Aryne cycloaddition reactions of benzodioxasilines as aryne precursors generated by catalytic reductive ortho-C[sbnd]H silylation of phenols with traceless acetal directing groups

Article abstract of DOI:10.1016/j.tet.2016.12.002

Diversely substituted arylsilyl triflates, as aryne precursors for aryne cycloaddition reactions, were accessed from benzodioxasilines. Catalytic reductive C[sbnd]H ortho-silylation of phenols with traceless acetal directing groups was exploited to prepare benzodioxasilines. Sequential addition of MeLi and then trifluoromethanesulfonic anhydride to benzodioxasilines provided arylsilyl triflates in a single pot. Notably, this approach was successfully utilized to prepare sterically hindered 1,2,3-trisubstituted arylsilyl triflates, which ultimately underwent fluoride-mediated aryne cycloaddition.

Full text of DOI:10.1016/j.tet.2016.12.002

Accepted Manuscript
Aryne cycloaddition reactions of benzodioxasilines as aryne precursors generated
by catalytic reductive ortho-C–H silylation of phenols with traceless acetal directing
groups
Parham Asgari, Udaya Sree Dakarapu, Hiep H. Nguyen, Junha Jeon
PII:
S0040-4020(16)31269-8
10.1016/j.tet.2016.12.002
TET 28294
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 September 2016
Revised Date: 1 December 2016
Accepted Date: 4 December 2016
Please cite this article as: Asgari P, Dakarapu US, Nguyen HH, Jeon J, Aryne cycloaddition reactions of
benzodioxasilines as aryne precursors generated by catalytic reductive ortho-C–H silylation of phenols
with traceless acetal directing groups, Tetrahedron (2017), doi: 10.1016/j.tet.2016.12.002.
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Aryne cycloaddition reactions of benzodioxasilines as Leave this area blank for abstract info.
aryne precursors generated by catalytic reductive
ortho-C–H silylation of phenols with traceless acetal
directing groups
Parham Asgari, Udaya Sree Dakarapu, Hiep H. Nguyen,
Junha Jeon*
Department of Chemistry and Biochemistry, University of Texas at Arlington, TX 76019, United States
1

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Tetrahedron
journal homepage: www.elsevier.com
Aryne cycloaddition reactions of benzodioxasilines as aryne precursors generated
by catalytic reductive ortho-C–H silylation of phenols with traceless acetal
directing groups
Parham Asgari,a Udaya Sree Dakarapu,a Hiep H. Nguyen,a and Junha Jeona
aDepartment of Chemistry and Biochemistry, University of Texas at Arlington, TX 76019, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Diversely substituted arylsilyl triflates, as aryne precursors for aryne cycloaddition reactions,
were accessed from benzodioxasilines. Catalytic reductive C–H ortho-silylation of phenols
with traceless acetal directing groups was exploited to prepare benzodioxasilines. Sequential
addition of MeLi and then trifluoromethanesulfonic anhydride to benzodioxasilines provided
arylsilyl triflates in a single pot. Notably, this approach was successfully utilized to prepare
sterically hindered 1,2,3-trisubstituted arylsilyl triflates, which ultimately underwent fluoride-
mediated aryne cycloaddition.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
AryneArrylsilyl triflatesBenzodioxasilinesC-H
activationCycloaddition
Silyl acetals
Corresponding author. Tel.: +1-817-272-0262; fax: +1-817-272-3808; e-mail: jjeon@uta.edu
1

oxyanion intermediates 4 by trifluoromethanesulfonic anhydride
can directly afford diversely substituted silylaryl triflates
(Scheme 2b).
ACCEPTED MANUSCRIPT
1. Introduction
Ever since the discovery of benzynes in the mid 1950s,1 these
highly reactive intermediates have been employed in a wide
variety of important applications, such as the synthesis of
bioactive molecules,2 organic materials,3 and catalysts.4
Additionally, benzynes enable the formation of diverse
heterocyclic frameworks, which are difficult to obtain by
conventional methods, via reactions with various arynophiles.5
Among the several methods that have been developed for the
efficient generation of arynes,6 the reaction of silylaryl triflates
with fluoride is one of the most widely used approaches.7 These
stable benzyne precursors, which can undergo aryne
cycloadditions under mild conditions, have led to a resurgence in
aryne chemistry. Generally, these highly useful 1,2-silylaryl
triflates have been prepared by one of the following three
methods: 1) a sequence of directed ortho metalation (DoM),8
silylation and triflation, 2) catalytic cross-coupling of ortho-
haloarenes9 and triflation, and 3) ortho-halo-phenols via retro-
Brook rearrangement10 followed by triflation (Scheme1).
However, each of these methods suffer from challenges and/or
limitations: the commercial availability of starting materials,
challenging post-directing group manipulation due to potential
protodesilylation, the need for either pre-functionalization of
arene substrates or stoichiometric basic reagents, and limited
functional group compatibility.11 Furthermore, preparation of
site-selectively installed silyl and triflate moieties within multi-
substituted arenes for regioselective aryne cycloaddition is often
difficult to access by these methods.
Scheme 2. Synthetic approach to silylaryl triflates via ortho-
C–H silylation
2. Results and Discussion
This work:
Benzodioxasilines were efficiently prepared through Ir-
catalyzed hydrosilylation of phenyl acetates followed by Rh-
catalyzed C–H silylation in a single pot. We then examined the
efficiency of the nucleophilic ring-opening reaction of
benzodioxasilines 3 with simple, readily available organometallic
reagents (e.g., organolithium reagents), followed by direct
triflation with trifluoromethanesulfonic anhydride. The single-
pot, sequential reactions with benzodioxasiline 3a, generated
from phenyl acetate 1a via catalytic reductive ortho-C–H
silylation and used without purification, produced the desired
silylaryl triflate 5a by MeLi ring-opening and trifilation reactions
in excellent yield (91% from 1a) (Table 1). Electronically
differentiated, diverse substituted benzodioxasilines provided
silylaryl triflates 5 in moderate to excellent yields (four steps
from 1) under this reaction conditions. Specifically, halogens,
trifluoromethyl, TBS-protected primary alcohol group, ortho-
methyl, methoxy within benzodioxasilines 3 were tolerated by
the four-step reaction conditions to furnish silylaryl triflates (5b–
5i). 1- and 2-naphthyl silyl triflates (5j and 5k) were produced
from 1j and 1k in modest yields via the reaction sequence.
Moreover, disubstituted benzodioxasilines 3l and 3m afforded 5l
and 5m in 53% and 72% yields, respectively. Finally, dual
functionalization produced bis-silylaryl triflate 5n in 74% yield.
directed
catalytic ortho-
C–H silylation
O
X
ODG
ortho-silylation
Ar
O
Ar
H
[Si]H
H
X = H, Cl
DG:
OTf
[Si]
directing group
Ar
O[Si]
OPG
Ar
Ar
retro-Brook
rearrangement
catalytic
cross-coupling
Br
I
PG:
protecting group
Scheme 1. Methods to prepare silylaryl triflates
We recently developed method to access versatile
a
benzodioxasilines 3 from readily accessible phenyl acetates,
derived from simple phenol, via catalytic reductive C–H ortho-
silylation with traceless acetal directing groups (Scheme 2a).12
Specifically, a relay of iridium and rhodium catalysts involving
hydrosilylation of esters with dihydrosilanes and arene ortho-C–
H silylation, respectively, which were followed by a subsequent
nucleophile addition to the electrophilic silicon to remove the
acetal directing group, directly provides unmasked ortho-silyl
phenol products in a single vessel. This strategy was successfully
applied to the preparation of multi-substituted arenes by
exploiting a new, formal α-chloroacetyl directing group. In
particular, this new directing group tactic permits access to
sterically hindered ortho-silyl phenols. Importantly the synthesis
of 1,2,3-trisubstituted phenolic arenes, which are difficult to
obtain by other catalytic means, was established. Following this
study, we speculated that diversely substituted benzodioxasilines
3 could be excellent precursors for preparation of silylaryl
triflates. For example, addition of organometallic agents to
silicon and then subsequent trapping of the resulting ortho-silyl
During these processes, we found that noticeable, yet minor
desilylation phenol byproducts 7 were also produced with most
substrates (Scheme 3). Especially, substrates such as 5d, 5j, and
5k produced a significant amount of 7. For the desilylation event,
we reasoned that a nucleophilic attack of MeLi to dioxasilines
first generates putative penta-coordinate silicate species 8, which
undergoes a fragmentation process to afford lithium ortho-silyl
phenoxide 10 (via lithio acetal 9) and acetaldehyde.
