 2 H), 5.08–
.10 (m, 1 H), 5.78–5.84 (m, 1 H), 6.24 (d, J = 2.5 Hz, 1 H), 6.32 (d, J = 2.5 Hz, 1 H), 8.49 (s, 1
5
1
3
H); C NMR (CDCl , 125 MHz) δ 19.8 (q), 26.0 (t), 28.9 (t), 29.1 (t), 29.4 (t), 29.4 (t), 29.5 (t),
3
3
3.8 (t), 36.3 (t), 55.2 (q), 72.7 (d), 100.6 (d), 108.3 (d), 114.1 (t), 118.3 (s), 135.8 (s), 139.2 (d),
–
1
57.5 (s), 159.6 (s); exact mass (electrospray) m/z calcd for C H O (M–H) 305.2122, found
1
9
29
3
305.2123.
2
-Bromo-6-(phenylsulfanyl)cyclohex-2-en-1-one (36). n-BuLi (2.5 M in hexanes, 0.26
mL, 0.650 mmol) was added dropwise to a stirred and cooled (–78 °C) solution of i-Pr NH (0.10
2
mL, 0.714 mmol) in THF (3.0 mL). Stirring at –78 °C was continued for 30 min and then a
6b
solution of 2-bromocyclohex-2-enone (96 mg, 0.548 mmol) in THF (3.0 mL) was added
dropwise over < 1 min. The cold bath was left in place, but not recharged, so that the
temperature rose to 0 °C over 3.5 h. The mixture was then recooled to –78 °C and PhCHO (0.24
mL, 2.39 mmol) was added dropwise over < 1 min. The cold bath was left in place, but not
recharged, and stirring was continued for 4 h, during which the mixture reached room
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temperature. The reaction mixture was diluted with saturated aqueous NH Cl and extracted with
4
EtOAc. The combined organic extracts were washed with brine, dried (MgSO ) and evaporated.
4
Flash chromatography of the residue over silica gel (1 × 15 cm), using 1:8 EtOAc–hexanes, gave
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
–
1 1
3
6 (139.5 mg, 90%) as a colorless oil: FTIR (CDCl , cast) 1684 cm ; H NMR (CDCl , 500
3
3
MHz) δ 2.28–2.32 (m, 1 H), 2.46–2.49 (m, 2 H), 2.71–2.77 (m, 1 H), 4.04 (dd, J = 4.5 Hz, 1 H),
1
3
7
.32–7.37 (m, 4 H), 7.48–7.50 (m, 2 H); C NMR (CDCl , 125 MHz) δ 25.9 (t), 28.7 (t), 53.2
3
(d), 122.1 (s), 128.4 (d), 129.2 (d), 132.2 (s), 133.5 (d), 149.5 (d), 186.9 (s); exact mass (electron
79
+
ionization) m/z calcd for C H O BrS (M) 281.9714, found 281.9716.
12
11
1
6
2
-(Phenylsulfanyl)phenol (37).
DBU (89 mg, 0.585 mmol) was added to a stirred
solution of 36 (83.4 mg, 0.293 mmol) in PhMe (2 mL). Stirring was continued for 30 min and
the reaction mixture was diluted with 5% hydrochloric acid and extracted with EtOAc. The
combined organic extracts were washed with brine, dried (MgSO ) and evaporated. Flash
4
chromatography of the residue over silica gel (0.8 × 10 cm), using 1:15 EtOAc-hexanes, gave 37
–1 1
(
50.3 mg, 84%) as a pale yellow oil: FTIR (CDCl , cast) 3424, 1595 cm ; H NMR (CDCl ,
3
3
5
00 MHz) δ 6.50 (s, 1 H), 6.96 (ddd, J = 7.5, 1.5 Hz, 1 H), 7.06–7.10 (m, 3 H), 7.14–7.17 (m, 1
1
3
H), 7.22–7.25 (m, 3 H), 7.36–7.40 (m, 1 H), 7.53 (dd, J = 7.5 Hz, 1.5 Hz, 1 H); C NMR
(
CDCl , 125 MHz) δ 115.6 (d), 116.3 (s), 121.3 (d), 126.2 (d), 126.9 (d), 129.2 (d), 132.3 (d),
3
–
1
35.9 (s), 136.9 (d), 157.3 (s); exact mass (electrospray) m/z calcd for C H OS (M–H)
12 9
201.0380, found 201.0387.
