Oxidative ipso -Rearrangement performed by a hypervalent iodine reagent and its application

Article abstract of DOI:10.1021/jo301408j

An oxidative ipso-rearrangement mediated by a hypervalent iodine reagent that enables rapid generation of a functionalized dienone system containing a quaternary carbon center connected to several sp² centers has been developed. The process occurs through transfer of an aryl group from a silyl segment present on the lateral chain. As an illustration of the potential of this transformation, a total synthesis of sceletenone, a small alkaloid, is described.

Full text of DOI:10.1021/jo301408j

Article
pubs.acs.org/joc
Oxidative ipso-Rearrangement Performed by a Hypervalent Iodine
Reagent and Its Application
Guillaume Jacquemot and Sylvain Canesi*
Laboratoire de Met
́
hodologie et Synthes
̀ ́ ́ ̀ ́
e de Produits Naturels, Universite du Quebec a Montreal, C.P. 8888, Succ. Centre-Ville,
Montreal, H3C 3P8 Queb
́
́
ec, Canada
S
* Supporting Information
ABSTRACT: An oxidative ipso-rearrangement mediated by a
hypervalent iodine reagent that enables rapid generation of a
functionalized dienone system containing a quaternary carbon
center connected to several sp2 centers has been developed.
The process occurs through transfer of an aryl group from a
silyl segment present on the lateral chain. As an illustration of
the potential of this transformation, a total synthesis of sceletenone, a small alkaloid, is described.
INTRODUCTION
■
Structures containing a quaternary carbon center connected to
an aryl group and including a cyclohexanone derivative have
attracted substantial interest due to the large number of
bioactive natural products containing a similar motif, including
Amaryllidaceae alkaloids such as O-methylsceletenone 1a,
isolated from Aptenia Cordifolia1 in South Africa, and its O-
demethylated analogue sceletenone, isolated from the phenolic
alkaloid fraction of Sceletium strictum.1 Both of these
compounds are potent serotonin reuptake inhibitors. Other
examples include narwedine2 2 and vindoline 3, which is an
important moiety of vincristine, a mitotic inhibitor isolated
from catharanthus roseus3 and used in cancer chemotherapy
(Figure 1).
Figure 2. Oxidative ipso-rearrangement pathway.
RESULTS AND DISCUSSION
■
The approach requires activation to transform the electron-rich
phenol into an electrophilic species susceptible to trapping by
the silyl-aryl group. When the process involves an intermediate
such as 5 it may be termed “aromatic ring umpolung”.4
Although electron-rich aromatic systems such as 4 normally
react as nucleophiles, oxidative activation converts them into
highly electrophilic species that may then be intercepted with
appropriate nucleophiles. This umpolung activation is mediated
by hypervalent iodine reagents such as iodobenzene diacetate
(DIB) or equivalent mild oxidizing agents. The potential of this
environmentally benign reagent was made evident in the
pioneering work of Kita.5 In particular, DIB promotes oxidative
transformation of phenols6,7 in a manner consistent with recent
requirements for green chemical processes. As observed by Kita
and co-workers,8 DIB reactions generally occur best in non-
nucleophilic highly polar solvents such as trifluoroethanol
(TFE) or hexafluoroisopropanol (HFIP). In this paper, we
propose an unprecedented ipso-rearrangement initiated by a
hypervalent iodine reagent to form a functionalized dienone
system containing a quaternary carbon center connected to
several sp2 atoms including an aromatic moiety, a structural
feature present in a large number of bioactive natural products.
Our first attempts to verify the feasibility of this transformation
were undertaken using a simple TBDPS (or a derivative)-
Figure 1. Natural alkaloids containing quaternary carbon centers.
To generate these structures, we have developed an approach
involving a hypothetical intramolecular “oxidative ipso-rear-
rangement” promoted by subsequent oxidation of a substituted
phenol containing a preactivated migrating group and
connected to a silicon atom on the lateral chain. We assume
that this process occurs via a chairlike transition state 5 leading
to compound 6 (Figure 2).
In this paper, we describe an oxidative ispo-shift process
occurring in electron-rich aromatic compounds and leading to
the formation of a prochiral dienone system containing a
quaternary carbon center connected to several sp2 centers. The
method is then applied to the total syntheses of O-
methylsceletenone and sceletenone, two natural alkaloids.
Received: July 5, 2012
Published: August 6, 2012
© 2012 American Chemical Society
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protected alcohol functionality easily accessible on a large scale
by protection of inexpensive starting materials 7 (Table 1).
products, an o-anisole subunit was used as a migrating group.
The corresponding dimer was obtained by treatment of
dichloro-diarylsilane with an O-TBS-protected phenol followed
by a selective phenol deprotection in 57% overall yield (Scheme
2).