A
nucleophilic addition of MeLi to acetaldehyde can then furnish
XCH2CH(Me)OLi. At this moment two possible scenarios
explaining the observed desilylation are feasible: 1)
Intramolecular silyl transfer–a [1,3]-silatropic rearrangement can

be attributed to this issue. For example,
a
[1,3]-Brook
upon work-up. To minimize the potential rearrangement (10 to
ACCEPTED MANUSCRIPT
rearrangement13 of ortho-silyl phenols to afford silyl ethers has
been reported, however, this process was explored mainly under
acidic conditions,14 elevated temperatures15 or catalytic aerobic
conditions.16 Additionally, under strong basic conditions a retro-
[1,3]-silatropic process within ortho-silyl phenols has been well
reported.10 2) Intermolecular silyl transfer–nucleophiles (e.g.,
MeLi, LiOPh, LiOR), present in the reaction, can engage with 10
to produce dianions of type 12, which eventually afford phenols 7
i) [Ir(coe)2Cl]2 (0.1 mol %)
11, path 1) or reversible association of nucleophiles (10 to 12,
path 2) to silyl moiety after the first fragmentation (3 to 10), we
quickly quenched the reaction within <1 min with Tf2O at –78 °C
(achieving a full consumption of 3). This procedure substantially
reduced the formation of 7, thereby enhancing yields of desirable
products 6.
iii) MeLi (2 equiv)
H
2SiEt2 (2 equiv)
Me
O
Me
O
OTf
Et2O, –78 °C
THF, 60°C;
O
O
Si
SiEt2Me
iv) Tf2O
ii) [Rh(nbd)Cl]2 (0.4 mol %)
P(4-MeOPh)3 (2.4 mol %)
nbe (2 equiv), THF, 120°C
Et2
3
5
1
OTf
OTf
SiEt2Me
5b 88%
Me
OTf
OTf
SiEt2Me
OTf
SiEt2Me MeO
OTf
TBSO
SiEt2Me
F
Cl
SiEt2Me
F3C
SiEt2Me
5a 91%
5c 82%
5d 70%
5e 74%
5f 83%
OTf
SiEt2Me
OMe
OTf
Me
OTf
OTf
SiEt2Me
5k 66%
OTf
OTf
SiEt2Me
O
SiEt2Me
SiEt2Me
SiEt2Me
O
5g 72%
Me
5h 66%
5i 65%
5j 60%
5l 53%
MeEt2Si
TfO
OTf
OTf
SiEt2Me
Me
SiEt2Me
5m 72%
5n 74%
Table 1. Preparation of silylaryl triflates 5 from benzodioxasilines 3
benzodioxasilines 3o-r, obtained by a column chromatography
after the reductive C–H silylation, were employed under the
reaction conditions, we were able to isolate 5o-r in good yields.
Of note, these 1,2,3-trisubstituted arylsilyl triflates are difficult
to access by other catalytic means.
R
R
O
1. MeLi, Et2O, –78 °C
2. Tf2O, –78 °C
OTf
Cl
O
Si
Et2
SiEt2Me
3
5
Me
Me
Me
Me
OTf
SiEt2Me
5p 73%
Me
Me
OTf
Ph
OTf
OTf
SiEt2Me
5o 81%
SiEt2Me
SiEt2Me
5q 70%
5r 75%
Table 2. Preparation of sterically hindered silylaryl triflates 5
from benzodioxasilines 3
Scheme 3. Proposed mechanism of desilylation
We next explored fluoride-mediated [4+2] aryne
cycloaddition reactions of diethylmethylsilylaryl triflates 5 with
furan (Table 3). Cycloaddition reactions with electron-rich and
-deficient arylsilyl triflates with furan (solvent) provided a
Next we investigated the single-pot, sequential strategy
concerning nucleophilic attack of MeLi and triflation of the
sterically demanding benzodioxasilines 3 bearing substituents
at ortho position relative to the hydroxyl group (Table 2).
These substrates consistently produced substantial desilylation
adducts 7 even in a short period of reaction time. We found that
the purity of the dioxasilines 3 was crucial to affect the MeLi
variety
of
1,4-dihydro-1,4-epoxynaphthalenes
13,
demonstrating good functional group tolerance. Under these
reaction conditions, meta and para-substituted arylsilyl triflates
(5b-g) produced the corresponding 6-substituted 1,4-dihydro-
1,4-epoxynaphthalenes (13b-g) in good yields. In particular, a
addition
reaction.
Specifically,
when
purified
3

4
Tetrahedron
ACCEPTED MANUSCRIPT
TBS-protected primary alcohol group within 5f survived under
the reaction conditions at 0 ºC. The ortho-substituted arylsilyl
triflates (5h and 5i) underwent aryne cycloadditions to provide
13h and 13i in 86% and 67% yields, respectively. This
approach is also successful with 1- and 2-silylnaphthyl triflates
(5j and 5k, respectively) to afford 13j and 13k in modest
yields. Furthermore, cycloadditions with di-substituted arylsilyl
triflates (i.e., 5l and 5m) and tetra-substituted arylsilyl triflate
(5n) produced 13l, 13m, and 13n (1:1 dr) in good yields. Next,
we studied the cycloaddition of sterically hindered, 1,2,3-
trisubstituted arylsilyl triflates 5o-r. The corresponding
cycloadducts 13o-r were successfully produced in moderate
yields.
hindered environment. Catalytic reductive ortho-C–H bond
silylation of the resulting phenyl acetate with the α-
chloroacetyl formal directing group provided dioxasiline 16
(only C2). A MeLi addition to 16 afforded C2-silyl phenol 17
in 82% yield over 3 steps. The reaction of 17 and Tf2O in the
presence of pyridine gave arylsilyl triflate 18, which in turn
was utilized for the aryne cycloaddition with furan to afford
cycloadduct 19. During the course of the cycloaddition reaction
partial deprotection of the ketal group was observed (19:20 =
4:1). ketal deprotection of 19 afforded 20 (72% yield, 1.2:1 dr).
(scheme 4)
1. HOCH2CH2OH
O
p-TSA (5 mol %)
O
Me
H
Me
O
PhMe, reflux
H
H
O
2.
H
O
H
H
Cl
HO
Cl
O
OH
14
15
DCC
DMAP (5 mol %)
CH2Cl2, rt
i) [Ir(coe)2Cl]2, Et2SiH2
THF, 50 °C;
O
Me
O
MeLi
Et2
Si
O
H
THF, –78 °C
ii) [Rh(nbd)Cl]2
(4-MeOPh)3P, nbe
THF, 120 °C
H
H
Cl
O
16
O
O
Me
Me
O
O
Tf2O
TBAF
Et2
Si
Et2
Si
H
H
Me
Me
pyridine
CH2Cl2
furan
rt
H
H
H
H
HO
17 82% over 3 steps
TfO
0 °C to rt
(19:20 = 4:1)
18 90%
O
O
Me
Me
O
HCl
H
H
20
+
(72%,
THF/H2O
rt
H
H
O
H
H
O
1.2:1 dr)
19
20
Scheme 4. Synthetic approach to estrone derivative 20
3. Conclusion
To summarize, we have developed an efficient strategy to
prepare diversely substituted arylsilyl triflates. The catalytic
reductive ortho-C–H silylation of phenols via a traceless acetal
directing group to afford benzodioxasilines 3, followed by a
sequential addition of MeLi and trifluoromethanesulfonic
anhydride, furnished arylsilyl triflates 5 in a single pot. In
particular, α-chloroacetyl formal directing group was required
for the effective reductive ortho-C–H silylation to afford 1,2,3-
trisubstitued arylsilyl triflates 5. Furthermore, this class of
arylsilyl triflates demanded purification of benzodioxasilines
3o-r for subsequent nucleophilic ring-opening and triflation
processes, in order to minimize unwanted desilylation
byproduct 7. We demonstrated that fluoride-mediated [4+2]
Table 3. Fluoride-mediated [4+2] aryne cycloaddition
reaction of diethylmethylsilylaryl triflates 5
An important component of this project was broadening the
scope of the approach towards the synthesis of bioactive
molecules. For this purpose, we examined the [4+2] aryne
cycloaddition of arylsilyl triflates derived from estrone 14. The
C17 ketone in estrone, which was not compatible in Ir-
catalyzed ester hydrosilylation, was first protected with a ketal
group. Next, the α-Chloroacetyl group was installed to the
phenol for an effective arene C–H silylation reaction in a
aryne
cycloaddition
reaction
of
the
resulting
4

ACCEPTED MANUSCRIPT
replaced by a screw cap with a Teflon liner, and the mixture
diethylmethylsilylaryl triflates 5 with furan to afford distinctly
substituted cycloadducts 13, some of which were not accessed
previously.
was stirred at 120 °C for 15 min. The reaction progress was
monitored by GC/MS spectrometry. The resulting
benzodioxasilines 3 were directly used for a subsequent
reaction without further purification. For hindered substrates
3o-r, the resulting benzodioxasilines 3 were purified for the
subsequent reactions; volatiles were removed in vacuo, and the
resulting mixture was dissolved with pentane, filtered through a
pad of Celite®, and concentrated in vacuo. The crude product
was purified by MPLC (hexanes/EtOAc = 80:1, 5 mL/min,
retention time 5-15 min). (iii) The crude benzodioxasilines 3 (1
mmol, THF, 1 M) were diluted with diethyl ether (3 mL, 0.33
M) and cooled to –78 °C. MeLi (3 mmol, 1.6 M in Et2O) were
added into the reaction mixture at –78 °C and stirred for 1 min.