2
-Bromo-6-fluoro-3-methoxy-5-methylcyclohex-2-en-1-one (38) and 2-Bromo-4,6-
difluoro-3-methoxy-5-methylcyclohex-2-en-1-one (40). n-BuLi (2.5 M in hexanes, 0.26 mL,
0.65 mmol) was added dropwise to a stirred and cooled (–78 °C) solution of i-Pr NH (0.10 mL,
2
0
.713 mmol) in THF (3.0 mL). Stirring at –78 °C was continued for 30 min and then a solution
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2
2
2
2
2
2
2
2
2
3
3
3
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3
3
3
3
3
3
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
of 1 (130 mg, 0.594 mmol) in THF (3.0 mL) was added dropwise over < 1 min. The cold bath
was left in place, but not recharged, so that the temperature rose to 0 °C over 3.5 h. The mixture
was then recooled to –78 °C and a solution of commercial N-fluorobenzenesulfonimide (196 mg,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
.622 mmol) in THF (3.0 mL) was added dropwise over < 1 min. The cold bath was left in place,
but not recharged, and stirring was continued for 4 h, during which the mixture reached room
temperature. The reaction mixture was diluted with saturated aqueous NaHCO and extracted
3
with EtOAc. The combined organic extracts were washed with brine, dried (MgSO ) and
4
evaporated. Flash chromatography of the residue over silica gel (1 × 15 cm), using 1:3 EtOAc–
hexanes, gave 38 (105 mg, 75%) and 40 (12 mg, 8%) as colorless oils: Compound 38 had:
–
1 1
FTIR (CDCl , cast) 1677 cm ; H NMR (CDCl , 500 MHz) δ 1.22 and 1.29 (d, J = 7.0 Hz,
3
3
integration together 3 H), 2.37–2.96 (m, 3 H), 3.98 and 3.99 (s, integration together 3 H), 4.59
13
(
dd, J = 48.5, 11.5 Hz) and 4.82 (dd, J = 49.5, 3.0 Hz) integration together 1 H; C NMR
(
CDCl , 125 MHz) δ (major isomer) 14.6 (q), 30.8 (t), 32.3 (d), 56.7 (q), 91.1 (d), 100.2 (s),
3
7
9
+
1
71.9 (s), 185.6 (s); exact mass (electron ionization) m/z calcd for C H O BrF (M) 235.9848,
8 10 2
–
1
1
found 235.9852; Compound 40 had: FTIR (CDCl , cast) 1698 cm ; H NMR (CDCl , 500
3
3
MHz) δ (major isomer) 1.13 (d, J = 7.0 Hz, 3 H), 2.54–3.00 (m, 1 H), 4.12 (s, 3 H), 4.91–5.41 (m,
13
2 H); the C NMR (CDCl , 125 MHz) was too complicated to be informative; exact mass
3
7
9
+
(electron ionization) m/z calcd for C H O BrF (M) 253.9754, found 253.9753.
8 9 2 2
2
-Fluoro-5-methoxy-3-methylphenol (39). DBU (98 mg, 0.644 mmol) was added to a
stirred solution of 38 (75.4 mg, 0.318 mmol) in PhMe (1.5 mL). Stirring was continued
overnight and the reaction mixture was diluted with 5% hydrochloric acid and extracted with
EtOAc. The combined organic extracts were washed with brine, dried (MgSO ) and evaporated.
4
Flash chromatography of the residue over silica gel (1 × 15 cm), using 1:5 EtOAc-hexanes, gave
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7
1
2
3
4
5
6
7
8
9
–1
1
3
9 (43.5 mg, 88%) as a colorless, thick oil: FTIR (CDCl , cast) 3390, 1604 cm ; H NMR
3
(CDCl , 500 MHz) δ 2.24 (tt, J = 2.5, 0.5 Hz, 3 H), 3.73 (s, 3 H), 5.02 (br s, 1 H), 6.23–6.25 (m,
3
13
2
1
H), 6.39–6.41 (m, 2 H); C NMR (CDCl , 125 MHz) δ 14.6 (q), 55.6 (q), 100.2 (d), 107.4 (d),
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
25.4 (s), 143.7 (s), 145.5 (s), 155.6 (s); exact mass (electrospray) m/z calcd for C H O F (M–
8
8
2
–
H) 155.0514, found 155.0514.