Table 1. Oxidative ipso-shift process
Scheme 2. Application to Dimeric Substrates
entry
Ar1
Ar2
R
R1
R2
yield (%)
a
b
c
d
e
f
Ph
Ph
H
H
H
40
74
51
p-anisole
p-toluene
Ph
p-anisole
p-toluene
OH
H
H
H
H
H
H
a
Me
H
H
H
37
Ph
Ph
Br
t-Bu
t-Bu
H
62
a
Ph
Ph
H
t-Bu
OMe
85
a
g
Ph
Ph
H
44
The potential utility of this new method is demonstrated in
an expeditious two-step method to generate the tetracyclic
system 15, an oxygenated version of the main core of vindoline
3 (Figure 1). The oxidation occurs via ipso-rearrangement
followed by a tetrahydropyran deprotection and subsequent
1,4-conjugate addition from the resulting phenol moiety,
provoked by the acidity of the medium used (HFIP and acetic
acid released). Further treatment with TBAF furnishes the
elaborated tetracyclic core 15 in 40% overall yield from the
simple dimer 14 (Scheme 3).
a
A minor amount of OCH(CF3)2 has been substituted by an acetate
or an hydroxyl
It should be stressed that the reaction occurs in moderate to
good yield (37−85%) with a simple benzene derivative;
however, the one-step transformation of the simple and easily
accessible starting material 7 in a highly functionalized core 8
would provide even more favorable results in terms of global
yield and number of steps than traditional methodologies. As
expected with p-toluene and p-anisole derivatives (entries 7c
and 7b), the reaction occurs in higher yield compared to entry
7a due to the presence of an electron-donating methyl or
methoxy group in the para position. As previously observed in
similar transformations, the reaction occurs in greater yields (up
to 85%, entries 7e and 7f) when the phenol moiety is
substituted with a tert-butyl group.4d This can be rationalized by
considering the tert-butyl group as an electron donor stabilizing
the electrophilic species 5, enabling the ipso rearrangement and
limiting alternate reaction pathways such as elimination of a
benzilic hydrogen. A surprising aspect of this process is the
nucleophilic addition of HFIP to the nascent asymmetric silicon
center, sometimes accompanied by a small amount of acetate
(∼10%) released from the hypervalent iodine reagent. HFIP is
a weakly reactive nucleophile and is normally considered an
inert solvent. Further treatment of the resulting dienone system
with TBAF furnishes oxygenated versions of bicyclic systems
similar to the natural products illustrated in Figure 1. For
example, oxidation of compound 9 followed by direct treatment
of the crude mixture with TBAF leads to the bicyclic system 10
in 45% yield over two steps (Scheme 1).
Scheme 3. Rapid Formation of Oxygenated Tetracyclic Core
The process is not restricted to phenol derivatives, as
illustrated by the generation of 17 from the aniline derivative
16 under similar conditions. The reaction proceeds via
formation of a sulfonyl dieniimine that is subsequently
hydrolyzed under acidic conditions into dienone subunit 17
in similar yield (Scheme 4).
Scheme 4. N-(Sulfonyl)-aniline ipso-Transformation
Scheme 1. Oxidative ipso-1,4-Conjugate Addition
As an initial application of the oxidative ipso-rearrangement,
we describe the total syntheses of O-methylsceletenone 1a and
sceletenone 1b.1 These small molecules belonging to the
Amaryllidaceae family are generally isolated in racemic form,
most probably due to an aza-Michael/retro-Michael equili-
brium. The compounds are known to have antidepressant
properties and are bioprecursors to the natural analogue
mesembrine.1c,9 A retrosynthetic pathway is presented in Figure
3.
In order to develop a method with favorable atom economy,
dimers such as 12 containing two phenol moieties and two
aromatic segments have been prepared. In this case, only one
silicon atom is used as a tether to generate two dienone
subunits, and subsequent treatment with TBAF produces the
tricyclic core 13. In order to generate the more elaborate
quaternary carbon-connected aromatic systems found in natural
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Figure 3. Retrosynthetic pathway to O-methylsceletenone and sceletenone.
Starting from compound 11,10 the primary alcohol
functionality is protected with a modified p-methoxy-TBDPSCl
segment 19 using classical conditions. The modified TBDPSCl
reagent 19 is obtained by treatment of tert-butyltrichlorosilane
with 2 equiv of the corresponding aryl-organolithium reagent
18. Selective deprotection of the phenol group using potassium
carbonate in methanol furnishes 7b in 57% yield over two steps.
At this stage, the key oxidative ispo-rearrangement promoted by
a hypervalent iodine reagent produces the functionalized
dienone system 8b in 74% yield. It should be noted that the
silicon moiety used during this transformation not only acts as a
simple protecting group but also enables the formation of an
important component of the target as a tether. In addition, the
modified fluorinated protecting group emerging in compound
8b remains available for further transformations (Scheme 5).
primary alcohol into a leaving group performed in the presence
of a hindered sulfonyl moiety such as o-nosyl chloride furnishes
compound 21 in 40% yield. Oxidation with TPAP/NMO
regenerates the dienone system and further treatment of this
core with methylamine via a SN2-aza-Michael tandem process
leads to the target O-methylsceletenone 1a in 76% yield.
Despite the fact that O-methylsceletenone 1a are isolated in
racemic form,1 You and Gu11 recently reported an asymmetric
synthesis based on a sulfonamide derivative and employing a
cinchonine-derived thiourea catalyst11 to desymmetrize enan-
tioselectively similar dienone systems. In addition, sceletenone
1b can also be easily and quantitatively obtained from 1a by
treatment with BBr3 (Scheme 6).
CONCLUSION
■
A practical new method for inducing intramolecular oxidative
ipso-rearrangements is now available. The transformation
provides new strategic opportunities by enabling one-step
transformation of stable and simple aromatic compounds into
more reactive dienone cores containing a polyfunctionalized
quaternary carbon center, a prominent feature of several natural
products. The utility of this method is illustrated through its
application to total syntheses of O-methylsceletenone and
sceletenone.