(iv) Trifluoromethanesulfonyl anhydride (1.2 mmol, 0.2 mL)
was added into the reaction mixture. The reaction mixture was
warmed to rt and stirred for 30 min. The reaction mixture was
cooled to 0 °C and saturated aqueous ammonium chloride
solution was added. The mixture was extracted with diethyl
ether three times. The combined organic layer was washed with
water and brine, and dried over anhydrous sodium sulfate.
Volatiles were removed in vacuo, and the crude mixture was
purified by MPLC to afford arylsilyl triflates 5 (hexanes/EtOAc
= 40:1, 5 mL/min, retention time 6-20 min).
4. Experimental section
4.1. General
Reactions requiring anhydrous conditions were performed
under an atmosphere of nitrogen or argon in flame or oven-
dried glassware. Anhydrous toluene and dichloromethane
(DCM) were distilled from CaH2. Anhydrous tetrahydrofuran
(THF) and diethyl ether (Et2O) were distilled from sodium and
benzophenone. Triethylamine and pyridine were distilled from
KOH. DMF and DMSO were stored over 4 Å molecular sieves.
All other solvents and reagents from commercial sources were
used as received. NMR spectra were recorded on a 500 or 300
MHz NMR spectrometer. 1H NMR chemical shifts are
referenced to chloroform (7.26 ppm) and DMSO-d6 (2.50
ppm). 13C NMR chemical shifts are referenced to 13CDCl3
(77.23 ppm) and DMSO-d6 (39.52 ppm). The following
abbreviations are used to describe multiplets: s (singlet), d
(doublet), t (triplet), q (quartet), pent (pentet), m (multiplet),
nfom (nonfirst-order multiplet), and br (broad). The following
format was used to report peaks: chemical shift in ppm
[multiplicity, coupling constant(s) in Hz, integral, and
4.2.1.
2-[Diethyl(methyl)silyl]-4-(trifluoromethyl)phenyl
1
assignment]. H NMR assignments are indicated by structure
trifluoromethanesulfonate (5d). Yield (70%, 276 mg); colorless
oil; 1H NMR (CDCl3, 500 MHz) δ 7.76 (d, J = 2.4 Hz, 1H, Ar-
H), 7.71 (dd, J = 8.7, 2.4 Hz, 1H, Ar-H), 7.49 (d, J = 8.7 Hz,
environment (e.g., CHaHb). 1H NMR and 13C NMR were
processed with the iNMR software program. Infrared (IR)
spectra were recorded using neat (for liquid compound) or a
thin film from a concentrated DCM solution. Absorptions are
reported in cm−1. Only the most intense and/or diagnostic peaks
are reported. MPLC refers to medium pressure liquid
chromatography (25−200 psi) using hand-packed columns of
silica gel (20−45 ꢀm, spherical, 70 Å pore size), an HPLC
pump, and a differential refractive index detector. High-
resolution mass spectra (HRMS) were recorded in atmospheric-
pressure chemical ionization and time-of-flight (APCI/TOF)
mode. Samples were introduced as solutions in a mixed
solution of methanol and DCM. Analytical TLC experiments
were performed on an F254 plate with 250 ꢀm thickness.
Detection was performed by UV light or potassium
phosphomolybdic acid, potassium permanganate, and p-
anisaldehyde staining.
1H, Ar-H), 0.98-0.90 [m, 10H, Si(CH2CH3)2], and 0.38 (s, 3H,
3
SiCH3); 13C NMR (CDCl32, 125 MHz) δ 157.3, 134.0 (q, JF-C
=
3
3.6 Hz), 132.6, 129.9 (q, JF-C = 32.5 Hz), 128.7 (q, JF-C = 3.6
1
1
Hz), 123.8 (q, JF-C = 273.2 Hz), 119.9, 118.8 (q, JF-C = 320.3
Hz), 7.3, 5.3, and –5.6; IR (neat) 2962 (m), 2857 (w), 1566 (w),
1421 (s), 1201 (s), 1131 (s), 1045 (m), 889 (s), and 773 (s) cm-
1; TLC Rf = 0.5 in 40:1 hexanes:EtOAc; HRMS (APCI/TOF)
calcd for (M+H)+ (C13H16F6O3SSi)+: 394.0494. Found:
394.0463.
4.2.2.
4-{[(tert-Butyldimethylsilyl)oxy]methyl}-2-
(diethyl[methyl]silyl)phenyl trifluoromethanesulfonate (5e).
Yield (74%, 348 mg); colorless oil; 1H NMR (CDCl3, 500
MHz) δ 7.48 (d, J = 2.2 Hz, 1H, Ar-H), 7.37 (dd, J = 8.6, 2.2
Hz, 1H, Ar-H), 7.30 (d, J = 8.6 Hz, 1H, Ar-H), 4.76 (s, 2H, Ar-
CH2OTBS), 0.95 [s, 9H, OSiC(CH3)3], 0.97-0.85 [m, 10H,
Si(CH2CH3)2], 0.34 (s, 3H, SiCH3), and 0.11 [s, 6H,
OSi(CH3)2]; 13C NMR (CDCl3, 125 MHz) δ 154.3, 140.7,
4.2. General Procedure for Preparation of Arylsilyl triflates
from Phenyl Acetates (5)
1
134.3, 130.4, 128.8, 119.4, 118.7 (q, JF-C = 320.3 Hz), 64.3,
(i) [Ir(coe)2Cl]2 (0.9 mg, 0.1 mol %) and aryl acetates 1 (1
mmol) were added to a flame-dried, nitrogen-purged septum-
capped vial. The mixture was dissolved with THF (0.3 mL, 3.3
M), and diethylsilane (0.26 mL, 2 mmol) was added to the
mixture. The septum on the vial was replaced by a screw cap
with a Teflon liner under a N2 atmosphere [note: diethylsilane
(bp 56 °C and density 0.686 g/mL) is volatile]. The reaction
mixture was stirred for 3-12 h at 60 °C. Volatiles were
removed in vacuo to afford silyl acetals, which were directly
used for subsequent reactions without further purification. (ii)
26.1, 18.5, 7.5, 5.6, –5.1, and –5.3; IR (neat) 2954 (m), 2873
(w), 1571 (w), 1454 (s), 1244 (s), 1133 (s), 1061 (m), 888 (s),
and 621 (s) cm-1; TLC Rf = 0.5 in 40:1 hexanes:EtOAc; HRMS
(APCI/TOF) calcd for (M+H)+ (C19H34F3O4SSi2)+: 471.1663.
Found: 471.1689.
4.2.3.
2-[Diethyl(methyl)silyl]-4-methoxyphenyl
trifluoromethanesulfonate (5f). Yield (83%, 295 mg); colorless
oil; 1H-NMR (CDCl3, 500 MHz) δ 7.26 (d, J = 9.0 Hz, 1H, Ar-
H), 7.00 (d, J = 3.2 Hz, 1H, Ar-H), 6.90 (dd, J = 9.0, 3.2 Hz,
1H, Ar-H), 3.82 (s, 3H, Ar-OCH3), 0.98-0.84 [m, 10H,
[Rh(nbd)Cl]2
(1.8
mg,
0.4
mol
%),
tris(4-
Si(CH2CH3)2], and 0.34 (s, 3H, SiCH3); 13C NMR (CDCl3, 125
methoxyphenyl)phosphine (8.4 mg, 2.4 mol %), norbornene
(188 mg, 2 mmol), and THF (1 mL, 1 M) were added to the
crude silyl acetals (1 mmol). The septum on the vial was
1
MHz) δ 158.1, 148.6, 132.4, 122.2, 120.8, 118.7 (q, JF-C
=
320.3 Hz), 115.0, 55.6, 7.3, 5.4, and –5.5; IR (neat) 2957 (m),
5

6
Tetrahedron
ACCEPTED MANUSCRIPT
2878 (w), 1576 (w), 1467 (s), 1211 (s), 1121 (s), 1034 (m), 889
(s), and 618 (s) cm-1; TLC Rf = 0.5 in 40:1 hexanes: EtOAc;
HRMS (APCI/TOF) calcd for (M+H)+ (C13H20F3O4SSi)+:
357.0798. Found: 357.0815.
10H Si(CH2CH3)2], and 0.42 (s, 3H, SiCH3); 13C NMR (CDCl3,
125 MHz) δ 152.9, 138.5, 134.3, 131.9, 129.2, 128.15, 127.99,
1
127.95, 127.1, 118.8 (q, JF-C = 320.3 Hz), 116.6, 7.5, 5.6, and
–5.2; IR (neat) 2957 (m), 2874 (w), 1532 (w), 1474 (s), 1202
(s), 1109 (s), 1046 (m), 874 (s), and 637 (s) cm-1; TLC Rf = 0.5
in 40:1 hexanes:EtOAc. HRMS (APCI/TOF) calcd for (M+H)+
(C16H20F3O3SSi)+: 377.0849. Found: 377.0817.