,4-Difluoro-5-methoxy-3-methylphenol (41). DBU (50.6 mg, 0.333 mmol) was added
2
to a stirred solution of 40 (42.4 mg, 0.166 mmol) in PhMe (1 mL). Stirring was continued
overnight and the reaction mixture was diluted with 5% hydrochloric acid and extracted with
EtOAc. The combined organic extracts were washed with brine, dried (MgSO ) and evaporated.
4
Flash chromatography of the residue over silica gel (1 × 15 cm), using 1:5 EtOAc-hexanes, gave
–1
1
4
1 (24.4 mg, 84%) as a colorless, thick oil: FTIR (CDCl , cast) 3429, 1613 cm ; H NMR
3
(CDCl , 500 MHz) δ 2.21 (t, J = 2.5 Hz, 3 H), 3.82 (s, 3 H), 4.86 (br s, 1 H), 6.50 (t, J = 10.0 Hz,
3
13
1
H); C NMR (CDCl , 125 MHz) δ 7.6 (q), 56.7 (q), 99.4 (d), 114.1 (s), 138.9 (s), 142.1 (s),
3
–
143.9 (s), 145.3 (s); exact mass (electrospray) m/z calcd for C H O F (M–H) 173.0420, found
8
7
2 2
1
73.0419.
2
-Bromo-4-{[(4-methoxyphenyl)methyl]sufanyl}-5-methylcyclohex-2-en-1-one (45).
DIBAL-H (1.0 M in hexanes, 0.21 mL) was added over < 1 min to a stirred solution of 21 (74.0
mg, 0.20 mmol) in toluene at 0 °C. The mixture was stirred for 5 min, diluted at 0 °C with 3 N
hydrochloric acid, stirred for 5 min and extracted with EtOAc. The combined organic extracts
were washed with brine, dried (MgSO ) and evaporated. Flash chromatography of the residue
4
over silica gel (0.8 × 12 cm), using 1:4 EtOAc-hexanes, gave 45 (64.4 mg, 95%) as a colorless,
–
1 1
thick oil: FTIR (CDCl , cast) 1678 cm ; H NMR (CDCl , 500 MHz) δ (major isomer) 1.11 (d,
3
3
J = 7.0 Hz, 3 H), 2.65–2.39 (m, 1 H), 2.49–2.92 (m, 2 H), 3.12–3.36 (m, 1 H), 3.78 (s, 2 H), 3.81
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1
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
(
s, 3 H), 6.86–6.89 (m, 2 H), 7.18–7.26 (m, 3 H); C NMR (CDCl , 125 MHz) δ (major isomer)
3
19.2 (q), 34.9 (d), 35.3 (t), 43.6 (t), 48.9 (d), 55.3 (q), 114.2 (d), 123.4 (s), 129.1 (s), 130.1 (d),
8
1
+
1
49.3 (d), 159.1 (s), 190.5 (s); exact mass (electron ionization) m/z calcd for C H O S Br (M)
15 17 2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
42.0112, found 342.0111.
4-{[(4-Methoxyphenyl)methyl]sulfanyl}-3-methylphenol (46). DBU (57.2 mg, 0.376
mmol) was added to a stirred solution of 45 (60.3 mg, 0.184 mmol) in PhMe (1 mL). Stirring
was continued for 30 min and the reaction mixture was diluted with aqueous NH Cl and
4
extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4)
and evaporated. Flash chromatography of the residue over silica gel (0.8 × 12 cm), using 1:4
EtOAc-hexanes, gave 46 (41.6 mg, 91%) as a white solid: mp 81–83 °C; FTIR (CDCl , cast)
3
–1
1
3
397, 1609 cm ; H NMR (CDCl , 500 MHz) δ 2.28 (s, 3 H), 3.78 (s, 3 H), 3.87 (s, 2 H), 4.68
3
(br s, 1 H), 6.58 (ddd, J = 10.5, 3.5, 0.5 Hz, 1 H), 6.67 (dd, J = 3.5, 0.5 Hz, 1 H), 6.77–6.79 (m, 2
13
H), 7.06–7.08 (m, 2 H), 7.19 (d, J = 10.5 Hz, 1 H); C NMR (CDCl , 125 MHz) δ 20.8 (q), 39.9
3
(
t), 55.3 (q), 113.4 (d), 113.8 (d), 117.1 (d), 125.8 (s), 130.0 (d), 130.1 (s), 135.0 (d), 142.5 (s),
–
1
55.1 (s), 158.6 (s); exact mass (electrospray) m/z calcd for C H O S (M–H) 259.0798, found
1
5
15
2
2
59.0797.