Scheme 5. Oxidative Key Step
EXPERIMENTAL SECTION
■
Unless otherwise indicated, 1H and 13C NMR spectra were recorded at
300 and 75 MHz, respectively, in CDCl3 solutions. Chemical shifts are
reported in ppm on the δ scale. Multiplicities are described as s
(singlet), d (doublet), dd, ddd, etc. (doublet of doublets, doublet of
doublets of doublets, etc.), t (triplet), q (quartet), quin (quintuplet), m
(multiplet) and further qualified as app (apparent), br (broad).
Coupling constants, J, are reported in Hz. IR spectra (cm−1) were
A reduction of the ketone functionality in 8b with DIBAL-H
leads stereoselectively to the diastereoisomer 20 in a 9:1 ratio.
Subsequent deprotection of the primary alcohol using TBAF
produces the diol in 85% yield. A selective activation of the
Scheme 6. Syntheses of O-Methylsceletenone and Sceletenone
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recorded from thin films. HRMS were measured in the electrospray
(ESI) mode on a LC-MSD TOF mass analyzer.
3354, 1654, 1617, 1376, 1292, 1227, 1195, 1103; HRMS (ESI) calcd
for C22H26F6NaO4Si (M + Na)+ 519.1397, found 519.1399.
3-Bromo-5-(tert-butyl)-1-(2-((tert-butyl((1,1,1,3,3,3-hexa-
fluoropropan-2-yl)oxy)(phenyl)silyl)oxy)ethyl)-[1,1′-biphenyl]-
4(1H)-one (8e). Pale yellow oil: 0.018 mmol, 12.0 mg, 62% yield; 1H
NMR (300 MHz, CDCl3) δ 7.57 (m, 2H), 7.39 (m, 8H), 7.29 (d, 1H,
J = 1.7 Hz), 6.71 (dd, 1H, J = 4.6, 2.8 Hz), 4.46 (hept, 1H, J = 5.8 Hz),
3.84 (m, 2H), 2.49 (m, 2H), 1.24 (s, 9H), 1.00 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 178.5, 152.1, 152.1, 147.0, 146.9, 145.3, 145.19, 139.3,
139.3, 135.3, 135.2, 131.2, 129.5, 128.5, 128.4, 128.3, 128.1, 126.4,
125.7, 125.5, 70.5 (hept, J2 = 33.6 Hz), 60.6, 49.8, 49.8, 40.2, 35.5,
29.2, 26.0, 19.4; IR υ (cm−1) 1659, 1232, 1229, 1197, 1106; HRMS
(ESI) calcd for C31H35BrF6NaO3Si (M + Na)+ 701.1320, found
701.1314.
General Procedure for the Formation of Phenols 7. To a
solution of 11 (2.52 mmol, 1.0 equiv) in DMF (3.0 mL) was added
imidazole (7.56 mmol, 3.0 equiv), and the solution was stirred for 5
min. TBDPS-Cl (3.78 mmol, 1.5 equiv) was then added, and the
reaction mixture was stirred at room temperature. The reaction was
followed by TLC. After completion, ether was added, followed by
water. The aqueous phase was extracted with ether, and the organic
phases were then washed with water and brine and then dried with
Na2SO4. The solution was filtered and concentrated under vacuum,
and the residue was purified by silica gel chromatography with a
mixture of ethyl acetate/hexane to afford the protected alcohol. The
substrate was then diluted in methanol (16.0 mL), K2CO3 (5.04 mmol,
2.0 equiv) was added, and the solution was stirred at 60 °C. The
reaction was followed by TLC. After completion, aqueous NH4Cl was
added, and the aqueous phase was extracted with DCM. The organic
phases were dried with Na2SO4, filtered, and concentrated under
vacuum. The residue was then purified by silica gel chromatography
with a mixture of ethyl acetate/hexane to give the corresponding
phenol for more details.
General Procedure for the Oxidative ipso-Rearrangement. A
solution of PhI(OAc)2 (“DIB”, 78 mg, 0.24 mmol, 1.2 equiv) in
(CF3)2CHOH (“HFIP”, 0.35 mL) was added dropwise over 30 s to a
vigorously stirred solution of phenol (0.2 mmol, 1 equiv) in HFIP (0.6
mL) at 0 °C. The mixture was then stirred for 30 s and concentrated
under vacuum, and the residue was purified by silica gel
chromatography with a mixture of ethyl acetate/hexane.
1-(2-((tert-Butyl((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-
(phenyl)silyl)oxy)ethyl)-[1,1′-biphenyl]-4(1H)-one (8a). Pale yel-
low oil: 0.059 mmol, 31.9 mg, 40% yield; 1H NMR (300 MHz,
CDCl3) δ 7.56 (m, 2H), 7.36 (m, 8H), 6.98 (d, 2H, J = 10.0 Hz), 6.36
(d, 2H, J = 10.7 Hz), 4.46 (hept, 1H, J = 5.8 Hz), 3.90 (m, 2H), 2.51
(t, 2H, J = 6.9 Hz), 0.98 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 186.0,
153.7, 153.7, 139.5, 135.7, 135.2, 131.1, 129.3, 128.7, 128.6, 128.6,
128.3, 128.0, 127.8, 126.5, 70.6 (hept, J2 = 33.6 Hz), 60.8, 47.6, 40.1,
27.0, 26.0, 19.4; HRMS (ESI) calcd for C27H28F6O3Si (M + H)+
543.1785, found 543.1776.