4.2.4.
2-[Diethyl(methyl)silyl]-5-methylphenyl
trifluoromethanesulfonate (5g). Yield (72%, 245 mg); colorless
oil; 1H NMR (CDCl3, 500 MHz) δ 7.39 (d, J = 7.9 Hz, 1H, Ar-
H), 7.17-7.14 (m, 2H, Ar-H), 2.39 (s, 3H, Ar-CH3), 0.95-0.83
[m, 10H, Si(CH2CH3)2], and 0.32 (s, 3H, SiCH3); 13C NMR
(CDCl3, 125 MHz) δ 155.6, 142.2, 136.9, 128.5, 127.0, 120.3,
4.2.9.
4-[Diethyl(methyl)silyl]benzo[d][1,3]dioxol-5-yl
trifluoromethanesulfonate (5l). Yield (53%, 196 mg); colorless
oil; 1H NMR (CDCl3, 500 MHz) δ 6.79 (app s, 2H, Ar-H), 5.98
(s, 2H, OCH2O), 0.98-0.84 (m, 10H, Si(CH2CH3)2], and 0.38 (s,
3H, SiCH3); 13C NMR (CDCl3, 125 MHz) δ 153.8, 148.7,
1
118.7 (q, JF-C = 320.3 Hz), 21.5, 7.5, 5.6, and –5.3; IR (neat)
2957 (m), 2877 (w), 1610 (w), 1417 (s), 1204 (s), 1139 (s),
1046 (m), 839 (s), and 597 (s) cm-1; TLC Rf = 0.5 in 40:1
hexanes:EtOAc; HRMS (APCI/TOF) calcd for (M+H)+
(C13H20F3O3SSi)+: 341.0849. Found: 341.0873.
1
145.8, 118.7 (q, JF-C = 320.3 Hz), 113.5, 112.7, 109.1, 101.6,
7.4, 6.0, and –4.6; IR (neat) 2955 (m), 2865 (w), 1581 (w),
1465 (s), 1208 (s), 1124 (s), 1030 (m), 869 (s), and 661 (s) cm-
1; TLC Rf = 0.5 in 40:1 hexanes:EtOAc; HRMS (APCI/TOF)
calcd for (M+H)+ (13H18F3O5SSi)+: 371.0591. Found: 371.0585.
4.2.5.
2-[Diethyl(methyl)silyl]-6-methylphenyl
trifluoromethanesulfonate (5h). Yield (66%, 224 mg); colorless
1
oil; H NMR (CDCl3, 500 MHz) δ 7.39 (dd, J = 6.9, 2.2 Hz,
4.2.10.
2-[Diethyl(methyl)silyl]-4,6-dimethylphenyl
1H, Ar-H), 7.31 (dd, J = 7.5, 2.2 Hz, 1H, Ar-H), 7.28 (dd, J =
7.5, 6.9 Hz, 1H, Ar-H), 2.40 (s, 3H, Ar-CH3), 0.99-0.87 [m,
10H, Si(CH2CH3)2], and 0.37 (s, 3H, SiCH3); 13C NMR
(CDCl3, 125 MHz) δ 151.6, 135.3, 134.0, 132.8, 131.7, 128.1,
trifluoromethanesulfonate (5m). Yield (72%, 255 mg);
colorless oil; 1H NMR (CDCl3, 500 MHz) δ 7.18 (d, J = 2.3 Hz,
1H, Ar-H), 7.13 (d, J = 2.3 Hz, 1H, Ar-H), 2.38 (s, 3H, Ar-
CH3), 2.36 (s, 3H, Ar-CH3), 1.01-0.92 [m, 10H Si(CH2CH3)2],
and 0.39 (s, 3H, SiCH3); 13C NMR (CDCl3, 125 MHz) δ 149.6,
1
118.9 (q, JF-C = 319.8 Hz), 17.6, 7.5, 6.1, and –4.5; IR (neat)
1
2957 (m), 2875 (w), 1587 (w), 1455 (s), 1232 (s), 1115 (s),
1026 (m), 881 (s), and 610 (s) cm-1; TLC Rf = 0.5 in 40:1
hexanes:EtOAc; HRMS (APCI/TOF) calcd for (M+H)+
(13H20F3O3SSi)+: 341.0849. Found: 341.0818.
137.7, 135.7, 134.6, 132.4, 131.2, 119.0 (q, JF-C = 320.1 Hz),
20.9, 17.5, 7.6, 6.1, and –4.5; IR (neat) 2956 (m), 2877 (w),
1460 (s), 1221 (s), 900 (s), 1039 (m), 865 (s), and 633 (s) cm-1;
TLC Rf = 0.5 in 40:1 hexanes:EtOAc; HRMS (APCI/TOF)
calcd for (M+H)+ (C14H22F3O3SSi)+: 355.1006. Found:
355.1013.
4.2.6.
2-[Diethyl(methyl)silyl]-6-methoxyphenyl
trifluoromethanesulfonate (5i). Yield (65%, 231 mg); colorless
1
oil; H NMR (CDCl3, 500 MHz) δ 7.30 (dd, J = 7.8, 7.8 Hz,
4.2.11.
2,5-bis[Diethyl(methyl)silyl]-1,4-phenylene
1H, Ar-H), 7.04 (dd, J = 7.8, 1.5 Hz, 1H, Ar-H), 7.03 (dd, J =
7.8, 1.5 Hz, 1H, Ar-H), 3.86 (s, 3H, Ar-OCH3), 0.96-0.86 [m,
10H, Si(CH2CH3)2], and 0.35 (s, 3H, SiCH3); 13C NMR
(CDCl3, 125 MHz) δ 150.3, 143.6, 133.4, 128.7, 127.6, 119.2
bis(trifluoromethanesulfonate) (5n). Yield (74%, 425 mg);
colorless oil; 1H NMR (CDCl3, 500 MHz) δ 7.47 (s, 2H, Ar-H),
0.99-0.88 [m, 20H, Si(CH2CH3)2], and 0.37 (s, 6H, SiCH3); 13
C
1
NMR (CDCl3, 125 MHz) δ 153.5, 135.8, 127.7, 118.8 (q, JF-C
= 320.6 Hz), 7.2, 5.2, and –5.7; IR (neat) 2958 (m), 2879 (w),
1461 (w), 1422 (s), 1223 (s), 1137 (s), 1078 (m), 884 (s), and
615 (s) cm-1; TLC Rf = 0.5 in 20:1 hexanes:EtOAc; HRMS
(APCI/TOF) calcd for (M+H)+ (8H29F6O6S2Si2)+: 575.0843.
Found: 575.0817.
1
(q, JF-C = 321.6 Hz), 114.1, 55.7, 7.5, 5.6, and –5.1; IR (neat)
2957 (m), 2879 (w), 1575 (w), 1461 (s), 1203 (s), 1137 (s),
1030 (m), 870 (s), and 631 (s) cm-1; TLC Rf = 0.5 in 40:1
hexanes:EtOAc; HRMS (APCI/TOF) calcd for (M+H)+
(C13H20F3O4SSi)+: 357.0798. Found: 357.0776.
4.2.7.
2-[Diethyl(methyl)silyl]naphthalen-1-yl
4.2.12.