2-Bromo-3-ethenyl-5-methyl-4-(methylsulfanyl)cyclohex-2-en-1-one (48).
Vinyl-
magnesium bromide solution (1.0 M in THF, 0.15 mL) was added dropwise over < 1 min to a
stirred solution of 17 (26.0 mg, 0.098 mmol) in THF (2.0 mL) and stirring at 0 °C was continued
for 1 h. The ice bath was left in place, but not recharged, and stirring was continued for 12 h,
during which the mixture reached room temperature. The reaction mixture was diluted with 2 N
hydrochloric acid, stirred for 10 min and extracted with EtOAc. The combined organic extracts
were washed with brine, dried (MgSO ) and evaporated. Flash chromatography of the residue
4
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8
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over silica gel (0.5 × 10 cm), using 1:5 EtOAc-hexanes, gave 48 (22.5 mg, 88%) as a colorless,
–
1 1
thick oil: FTIR (CDCl , cast) 1676 cm ; H NMR (CDCl , 500 MHz) δ (major isomer) 1.23 (d,
3
3
J = 6.5 Hz, 3 H), 2.15 (s, 3 H), 2.47–3.35 (m, 3 H), 3.68–3.74 (m, 1 H), 5.74 (d, J = 11.0 Hz, 1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
H), 5.98 (d, J = 17.5 Hz, 1 H), 7.13 (dd, J = 17.5, 11.0 Hz, 1 H); C NMR (CDCl , 125 MHz) δ
3
(
major isomer) 17.5 (q), 18.5 (q), 34.3 (d), 41.4 (t), 49.7 (d), 123.7 (t), 125.8 (s), 135.6 (d), 153.3
8
1
+
(
s), 191.2 (s); exact mass (electron ionization) m/z calcd for C H OS Br (M) 261.9850, found
10 13
261.9852.
3
-Ethenyl-5-methyl-4-(methylsulfanyl)phenol (49). DBU (29.3 mg, 0.192 mmol) was
added to a stirred solution of 48 (25.1 mg, 0.096 mmol) in PhMe (0.5 mL). Stirring was
continued for 4 h and the reaction mixture was diluted with saturated aqueous NH Cl and
4
extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4)
and evaporated. Flash chromatography of the residue over silica gel (0.5 × 12 cm), using 1:5
EtOAc-hexanes, gave 49 (14.7 mg, 85%) as a white solid: mp 98-101 °C; FTIR (CDCl , cast)
3
–
1 1
3375, 1598 cm ; H NMR (CDCl , 400 MHz) δ 2.16 (s, 3 H), 2.51 (s, 3 H), 4.73 (s, 1 H), 5.32
3
(
dd, J = 11.2, 1.6 Hz, 1 H), 5.63 (d, J = 11.2, 1.6 Hz, 1 H), 6.69 (d, J = 2.8 Hz, 1 H), 6.89 (d, J =
13
2
.8 Hz, 1 H), 7.50 (dd, J = 17.6, 10.8 Hz, 1 H); C NMR (CDCl , 125 MHz) δ 19.3 (q), 21.7 (q),
3
1
10.6 (d), 115.7 (t), 116.9 (d), 126.2 (s), 136.3 (d), 143.7 (s), 144.7 (s), 155.4 (s); exact mass
–
(
electrospray) m/z calcd for C H OS (M-H) 179.0538, found 179.0536.
1
0
11
ACKNOWLEDGEMENT
We thank the Natural Sciences and Engineering Research Council of Canada for financial
support.
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