1-(2-((tert-Butyl((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)(4-
methoxyphenyl)silyl)oxy)ethyl)-4′-methoxy-[1,1′-biphenyl]-
4(1H)-one (8b). Pale yellow oil: 0.033 mmol, 20.0 mg, 74% yield; 1H
NMR (300 MHz, CDCl3) δ 7.50 (d, J = 8.6 Hz, 2H), 7.23 (t, J = 6.0
Hz, 2H), 6.93 (dt, J = 14.3, 8.5 Hz, 6H), 6.34 (d, J = 9.9 Hz, 2H), 4.43
(hept, 1H, J = 5.8 Hz), 3.90 (m, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 2.46
(t, J = 6.9 Hz, 2H), 0.97 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 186.1,
161.9, 159.2, 154.1, 154.1, 137.3, 136.9, 131.1, 128.3, 128.2, 127.7,
119.3, 114.7, 114.1, 70.5 (hept, J2 = 33.6 Hz), 60.7, 55.5, 55.19, 55.1,
47.0, 40.1, 25.9, 19.5, 19.3; HRMS (ESI) calcd for C29H33F6O5Si (M +
H)+ 603.1996, found 603.1986.
1-(2-((tert-Butyl((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)(p-
tolyl)silyl)oxy)ethyl)-4′-methyl-[1,1′-biphenyl]-4(1H)-one (8c).
Pale yellow oil: 0.021 mmol, 12.2 mg, 51% yield; 1H NMR (300
MHz, CDCl3) δ 7.46 (d, J = 7.8 Hz, 2H), 7.25−7.15 (m, 6H), 6.96 (d,
J = 9.6 Hz, 2H), 6.34 (d, J = 9.8 Hz, 2H), 4.43 (hept, 1H, J = 5.8 Hz),
3.87 (m, 2H), 2.47 (t, J = 6.9 Hz, 2H), 2.38 (s, 3H), 2.34 (s, 3H), 0.97
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 186.1, 154.0, 154.0, 141.3,
137.8, 136.4, 135.3, 130.0, 129.1, 128.5, 128.4, 126.4, 125.0, 70.5 (hept,
J2 = 33.6 Hz), 60.7, 47.4, 40.1, 26.0, 25.9, 21.7, 21.1, 19.4; IR υ (cm−1)
1667, 1626, 1218, 1106; HRMS (ESI) calcd for C29H32F6NaO3Si (M +
Na)+ 593.1917, found 593.1910.
3,5-Di-tert-butyl-1-(2-((tert-butyl((1,1,1,3,3,3-hexafluoropro-
pan-2-yl)oxy)(phenyl)silyl)oxy)ethyl)-[1,1′-biphenyl]-4(1H)-one
1
(8f). Pale yellow oil: 0.02 mmol, 13.2 mg, 85% yield; H NMR (300
MHz, CDCl3) δ 7.59 (m, 2H), 7.40 (m, 6H), 7.29 (m, 2H), 6.55 (m,
2H), 4.45 (hept, 1H, J = 5.8 Hz), 3.79 (ddd, 2H, J = 10.7, 5.5, 2.7 Hz),
2.48 (m, 2H), 1.21 (s, 9H), 1.19 (s, 9H), 0.99 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 186.2, 146.7, 146.7, 144.6, 144.5, 141.8, 135.3, 131.1,
129.1, 128.8, 128.2, 127.4, 126.3, 70.5 (hept, J2 = 33.6 Hz), 61.1, 45.6,
39.9, 35.0, 35.0, 29.5, 29.4, 25.9, 19.4; IR υ (cm−1) 1644, 1215; HRMS
(ESI) calcd for C35H44ClF6O3Si (M + Cl)− 689.2658, found 689.2674.
1-(2-((tert-Butyl((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-
(phenyl)silyl)oxy)ethyl)-3-methoxy-[1,1′-biphenyl]-4(1H)-one
1
(8g). Pale yellow oil: 0.012 mmol, 7.0 mg, 44% yield; H NMR (300
MHz, CDCl3) δ 7.62 (m, 4H), 7.40 (m, 6H), 6.82 (dd, 1H, J = 9.9, 2.1
Hz), 6.12 (d, J = 2.1 Hz 1H), 6.01 (d, 1H, J = 9.9 Hz), 5.54 (hept, 1H,
J = 5.8 Hz), 3.83 (t, 2H, J = 6.0 Hz), 3.35 (s, 3H), 2.48 (t, 2H, J = 5.8
Hz), 1.03 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 143.9, 137.6, 135.7,
135.7, 135.1, 133.3, 133.3, 129.9, 129.6, 129.3, 128.7, 128.3, 127.9,
125.1, 124.9, 67.5 (hept, J2 = 33.6 Hz), 62.3, 52.2, 38.4, 29.9, 26.9,
25.8, 19.2; calcd for C28H30F6O4SiNa (M + Na)+ 595.1170, found
595.1171.