2-[Diethyl(methyl)silyl]-6-ethylphenyl
trifluoromethanesulfonate (5j). Yield (60%, 226 mg) colorless
oil; H NMR (CDCl3, 500 MHz) δ 7.90 (dd, J = 7.0, 1.3 Hz,
trifluoromethanesulfonate (5o). Yield (81%, 287 mg); colorless
oil; H NMR (CDCl3, 500 MHz) δ 7.40 (dd, J = 7.3, 2.1 Hz,
1
1
1H, Ar-H), 7.87 (ddd, J = 8.1, 1.1, 0.4 Hz, 1H, Ar-H), 7.82 (dd,
J = 8.2, 1.4 Hz, 1H, Ar-H), 7.77 (dd, J = 8.1, 1.1 Hz, 1H, Ar-
H), 7.53 (dd, J = 8.1, 7.0 Hz, 1H, Ar-H), 7.45 (dd, J = 8.1, 8.1
Hz, 1H, Ar-H), 0.99-0.90 [m, 10H, Si(CH2CH3)2], and 0.40 (s,
3H, SiCH3); 13C NMR (CDCl3, 76 MHz) δ 148.6, 137.9, 136.0,
1H, Ar-H), 7.37 (dd, J = 7.3, 2.1 Hz, 1H, Ar-H), 7.33 (dd, J =
7.3, 7.3 Hz, 1H, Ar-H), 2.79 (q, J = 7.6 Hz, 2H, Ar-CH2CH3),
1.25 (t, J = 7.6 Hz, 3H, Ar-CH2CH3), 0.99-0.87 [m, 10H,
Si(CH2CH3)2], and 0.37 (s, 3H, SiCH3); 13C NMR (CDCl3, 125
MHz) δ 150.7, 137.5, 135.3, 132.9, 131.9, 128.3, 118.9 (q, 1JF-C
= 319.35 Hz), 23.5, 14.2, 7.5, 6.2, and –4.4; IR (neat) 2957 (m),
2878 (w), 1576 (w), 1467 (s), 1211 (s), 1121 (s), 1034 (m), 889
(s), and 618 (s) cm-1; TLC Rf = 0.5 in 80:1 hexanes:EtOAc;
HRMS (APCI/TOF) calcd for (M+H)+ (C14H22F3O3SSi)+:
355.1006. Found: 355.1018.
1
132.2, 129.9, 129.3, 129.0, 126.2, 124.6, 118.9 (q, JF-C = 320.2
Hz), 114.9, 7.9, 7.3, –2.7; IR (neat) 2956 (m), 2877 (w), 1485
(s), 1192 (s), 1111 (s), 1051 (w), 890 (s), and 650 (s) cm-1; TLC
Rf = 0.5 in 80:1 hexanes: EtOAc; HRMS (APCI/TOF) calcd for
(M+H)+ (C16H20F3O3SSi)+: 376.0776. Found: 376.0759.
4.2.8.
3-[Diethyl(methyl)silyl]naphthalen-2-yl
4.2.13.
2-[Diethyl(methyl)silyl]-6-isopropylphenyl
trifluoromethanesulfonate (5k). Yield (66%, 248 mg); colorless
oil; 1H NMR (CDCl3, 500 MHz) δ 8.00 (s, 1H, Ar-H), 7.88 (dd,
J = 6.8, 2.2 Hz, 1H, Ar-H), 7.85 (dd, J = 6.8, 2.2 Hz, 1H, Ar-
H), 7.82 (s, 1H, Ar-H), 7.59-7.53 (m, 2H, Ar-H), 1.01-0.92 [m,
trifluoromethanesulfonate (5p). Yield (269 mg, 73%); colorless
oil; H NMR (CDCl3, 500 MHz) δ 7.42 (dd, J = 7.0, 2.5 Hz,
1H, Ar-H), 7.38-7.33 (m, 2H, Ar-H), 3.31 [hept, J = 6.8 Hz,
1H, Ar-CH(CH3)2], 1.24 [d, J = 6.8 Hz, 6H, Ar-CH(CH3)2],
1
6

ACCEPTED MANUSCRIPT
0.96-0.87 [m, 10H, Si(CH2CH3)2], and 0.35 (s, 3H, SiCH3); 13
C
1
oil; H NMR (CDCl3, 500 MHz) δ 7.24 (s, 1H, Ar-H), 7.18 (d,
J = 7.2 Hz, 1H, Ar-H), 7.01 [nfom, 2H, CH(O)CH=CH], 6.91
(d, J = 7.2 Hz, 1H, Ar-H), 5.70 (s, 2H, CHOCH), 4.67 (s, 2H,
Ar-CH2OTBS), 0.93 [s, 9H, OSiC(CH3)3], and 0.09 [s, 6H,
OSi(CH3)2]; 13C NMR (CDCl3, 125 MHz) δ 149.5, 147.9,
143.27, 143.12, 138.8, 122.7, 120.0, 118.8, 82.58, 82.41, 65.2,
26.2, 18.6, and –5.0; IR (neat) 3053 (m), 2874 (w), 1600 (w),
1460 (m), 1415 (s), 1278 (m), 1209 (s), 1139 (s), 1045 (s), 845
(w), 695 (s), and 571 (m) cm-1. TLC Rf = 0.5 in 5:1
hexanes:EtOAc; HRMS (APCI/TOF) calcd for (M+H)+
(C17H25O2Si)+: 289.1618. Found: 289.1602.
NMR (CDCl3, 125 MHz) δ 149.5, 142.2, 135.2, 133.0, 129.3,
128.4, 118.8 (q, JF-C = 317.3 Hz), 27.3, 23.7, 7.6, 6.2, and –
4.3; IR (neat) 2958 (m), 2877 (w), 1571 (w), 1447 (s), 1201 (s),
1154 (s), 1027 (m), 892 (s), and 636 (s) cm-1; TLC Rf = 0.5 in
80:1 hexanes:EtOAc; HRMS (APCI/TOF) calcd for (M+H)+
(C15H24F3O3SSi)+: 369.1162. Found: 369.1145.
1
4.2.14.
2-(tert-Butyl)-6-[diethyl(methyl)silyl]phenyl
trifluoromethanesulfonate (5q). Yield (70%, 267 mg); colorless
1
oil; H NMR (CDCl3, 500 MHz) δ 7.55 (dd, J = 7.8, 1.9 Hz,
1H, Ar-H), 7.37 (dd, J = 7.2, 1.9 Hz, 1H, Ar-H), 7.30 (dd, J =
7.8, 7.2 Hz, 1H, Ar-H), 1.43 [s, 9H, C(CH3)3], 0.95-0.84 [m,
10H Si(CH2CH3)2], and 0.32 (s, 3H, SiCH3); 13C NMR (CDCl3,
125 MHz) δ 148.2, 143.8, 135.6, 134.6, 131.8, 127.6, 118.6 (q,
1JF-C = 320.3 Hz), 36.5, 32.1, 7.6, 6.9, and –3.6; IR (neat) 2957
(m), 2878 (w), 1564 (w), 1443 (s), 1236 (s), 1163 (s), 1041 (m),
874 (s), and 608 (s) cm-1; TLC Rf = 0.5 in hexanes. HRMS
(APCI/TOF) calcd for (M+H)+ (C16H26F3O3SSi)+: 383.1319.
Found: 383.1304.
4.3.3. 6-Methoxy-1,4-dihydro-1,4-epoxynaphthalene (13f).
Yield (65%, 94 mg); colorless oil; 1H NMR (CDCl3, 500 MHz)
δ 7.13 (d, J = 7.8 Hz, 1H, Ar-H), 7.03 [dd, J = 5.6, 1.8 Hz, 1H
CH(O)CH=CH],
6.99 [dd,
J
=
5.6, 1.8 Hz, 1H
CH(O)CH=CH], 6.91 (d, J = 2.2 Hz, 1H, Ar-H), 6.42 (dd, J =
7.8, 2.2 Hz, 1H, Ar-H), 5.68 (app s, 1H, CHOCH), 5.66 (app s,
1H, CHOCH), and 3.77 (s, 3H, Ar-OCH3); 13C NMR (CDCl3,
125 MHz) δ 157.6, 151.2, 143.7, 142.4, 140.6, 120.6, 109.9,
107.4, 82.6, 82.2, and 55.8; IR (neat) 3036 (w), 2961 (w), 2909
(w), 1632 (m), 1516 (m), 1481 (m), 1264 (s), 1217 (s), 1030
(m), 812 (s), and 560 (m) cm-1; TLC Rf = 0.5 in 5:1
hexanes:EtOAc; HRMS (APCI/TOF) calcd for (M+H)+
(C11H11O2)+: 175.0754. Found: 175.0737.
4.2.15.
3-[Diethyl(methyl)silyl]-(1,1'-biphenyl)-2-yl
trifluoromethanesulfonate (5r). Yield (75%, 301 mg); colorless
1
oil; H NMR (CDCl3, 500 MHz) δ 7.54-7.52 (m, 1H, Ar-H),
7.45-7.37 (m, 7H, Ar-H), 1.02-0.93 [m, 10H, Si(CH2CH3)2],
and 0.42 (s, 3H, SiCH3); 13C NMR (CDCl3, 125 MHz) δ 150.1,
137.1, 136.5, 133.96, 133.85, 129.8, 128.6, 128.2, 118.2 (q, 1JF-
4.3.4. 6-Methyl-1,4-dihydro-1,4-epoxynaphthalene (13g). Yield
1
= 320.7 Hz), 7.6, 6.2, and –4.3; IR (neat) 2957 (m), 2878 (w),
(75%, 35 mg); colorless oil; H NMR (CDCl3, 500 MHz) δ
C
1556 (w), 1435 (s), 1221 (s), 1133 (s), 1024 (m), 869 (s), and
798 (s) cm-1; TLC Rf = 0.5 in 80:1 hexanes:EtOAc; HRMS
(APCI/TOF) calcd for (M+H)+ (C18H22F3O3SSi)+: 403.1006.
Found: 403.9985.
7.13 (d, J = 7.2 Hz, 1H, Ar-H), 7.10 (s, 1H, Ar-H), 7.02 [dd, J
= 5.5, 1.7 Hz, 1H CH(O)CH=CH], 7.01 [dd, J = 5.5, 1.7 Hz,
1H CH(O)CH=CH], 6.77 (d, J = 7.2 Hz, 1H, Ar-H), 5.69 (app
s, 1H, CHOCH), 5.67 (app s, 1H, CHOCH), and 2.30 (s, 3H,
Ar-CH3); 13C NMR (CDCl3, 125 MHz) δ 149.5, 146.2, 143.4,
143.0, 135.0, 125.2, 121.8, 120.1, 82.50, 82.38, and 21.5; IR
(neat) 3038 (m), 2954(w), 1620 (w), 1599 (w), 1459 (m), 1279
(s), 1165 (m), 1020 (s), 845 (s), 641 (s), and 573 (s) cm-1; TLC
Rf = 0.5 in 5:1 hexanes:EtOAc; HRMS (APCI/TOF) calcd for
(M+H)+ (C11H11O)+: 159.0804. Found: 159.0821.
4.3. General Procedure for Fluoride-Mediated Benzyne
Cycloaddition Reactions (13)
Arylsilyl triflate (0.5 mmol) 5 was dissolved in furan (0.2
mL) and placed in a 4 mL vial. TBAF (1.2 equiv, 1 M in THF)
was added into the reaction mixture at rt. The septum on the
vial was replaced by a screw cap with a Teflon liner, and the
mixture was stirred at rt for 2 h. The reaction was quenched by
adding saturated aqueous ammonium chloride. The reaction
mixture was extracted with diethyl ether and concentrated in
vacuo to afford the crude mixture, which was purified by
MPLC (hexanes/EtOAc = 10:1, 5 mL/min, retention time 7-15
min) to afford 1,4-dihydro-1,4-epoxynaphthalenes 13.
4.3.5. 5-Methyl-1,4-dihydro-1,4-epoxynaphthalene (13h). Yield
1
(86%, 68 mg); colorless oil; H NMR (CDCl3, 300 MHz) δ
7.09 (d,
J = 6.9 Hz, 1H, Ar-H), 7.07-6.99 [m, 2H,
CH(O)CH=CH], 6.88 (dd, J = 7.6, 6.9 Hz, 1H, Ar-H), 6.78 (d,
J = 7.6 Hz, 1H, Ar-H), 5.81 (app s, 1H, CHOCH), 5.71 (app s,
1H, CHOCH), and 2.32 (s, 3H, ArCH3); 13C NMR (CDCl3, 76
MHz) δ 148.7, 147.4, 143.2, 142.7, 130.1, 126.8, 125.1, 117.9,
82.6, 80.9, and 18.2; IR (neat) 3036 (m), 2841 (w), 1632 (w),
1465 (m), 1522 (s), 1216 (s), 1347 (s), 1014 (s), 835 (m), 662
(s), and 573 (m) cm-1; TLC Rf = 0.5 in 5:1 hexanes:EtOAc;
HRMS (APCI/TOF) calcd for (M+H)+ (C11H11O)+: 159.0804.
Found: 159.0791.
4.3.1. 6-(Trifluoromethyl)-1,4-dihydro-1,4-epoxynaphthalene
1
(13d). Yield (83%, 88 mg) colorless oil; H NMR (CDCl3, 300
MHz) δ 7.46 (s, 1H, Ar-H), 7.33 (d, J = 7.4 Hz, 1H, Ar-H),
7.29 (d, J = 7.4 Hz, 1H, Ar-H), 7.06 (dd, J = 5.5, 1.7 Hz, 1H,
CH(O)CH=CH), 7.04 (dd, J = 5.5, 1.8 Hz, 1H CH(O)CH=CH),
and 5.77 (app s, 2H, CHOCH); 13C NMR (CDCl3, 76 MHz) δ
4.3.6. 5-Methoxy-1,4-dihydro-1,4-epoxynaphthalene (13i).
Yield (60%, 56 mg); colorless oil; 1H NMR (CDCl3, 500 MHz)
δ 7.07 [dd, J = 5.5, 1.8 Hz, 1H, CH(O)CH=CH], 7.03 [dd, J =
5.5, 1.8 Hz, 1H CH(O)CH=CH], 6.97 (dd, J = 8.0, 7.0 Hz, 1H,
Ar-H), 6.93 (dd, J = 7.0, 0.8 Hz, 1H, Ar-H), 6.59 (dd, J = 8.0,
0.8 Hz, 1H, Ar-H), 5.95 (app s, 1H, CHOCH), 5.70 (app s, 1H,
CHOCH), and 3.83 (s, 3H, Ar-CH3); 13C NMR (CDCl3, 76
MHz) δ 153.1, 151.7, 143.23, 143.08, 135.2, 127.2, 113.9,
110.5, 82.7, 80.3, and 55.9; IR (neat) 3042 (m), 2874 (w), 1642
(w), 1453 (m), 1538 (s), 1312 (m), 1167 (s), 1041 (m), 844 (m),
2
153.4, 150.5, 143.3, 142.9, 127.7 (q, JF-C = 32.3 Hz), 124.3 (q,
1JF-C = 271.6 Hz), 123.2 (q, 3JF-C = 4.3 Hz), 120.2, 117.2 (q, 3JF-C
= 3.6 Hz), and 82.3 (2). IR (neat): 3035 (w), 2956 (m), 2924
(m), 2853 (m), 1703 (w), 1631 (m), 1527 (m), 1222 (s), 1087
(s), 1031 (s), and 826 (m) cm-1; TLC Rf = 0.5 in 5:1
hexanes:EtOAc; HRMS (APCI/TOF) calcd for (M+H)+
(C11H8F3O)+: 213.0522. Found: 213.0514.
4.3.2.
tert-Butyl[(1,4-dihydro-1,4-epoxynaphthalen-6-
yl)methoxy]dimethylsilane (13e). Yield (80%, 47 mg); colorless
7

8
Tetrahedron
ACCEPTED MANUSCRIPT
and 521 (m) cm-1; TLC Rf = 0.5 in 5:1 hexanes:EtOAc; HRMS
(APCI/TOF) calcd for (M+H)+ (C11H11O2)+: 175.0754. Found:
175.0731.
1528 (s), 1222 (s), 1147 (s), 1029 (s), 845 (m), 635 (s), and 516
(m) cm-1; TLC Rf = 0.5 in 3:1 hexanes:EtOAc; HRMS
(APCI/TOF) calcd for (M+H)+ (C14H11O2)+: 211.0754. Found:
211.0767.
4.3.7. 1,4-Dihydro-1,4-epoxyphenanthrene (13j). Yield (71%,
1
69 mg); pale yellow solid, mp 85-87 ºC; H NMR (CDCl3, 300
4.3.12. 5-Ethyl-1,4-dihydro-1,4-epoxynaphthalene (13o). Yield
1
MHz) δ 7.83 (dd, J = 8.3, 8.3 Hz, 2H, Ar-H), 7.56 (ddd, J =
7.9, 7.9, 7.9 Hz, 2H, Ar-H), 7.47 (dd, J = 8.1, 7.4 Hz, 1H, Ar-
H), 7.39 (dd, J = 8.1, 7.6 Hz, 1H, Ar-H), 7.31-7.12 [m, 2H,
CH(O)CH=CH], 6.28 (app s, 1H, CHOCH), and 5.94 (app s,
1H, CHOCH).; 13C NMR (CDCl3, 76 MHz) δ 148.5, 148.0,
145.1, 143.6, 132.0, 129.0, 127.8, 126.4, 125.6, 125.3, 122.9,
119.5, 83.6, and 81.4; IR (neat) 3050 (m), 2855 (w), 1655 (w),
1517 (m), 1451 (m), 1345 (s), 1147 (s), 1039 (s), 683 (s), and
482 (s); TLC Rf = 0.5 in 5:1 hexanes:EtOAc; HRMS
(APCI/TOF) calcd for (M+H)+ (C14H11O)+: 194.0732. Found:
194.0741.