5-Bromo-3a-phenyl-3,3a,7,7a-tetrahydrobenzofuran-6(2H)-
one (10). Pale yellow oil: 0.018 mmol, 5.2 mg, 45% yield over 2 steps;
1H NMR (300 MHz, CDCl3) δ 7.38 (m, 5H), 7.19 (d, 1H, J = 2.2
Hz), 4.35 (q, 1H, J = 2.8 Hz), 4.12 (td, 1H, J = 8.8, 3.1 Hz), 3.95 (ddd,
1H, J = 9.7, 8.6, 6.8 Hz), 3.01 (ddd, 1H, J = 17.2, 3.1, 0.7 Hz), 2.74 (m,
2H), 2.36 (ddd, 1H, J = 12.9, 6.8, 3.1 Hz); 13C NMR (75 MHz,
CDCl3) δ 188.6, 150.7, 138.6, 129.4, 128.1, 126.6, 124.0, 83.1, 67.1,
54.6, 40.2, 38.9; calcd for C14H14O2Br (M + H)+ 293.0172, found
293.0171.
4,4′-(((Bis(2-methoxyphenyl)silanediyl)bis(oxy))bis(ethane-
2,1-diyl))diphenol (12). To a solution of 18 (16.7 mg, 0.066 mmol,
1.0 equiv) in DMF (1.0 mL) was added imidazole (53.9 mg, 0.792
mmol, 12.0 equiv), and the solution was stirred during 5 min. The
solution was then added to a solution of “dichlorosilane” (0.198 mmol,
3.0 equiv) in DMF (1.0 mL). The reaction mixture was stirred at room
temperature, and the reaction was followed by TLC. After completion,
ether was added, followed by water. The aqueous phase was extracted
with ether, and the organic phases were then washed with water and
brine and then dried with Na2SO4. The solution was filtered and
concentrated under vacuum, and the residue was purified by silica gel
chromatography with a mixture of ethyl acetate/hexane to afford the
protected dimer. To this dimer in THF (1.0 mL) was added TBAF
(42 μL, 0.042 mmol, 1.8 equiv) at 0 °C under stirring, and the reaction
was followed by TLC. After completion, aqueous NH4Cl was added,
and the aqueous phase was extracted with EtOAc. The organic phases
were dried with Na2SO4, filtered, and concentrated under vacuum. The
residue was then purified by silica gel chromatography with a mixture
of ethyl acetate/hexane to give 9.7 mg (57% over 2 steps) of a
colorless oil; 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J = 7.1 Hz, 2H),
7.38 (t, J = 7.8 Hz, 2H), 7.00 (d, J = 8.2 Hz, 4H), 6.94 (t, J = 7.3 Hz,
2H), 6.82 (d, J = 8.3 Hz, 2H), 6.69 (d, J = 8.3 Hz, 4H), 3.90 (t, J = 7.3
Hz, 4H), 3.64 (s, 6H), 2.80 (t, J = 7.3 Hz, 4H); 13C NMR (75 MHz,
CDCl3) δ 164.4, 153.9, 137.4, 131.9, 130.3, 122.2, 120.6, 115.1, 109.9,
64.7, 55.3, 38.4; IR υ (cm−1) 3389, 1615, 1455, 1240; HRMS (ESI)
calcd for C30H33O6Si (M + H)+ 517.2041, found 517.2034.
1-(2-((tert-Butyl((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-
(phenyl)silyl)oxy)propyl)-[1,1′-biphenyl]-4(1H)-one (8d). Pale
1
yellow oil: 0.012 mmol, 6.1 mg, 37% yield; H NMR (300 MHz,
CDCl3) δ 7.45−7.28 (m, 5H), 7.08−6.99 (m, 2H), 6.41 (dd, J = 10.1,
1.8 Hz, 1H), 6.30 (dd, J = 10.1, 1.8 Hz, 1H), 4.63 (h, J = 5.8 Hz, 1H),
4.10 (m, 1H), 2.48 (dd, J = 14.1, 5.6 Hz, 1H), 2.21 (dd, J = 14.1, 3.5
Hz, 1H), 1.25 (d, J = 6.1 Hz, 3H), 0.95 (s, 9H). 13C NMR (75 MHz,
CDCl3) δ 187.0, 155.5, 154.0, 139.9, 129.3, 128.9, 127.9, 127.5, 126.6,
70.2 (hept, J2 = 33.6 Hz), 67.3, 48.2, 47.8, 25.8, 25.2, 17.4; IR υ (cm−1)
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3a-(2-Methoxyphenyl)-3,3a,7,7a-tetrahydrobenzofuran-
6(2H)-one (13). Pale yellow oil: 0.034 mmol, 8.3 mg, 40% yield over
2 steps; 1H NMR (300 MHz, CDCl3) δ 7.31 (t, 1H, J = 7.8 Hz), 7.19
(d, 1H, J = 7.6 Hz), 6.96 (d, 2H, J = 7.9 Hz), 6.92 (s, 1H), 6.09 (d, 1H,
J = 10.3 Hz), 4.73 (d, 1H, J = 2.6 Hz), 3.98 (m, 2H), 3.88 (s, 3H), 2.79
(m, 2H), 2.65 (dd, 1H, J = 17.2, 3.2 Hz), 2.38 (dt, 1H, J = 12.7, 6.7
Hz); 13C NMR (75 MHz, CDCl3) δ 197.1, 157.8, 151.7, 129.0, 128.7,
128.0, 127.6, 121.0, 111.9, 79.3, 66.7, 55.3, 49.8, 39.4, 38.7; IR υ
(cm−1) 1684, 1490, 1240, 1215; HRMS (ESI) calcd for C15H17O3 (M
+ H)+ 245.1172, found 245.1167.