(70%, 60 mg); colorless oil; H NMR (CDCl3, 500 MHz) δ
7.12 (d, J = 7.0 Hz, 1H, Ar-H), 7.05-7.02 [nfom, 2H,
CH(O)CH=CH], 6.92 (dd, J = 7.9, 7.0 Hz, 1H, Ar-H), 6.81 (d,
J = 7.9 Hz, 1H, Ar-H), 5.84 (app s, 1H, CHOCH), 5.72 (app s,
1H, CHOCH), 2.70 (dq, J = 14.1, 7.6 Hz, 1H, Ar-CHaHbCH3),
2.63 (dq, J = 14.1, 7.6 Hz, 2H, Ar-CHaHbCH3), and 1.21 (dd, J
= 7.7, 7.7 Hz, 3H, Ar-CHaHbCH3); 13C NMR (CDCl3, 125
MHz) δ 148.7, 146.9, 143.4, 142.9, 136.7, 125.40, 125.34,
118.2, 82.6, 81.0, 26.2, and 16.0; IR (neat) 3050 (m), 2963 (m),
2871 (w), 1643 (w), 1609 (w), 1470 (m), 1278 (m), 1141 (m),
1087 (m), 1003 (s), 870 (s), 675 (s), and 603 (m) cm-1; TLC Rf
= 0.5 in 10:1 hexanes:EtOAc; HRMS (APCI/TOF) calcd for
(M+H)+ (C12H13O)+: 173.0961. Found: 173.0942.
4.3.8. 1,4-Dihydro-1,4-epoxyanthracene (13k). Yield (67%, 65
1
mg) pale yellow solid, mp 160-162 ºC; H NMR (CDCl3, 500
4.3.13. 5-Isopropyl-1,4-dihydro-1,4-epoxynaphthalene (13p).
Yield (64%, 60 mg); colorless oil; 1H NMR (CDCl3, 500 MHz)
δ 7.11 (d, J = 6.9 Hz, 1H, Ar-H), 7.05-7.01 [nfom, 2H,
CH(O)CH=CH], 6.94 (dd, J = 7.9, 6.9 Hz, 1H, Ar-H), 6.86 (d,
J = 7.9, 0.5 Hz, 1H, Ar-H), 5.91 (app s, 1H, CHOCH), 5.70
(app s, 1H, CHOCH), 3.05 (hept, J = 6.9 Hz, 1H), 1.29 (d, J =
6.9 Hz, 3H), and 1.21 (d, J = 6.9 Hz, 3H); 13C NMR (CDCl3,
125 MHz) δ 148.7, 146.4, 143.5, 142.9, 141.2, 125.5, 122.8,
118.3, 82.6, 81.2, 31.8, 24.3, and 23.2; IR (neat) 3052 (m),
2956 (m), 2872 (w), 1641 (w), 1611 (w), 1475 (m), 1274 (m),
1121 (m), 1065 (m), 671 (s), and 653 (m) cm-1; TLC Rf = 0.5 in
10:1 hexanes:EtOAc; HRMS (APCI/TOF) calcd for (M+H)+
(C13H15O)+: 187.1117. Found: 187.1103.
MHz) δ 7.76-7.67 (m, 2H, Ar-H), 7.59 (s, 2H, Ar-H), 7.45-7.42
(m, 2H, Ar-H), 7.01-6.94 [m, 2H, CH(O)CH=CH], and 5.81 (
app s, 2H, CHOCH); 13C NMR (CDCl3, 125 MHz) δ 144.3,
141.9, 132.1, 128.3, 126.3, 118.8, and 82.0; IR (neat) 3024 (m),
2929 (w), 1666 (w), 1538 (m), 1454 (s), 1193 (s), 1025 (s), 843
(s), 744 (s), and 496 (m) cm-1; TLC Rf = 0.5 in 5:1
hexanes:EtOAc; HRMS (APCI/TOF) calcd for (M+H)+
(C14H11O)+: 195.0804. Found: 195.0788.
4.3.9. 6,9-Dihydro-6,9-epoxynaphtho[1,2-d][1,3]dioxole (13l).
Yield (60%, 56 mg); colorless oil; 1H NMR (CDCl3, 500 MHz)
δ 7.00 [dd, J = 5.6, 1.7 Hz, 1H, CH(O)CH=CH], 6.97 [dd, J =
5.6, 1.7 Hz, 1H, CH(O)CH=CH], 6.72 (d, J = 7.2 Hz, 1H, Ar-
H), 6.38 (d, J = 7.2 Hz, 1H, Ar-H), 5.90 (d, J = 10.7 Hz, 1H,
OCHaHbO), 5.90 (d, J = 10.7 Hz, 1H, OCHaHbO), 5.85 (app s,
1H, CHOCH), and 5.65 (app s, 1H, CHOCH); 13C NMR
(CDCl3, 125 MHz) δ 146.5, 143.2 (2), 141.5, 140.6, 127.3,
113.3, 103.5, 101.1, 82.5, and 79.7; IR (neat) 3053 (m), 2960
(w), 2777 (w), 1650 (w), 1572 (m), 1458 (s), 1232 (s), 1042 (s),
954 (s), 829 (m), 638 (s), and 522 (m) cm-1; TLC Rf = 0.5 in 5:1
hexanes:EtOAc; HRMS (APCI/TOF) calcd for (M+H)+
(C11H9O3)+: 189.0546. Found: 189.0565.
4.3.14. 5-(Tert-butyl)-1,4-dihydro-1,4-epoxynaphthalene (13q).
Yield (50%, 50 mg); white solid, mp 53-54 ºC; 1H NMR
(CDCl3, 500 MHz) δ 7.12 (d, J = 6.8, 1.1 Hz, 1H, Ar-H), 7.06-
7.02 [nfom, 2H, CH(O)CH=CH], 6.97 (dd, J = 8.1, 1.1 Hz, 1H,
Ar-H), 6.93 (dd, J = 8.1, 6.8 Hz, 1H, Ar-H), 6.15 (app s, 1H,
CHOCH), 5.68 (app s, 1H, CHOCH), and 1.36 (s, 9H); 13C
NMR (CDCl3, 125 MHz) δ 149.2, 146.7, 144.1, 143.8, 142.8,
125.2, 122.6, 118.4, 83.2, 82.1, 35.5, and 31.5; IR (neat) 3066
(m), 2963 (m), 2869 (w), 1686 (w), 1588 (w), 1470 (m), 1279
(m), 1187 (m), 1120 (m), 1008 (m), 878 (s), 710 (s), and 658
(m) cm-1; TLC Rf = 0.5 in 10:1 hexanes:EtOAc; HRMS
(APCI/TOF) calcd for (M+H)+ (C14H17O)+: 201.1274. Found:
201.1294.
4.3.10. 5,7-Dimethyl-1,4-dihydro-1,4-epoxynaphthalene (13m).
Yield (71%, 61 mg); colorless oil; 1H NMR (CDCl3, 500 MHz)
δ 7.03 [dd, J = 5.5, 1.7 Hz, 1H, CH(O)CH=CH], 7.02 [dd, J =
5.5, 1.7 Hz, 1H, CH(O)CH=CH], 6.94 (s, 1H, Ar-H), 6.60 (s,
1H, Ar-H), 5.78 (app s, 1H, CHOCH), 5.66 (app s, 1H,
CHOCH), 2.28 (s, 3H, Ar-CH3), and 2.27 (s, 3H, Ar-CH3); 13C
NMR (CDCl3, 125 MHz) δ 149.2, 144.5, 143.08, 143.03,
134.9, 129.8, 127.0, 119.4, 82.7, 80.9, 21.3, and 18.2; IR (neat)
3047 (m), 2964 (m), 2872 (w), 1612 (w), 1481 (m), 1532 (s),
1214 (s), 1121 (s), 644 (s), and 521 (m) cm-1; TLC Rf = 0.5 in
5:1 hexanes:EtOAc; HRMS (APCI/TOF) calcd for (M+H)+
(C12H13O)+: 173.0961. Found: 173.0942.
4.3.15. 5-Phenyl-1,4-dihydro-1,4-epoxynaphthalene (13r).
1
Yield (67%, 74 mg); pale yellow solid, mp 63-65 ºC; H NMR
(CDCl3, 500 MHz) δ 7.51-7.45 (m, 2H, Ar-H), 7.42-7.35 (m,
3H, Ar-H), 7.29-7.25 (m, 1H, Ar-H), 7.20-7.10 [m, 2H,
CH(O)CH=CH], 7.09-7.04 (m, 2H, Ar-H), 5.84 (app s, 1H,
CHOCH), and 5.78 (app s, 1H, CHOCH). 13C NMR (CDCl3,
125 MHz) δ 149.3, 147.1, 143.5, 143.0, 139.8, 135.1, 128.9,
128.3, 127.6, 125.6, 125.4, 119.5, 82.7, and 82.0; IR (neat)
3063 (m), 2962 (m), 2872 (w), 1662 (w), 1581 (w), 1473 (m),
1282 (m), 1193 (m), 1117 (m), 1003 (m), 871 (s), and 710 (s),
4.3.11. 1,4,5,8-Tetrahydro-1,4:5,8-diepoxyanthracene (13n).