NMR (300 MHz, CDCl3) δ 7.27 (d, J = 4.3 Hz, 4H), 7.23−7.15 (m,
1H), 6.60 (dd, J = 10.2, 2.3 Hz, 1H), 6.11 (d, J = 10.2 Hz, 1H), 4.23
(dd, J = 5.4, 2.9 Hz, 1H), 3.98 (td, J = 8.7, 3.0 Hz, 1H), 3.79 (ddd, J =
9.8, 8.5, 6.8 Hz, 1H), 2.71−2.58 (m, 2H), 2.44 (dd, J = 17.3, 3.0 Hz,
1H), 2.16 (ddd, J = 12.7, 6.6, 2.9 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 196.8, 150.6, 139.6, 129.7, 129.2, 127.8, 126.7, 83.3, 67.0,
51.0, 40.1, 38.6; HRMS (ESI) calcd for C14H15O2 (M + H)+ 215.1067,
found 215.1073.
tert-Butylchlorobis(4-methoxyphenyl)silane (19). To a sol-
ution of 4-bromoanisole (1.12 g, 6.0 mmol, 3.0 equiv) in THF (6.0
t
4,4′-(((Bis(2-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-
silanediyl)bis(oxy))bis(ethane-2,1-diyl))diphenol (14). To a
solution of 11 (283 mg, 1.12 mmol, 2.0 equiv) in DMF (1.0 mL)
was added imidazole (115 mg, 1.69 mmol, 3.0 equiv), and the solution
was stirred during 5 min. The solution was then added to a solution of
the corresponding “diaryldichlorosilane” (0.56 mmol, 1.0 equiv) in
DMF (1.0 mL). The reaction mixture was stirred at room temperature,
and the reaction was followed by TLC. After completion, ether was
added, followed by water. The aqueous phase was extracted with ether,
and the organic phases were then washed with water and brine and
then dried with Na2SO4. The solution was filtered and concentrated
under vacuum, and the residue was purified by silica gel
chromatography with a mixture of ethyl acetate/hexane (1:4) to
afford the protected dimer. The substrate was diluted in THF (1.0
mL), TBAF (569 μL, 1.8 equiv) was added at 0 °C under stirring, and
the reaction was followed by TLC. After completion, aqueous NH4Cl
was added, and the aqueous phase was extracted with EtOAc. The
organic phases were dried with Na2SO4, filtered, and concentrated
under vacuum. The residue was then purified by silica gel
chromatography with a mixture of ethyl acetate/hexane (2:3) to give
the corresponding dimeric substrate 94 mg (32% overall) as a pale oil
in a diastereomeric mixture (1:1): 1H NMR (300 MHz, CDCl3) δ 7.79
(d, J = 7.2 Hz, 2H), 7.34−7.27 (m, 2H), 7.04−6.94 (m, 8H), 6.69 (d, J
= 8.2 Hz, 4H), 5.23 (d, J = 13.2 Hz, 2H), 3.93−3.80 (m, 4H), 3.56 (t, J
= 10.5 Hz, 1H), 3.49−3.38 (m, 3H), 2.83−2.72 (m, 4H), 1.68−1.06
(m, 12H); 13C NMR (75 MHz, CDCl3) δ 162.1, 161.9, 154.2, 137.0,
131.7, 131.1, 130.2, 122.6, 122.6, 121.2, 121.1, 115.2, 112.8, 112.6,
95.8, 95.6, 64.7, 64.3, 61.3, 61.1, 38.4, 30.7, 25.3, 19.2, 17.8, 13.8;
HRMS (ESI) calcd for C38H45O8Si (M + H)+ 657.2878, found
657.2871.
mL) at −78 °C was added BuLi (7.3 mL, 12.4 mmol, 6.2 equiv)
dropwise. The solution was stirred during 5 min, and a solution of
tBuSiCl3 (383.2 mg, 2.0 mmol, 1.0 equiv) in THF (2.0 mL) was added
at 0 °C via a cannula. The solution was then stirred at room
1
temperature, and the reaction was followed by NMR. H NMR (300
MHz, CDCl3) δ 7.66 (d, J = 8.6 Hz, 4H), 6.94 (d, J = 8.5 Hz, 4H),
3.83 (s, 6H), 1.11 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 161.4,
137.0, 136.5, 113.7, 55.2, 26.6, 20.9; HRMS (ESI) calcd for
C18H25O3Si (M − Cl + H2O)+ 317.1567, found 317.1582.
4-(2-((tert-Butylbis(4-methoxyphenyl)silyl)oxy)ethyl)phenol
(7b). To a solution of 18 (161.5 mg, 0.64 mmol, 1.0 equiv) in DMF
(1.0 mL) was added imidazole (272.3 mg, 4.0 mmol, 6.0 equiv), and
the solution was stirred during 5 min. The solution was then added to
a solution of silane 19 (2.0 mmol, 3.0 equiv) in DMF (2.0 mL). The
reaction mixture was stirred at room temperature, and the reaction was
followed by TLC. After completion, ether was added, followed by
water. The aqueous phase was extracted with ether, and the organic
phases were then washed with water and brine and then dried with
Na2SO4. The solution was filtered and concentrated under vacuum,
and the residue was purified by silica gel chromatography with a
mixture of ethyl acetate/hexane to afford the protected alcohol along
with the corresponding silanol. To this mixture in methanol (3.0 mL)
was added K2CO3 (157.3 mg, 1.14 mmol, 2.0 equiv), and the solution
was stirred at 60 °C. The reaction was followed by TLC. After
completion, aqueous NH4Cl was added, and the aqueous phase was
extracted with DCM. The organic phases were dried with Na2SO4,
filtered, and concentrated under vacuum. The residue was then
purified by silica gel chromatography with a mixture of ethyl acetate/
1
hexane to give 159.2 mg (57% over 2 steps) of a pale yellow oil. H
NMR (300 MHz, CDCl3) δ 7.50 (d, J = 8.6 Hz, 4H), 7.01 (d, J = 8.4
Hz, 2H), 6.90 (d, J = 8.6 Hz, 4H), 6.72 (d, J = 8.4 Hz, 2H), 4.53 (s,
1H), 3.83 (s, 6H), 3.75 (t, J = 6.9 Hz, 2H), 2.76 (t, J = 6.9 Hz, 2H),
1.00 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 160.6, 154.3, 137.2,
130.9, 130.3, 125.0, 115.1, 113.4, 65.3, 60.8, 54.9, 38.4, 26.9, 21.1, 19.2,
14.1; IR υ (cm−1) 1664, 1228, 1197, 1107; HRMS (ESI) calcd for
C26H31O4Si (M − H)− 435.1997, found 435.2002.
Tetracyclic Compound (15). Pale yellow oil: 0.057 mmol, 13.1
1
mg, 40% yield over 2 steps; H NMR (300 MHz, CDCl3) δ 7.21 (m,
2H), 6.98 (t, 1H, J = 7.5 Hz), 6.83 (d, 1H, J = 8.4 Hz), 4.78 (d, 1H, J =
3.2 Hz), 4.09 (m, 2H), 3.93 (d, 1H, J = 3.2 Hz), 2.80 (dd, 1H, J = 17.9,
3.0 Hz). 2.77 (m, 2H), 2.72 (dd, 1H, J = 17.8, 3.0 Hz), 2.26 (dd, 1H, J
= 17.8, 3.0 Hz), 2.23 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 205.9,
159.6, 129.7, 129.5, 123.2, 121.7, 110.4, 87.9, 83.7, 67.4, 52.9, 39.8,
39.4, 38.8; IR υ (cm−1) 1652, 1215; HRMS (ESI) calcd for C14H15O3
(M + H)+ 231.1016, found 231.1017.
1-(2-((tert-Butyl((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)(4-
methoxyphenyl)silyl)oxy)ethyl)-4′-methoxy-1,4-dihydro-[1,1′-
biphenyl]-4-ol (20). To a solution of 8b (169.1 mg, 0.28 mmol, 1.0
equiv) in THF (3.0 mL) at −78 °C was added DIBAL-H (421 μL,
0.42 mmol, 1.5 equiv) dropwise under stirring. The reaction was
followed by TLC. After completion, aqueous Rochelle salt was added,
and the aqueous phase was extracted with EtOAc. The organic phases
were dried with Na2SO4, filtered, and concentrated under vacuum. The
residue was then purified by silica gel chromatography with a mixture
N-(4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)phenyl)-
methanesulfonamide (16). To a solution of N-(4-(2-hydroxyethyl)-
phenyl)methanesulfonamide (25.7 mg, 0.12 mmol, 1.0 equiv) in DMF
(1.0 mL) was added imidazole (24.4 mg, 0.36 mmol, 3.0 equiv), and
the solution was stirred during 5 min. TBDPS-Cl (49.2 mg, 0.18
mmol, 1.5 equiv) was then added, and the reaction mixture was stirred
at room temperature. The reaction was followed by TLC. After
completion, ether was added, followed by water. The aqueous phase
was extracted with ether, and the organic phases were then washed
with water and brine and then dried with Na2SO4. The solution was
filtered and concentrated under vacuum, and the residue was purified
by silica gel chromatography with a mixture of ethyl acetate/hexane
(1:3) to afford 16 in 95% (51.2 mg, 0.11 mmol). 1H NMR (300 MHz,
CDCl3) δ 7.59 (d, J = 7.7 Hz, 4H), 7.44−7.31 (m, 6H), 7.15 (s, 4H),
6.79 (s, 1H), 3.83 (t, J = 6.7 Hz, 2H), 2.97 (s, 3H), 2.83 (t, J = 6.7 Hz,
2H), 1.02 (s, 10H); 13C NMR (75 MHz, CDCl3) δ 137.0, 135.7,
134.8, 133.8, 130.6, 129.8, 127.8, 121.4, 65.0, 39.2, 38.7, 26.93, 25.8,
19.3; HRMS (ESI) calcd for C25H32NO3SSi (M + H)+ 454.1867,
found 454.1871.
1
of ethyl acetate/hexane to give 159.6 mg (94%) of a yellow oil. H
NMR (300 MHz, CDCl3) δ 7.54 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.8
Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.97 (dd, J
= 10.7, 2.9 Hz, 2H), 5.86 (dd, J = 8.6, 6.4 Hz, 2H), 4.49 (m, 2H), 3.89
(t, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 2.24 (t, J = 6.0 Hz, 2H),
0.98 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 161.8, 158.3, 137.3,
137.3, 137.0, 135.6, 135.5, 135.3, 135.2, 127.6, 127.4, 127.1, 126.9,
126.8, 126.72, 119.9, 114.1, 113.9, 70.5 (hept, J2 = 33.6 Hz), 62.2, 61.9,
55.4, 55.2, 42.8, 41.3, 40.8, 29.8, 27.0, 25.9, 19.5; IR υ (cm−1) 3408,
1218, 1105; HRMS (ESI) calcd for C29H34F6NaO5Si (M + Na)+
627.1972, found 627.1971.
1-(2-Hydroxyethyl)-4′-methoxy-1,4-dihydro-[1,1′-biphenyl]-
4-ol (20bis). To a solution of 20 (159.6 mg, 0.26 mmol, 1.0 equiv) in
THF (2.5 mL) at 0 °C was added TBAF (396 μL, 0.40 mmol, 1.5
equiv) dropwise under stirring. The reaction was followed by TLC.
3a-Phenyl-3,3a,7,7a-tetrahydrobenzofuran-6(2H)-one (17).
Pale yellow oil: 0.025 mmol, 5.3 mg, 38% yield over 2 steps; 1H
7592
dx.doi.org/10.1021/jo301408j | J. Org. Chem. 2012, 77, 7588−7594

The Journal of Organic Chemistry
Article
After completion, the solution was directly purified by silica gel
chromatography with a mixture of ethyl acetate/hexane to give 55.1
mg (85%) of a white solid. 1H NMR (300 MHz, CDCl3) δ 7.20 (d, J =
8.6 Hz, 2H), 6.85 (dd, J = 8.7, 3.1 Hz, 2H), 5.99 (d, J = 10.2 Hz, 2H),
5.87 (d, J = 9.7 Hz, 2H), 4.57 (s, 1H), 3.78 (s, 3H), 3.73 (t, J = 6.4 Hz,
2H), 2.16 (t, J = 6.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 158.3,
137.6, 136.8, 135.8, 127.6, 127.4, 126.9, 114.0, 61.9, 60.5, 60.2, 55.4,
43.2, 41.7, 41.0, 20.4, 13.7; HRMS (ESI) calcd for C15H18NaO3 (M +
Na)+ 269.1148, found 269.1145.
2-(4-Hydroxy-4′-methoxy-1,4-dihydro-[1,1′-biphenyl]-1-yl)-
ethyl 2-nitrobenzenesulfonate (21). To a solution of “diol” (33.9
mg, 0.14 mmol, 1.0 equiv) in DCM (2.0 mL) at −20 °C was added
Et3N (27.8 mg, 0.28 mmol, 2.0 equiv), followed by DMAP (8.4 mg,
0.07 mmol, 0.5 equiv) and NsCl (33.5 mg, 0.15 mmol, 1.1 equiv). The
reaction was followed by TLC. After completion, the solution was
directly purified by silica gel chromatography with a mixture of ethyl
acetate/hexane to give 23.1 mg (40%) of a colorless oil. 1H NMR (300
MHz, CDCl3) δ 8.11 (d, J = 7.2 Hz, 1H), 7.85−7.72 (m, 4H), 7.16 (d,
J = 8.9 Hz, 2H), 6.84 (d, J = 8.9 Hz, 2H), 6.01 (dd, J = 10.2, 3.2 Hz,
2H), 5.78 (dd, J = 10.2, 1.6 Hz, 2H), 4.54 (s, 1H), 4.34 (t, J = 6.7 Hz,
2H), 3.77 (s, 3H), 2.34 (t, J = 6.7 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 158.5, 136.6, 135.0, 133.9, 132.4, 131.3, 129.5, 128.2, 127.3,
124.8, 114.2, 70.1, 61.9, 55.4, 42.8, 36.9; HRMS (ESI) calcd for
C21H21NNaO7S (M + Na)+ 454.0931, found 454.0930.
(ddd, J = 21.7, 14.2, 10.1 Hz, 4H), 2.32 (s, 3H), 2.26−2.13 (m,1H);
13C NMR (75 MHz, CDCl3) δ 197.7, 154.9, 154.1, 135.2, 128.1, 126.7,
115.8, 73.9, 56.2, 50.8, 40.2, 38.7, 36.2; IR υ (cm−1) 3403, 1648, 1215;
HRMS (ESI) calcd for C15H17NO2Na (M + Na)+ 266.1151, found
266.1147.
ASSOCIATED CONTENT
* Supporting Information
■
S
Complete experimental procedures and characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: canesi.sylvain@uqam.ca.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are very grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC), the Canada Founda-
tion for Innovation (CFI), the provincial government of
Quebec (FQRNT and CCVC) and Boehringer Ingelheim
(Canada) Ltd. for their precious financial support in this
research.
2-(4′-Methoxy-4-oxo-1,4-dihydro-[1,1′-biphenyl]-1-yl)ethyl
2-nitrobenzenesulfonate (21bis). To a solution of 21 (22.8 mg,
0.05 mmol, 1.0 equiv) and molecular sieves 4Å in DCM (2.0 mL) at 0
°C was added TPAP (1.8 mg, 0.005 mmol, 0.1 equiv) under stirring,
followed by NMO (18.6 mg, 0.16 mmol, 3.0 equiv). The reaction was
followed by TLC. After completion, the reaction mixture was diluted
with ethyl acetate, filtered through a pad of Celite, and concentrated
under vacuum. The residue was then purified by silica gel
chromatography with a mixture of ethyl acetate/hexane to give 12.4
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O-methylsceletenone 1 in 76% yield. H NMR (300 MHz, CDCl3) δ
́
7.27 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.72 (dd, J = 10.1,
1.7 Hz, 1H), 6.10 (d, J = 10.1 Hz, 1H), 3.81 (s, 3H), 3.31 (t, J = 7.9
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