1
Yield (69%, 72 mg) (1:1 dr); white sold, mp 189-191 ºC ; H
cm-1; TLC Rf
= 0.5 in 10:1 hexanes:EtOAc; HRMS
NMR (CDCl3, 500 MHz) δ 7.20 (s, 2H, Ar-H), 7.06-6.99 (m,
4H, CH(O)CH=CH], and 5.63 (app s, 4H, CHOCH); 13C NMR
(CDCl3, 125 MHz) δ 148.0, 143.6, 114.3, and 82.6; IR (neat)
3047 (w), 2963 (m), 2877 (w), 1640 (w), 1603 (w), 1485 (m),
(APCI/TOF) calcd for (M+H)+ (C16H13O)+: 221.0961. Found:
221.0945.
8

ACCEPTED MANUSCRIPT
4.4. Procedure for Preparation of (8R,9S,13S,14S)-13-
crude mixture was purified by MPLC (hexanes/EtOAc = 5:1, 5
Methyl-6,7,8,9,11,12,13,14,15,16-deca-
hydrospiro[cyclopenta[a]phenanthrene-17,2'-
[1,3]dioxolan]-3-yl 2-chloroacetate (15)
mL/min) to afford arylsilyl triflate 18. White solid; Yield
(90%, 491 mg) H NMR (CDCl3, 500 MHz) δ 7.39 (s, 1H, Ar-
1
H), 7.01 (s, 1H, Ar-H), 3.99-3.88 (m, 4H, OCH2CH2O), 2.87
(dd, J = 8.4, 4.0 Hz, 2H, alkyl-H), 2.37-2.31 (m, 1H, alkyl-H),
2.30-2.25 (m, 1H, alkyl-H), 2.04 (ddd, J = 14.1, 11.6, 2.7 Hz,
1H, alkyl-H), 1.94-1.76 (m, 4H alkyl-H), 1.64 (ddd, J = 11.9,
10.9, 7.0 Hz, 1H alkyl-H), 1.56 (ddd, J = 12.6, 3.3, 2.6 Hz, 1H
alkyl-H), 1.55-1.33 (m, 4H), 0.89 [s, 3H CH(18)3], 0.97-0.80
[m, 10H, Si(CH2CH3)2], and 0.30 (s, 3H, SiCH3); 13C NMR
(CDCl3, 125 MHz) δ 153.5, 141.0, 139.8, 134.1, 126.8, 119.58,
119.51, 118.7 (q, 1JF-C = 319.6 Hz), 65.5, 64.8, 49.5, 46.3, 44.0,
38.8, 34.4, 30.8, 29.9, 26.8, 26.1, 22.6, 14.5, 7.6, 5.68, 5.59,
and –5.2; IR (neat) 2957 (m), 2874 (w), 1493 (m), 1304 (m),
1190 (s), 1042 (m), and 804 (m) (s) cm-1; TLC Rf = 0.5 in 5:1
hexanes:EtOAc; HRMS (APCI/TOF) calcd for (M+H)+
(C26H38F3O5SSi)+: 547.2156. Found: 547.2139.
A round-bottom flask (100 mL) with a magnetic stir bar and
a Dean-Stark apparatus was charged with estrone 14 (3.0 g,
11.0 mmol) and p-TsOH (105 mg, 5 mol %). Toluene (60 mL)
and ethylene glycol (3.1 ml, 55 mmol) were added and the
reaction mixture was heated at reflux for 14 h. The reaction was
cooled to rt, and the solvent was removed in vacuo, ethyl
acetate (30 mL) and brine (50 mL) were added. The mixture
was extracted with ethyl acetate three times, and the combined
organic extract was washed with water and brine, and dried
over anhydrous sodium sulfate. The volatiles were removed in
vacuo to afford the crude product, which was directly used for a
subsequent reaction without further purification. The crude
product (11 mmol) and chloroacetic acid (1.9 g, 20 mmol) and
DMAP (67 mg, 5 mol %) were dissolved with CH2Cl2 (20 mL),
the reaction mixture was cooled to 0 °C with an ice bath. DCC
(2.7 g, 13 mmol) was added into the reaction mixture slowly.
The reaction mixture was warmed to rt and stirred for 10 h.
Diethyl ether (30 mL) was added to precipitate the urea
byproduct. The mixture was filtered and the filtrate was treated
with saturated aqueous sodium bicarbonate. Aqueous phase
was extracted with ethyl acetate three times. The combined
organic extracts were washed with water and brine, and dried
over anhydrous sodium sulfate. The volatiles were removed in
vacuo, and the crude mixture was purified by flash column
(hexanes: EtOAc 3:1) to afford the ester 15 (3.27 g, 76% over
4.6. (3aS,3bR,11bS,13aS)-13a-Methyl-
2,3,3a,3b,4,5,7,10,11b,12,13,13a-dodecahydrospiro[7,10-
epoxycyclopenta[c]tetraphene-1,2'-[1,3]dioxolane] (19)
C2-Silyl triflate 18 (109 mg, 0.2 mmol) was dissolved in
furan (0.2 mL). TBAF (0.6 mL, 0.24 mmol, 1 M in THF) was
added to the reaction mixture at rt. The septum on the vial was
replaced by a screw cap with a Teflon liner, and the mixture
was stirred at rt for 2 h. Reaction progress was monitored by
TLC until full conversion of 18. TLC showed two spots,
indicating formation of compound 19 and 20. The reaction was
quenched by adding saturated aqueous ammonium chloride.
The reaction mixture was extracted with diethyl ether and
concentrated in vacuo to afford a mixture of 19 and 20 (4:1),
which was used for next step without further purification.
1
two steps). White solid, mp 113-115 °C; H NMR (CDCl3, 500
MHz) δ 7.30 [d, J = 8.1 Hz, 1H, H(1)], 6.88 [dd, J = 8.1, 2.6
Hz, 1H, H(2)], 6.83 [d, J = 2.6 Hz, 1H, H(4)], 4.28 (s, 2H,
CH2Cl), 3.98-3.88 (m, 4H, OCH2CH2O), 2.88-2.84 (m, 2H,
alkyl-H), 2.32 (dddd, J = 13.2, 4.2, 4.2, 2.7 Hz, 1H, alkyl-H),
2.26 (ddd, J = 10.6, 10.6, 4.1 Hz, 1H, alkyl-H), 2.03 (ddd, J =
14.0, 11.2, 3.1 Hz, 1H, alkyl-H), 1.93-1.74 (m, 4H, alkyl-H),
1.63 (ddd, J = 12.1, 10.8, 7.0 Hz, 1H, alkyl-H), 1.55-1.31 (m,
5H, alkyl-H), and 0.88 [s, 3H, CH(18)3]; 13C NMR (CDCl3, 125
MHz) δ 166.4, 148.2, 138.9, 138.8, 126.8, 121.2, 119.6, 118.2,
65.5, 64.8, 49.6, 46.3, 44.0, 41.1, 38.8, 34.4, 30.9, 29.7, 26.9,
26.2, 22.6, and 14.5; IR (neat) 2935 (m), 2864 (m), 1775 (s),
1724 (m), 1493 (m), 1304 (m), 1190 (s), 1042 (m), and 804 (m)
cm-1. m.p. 76-78 °C; TLC Rf = 0.5 in 3:1 hexanes:EtOAc;
HRMS (APCI/TOF) calcd for (M+H)+ (C22H28ClO4)+:
391.1671. Found: 391.1659.
1
White solid; Yield (60%, 44 mg) (1.2:1 dr). H NMR (CDCl3,
500 MHz) δ 7.25 (s, 0.45H, Ar-H), 7.24 (s, 0.55H, Ar-H), 7.02-
6.98 [m, 3H, Ar-H and CH(O)CH=CH], 5.66-5.65 (m, 2H,
CHOCH), 3.98-3.87 (m, 4H, OCH2CH2O), 2.85-2.72 (m, J =
2.9 Hz, 2H, Alkyl-H), 2.32-2.28 (m, 1H, Alkyl-H), 2.27-2.19
(m, 1H, Alkyl-H), 2.05-1.99 (m, 1H, Alkyl-H), 1.89-1.73 (m,
4H, Alkyl-H), 1.65-1.59 (m, 1H, Alkyl-H), 1.56-1.51 (m, 1H,
Alkyl-H), 1.49-1.31 (m, 4H, Alkyl-H), 0.88 [s, 1.35H,
CH(18)3], and 0.86 [s, 1.65H CH(18)3]; 13C NMR (CDCl3, 125
MHz) δ 146.34, 146.32, 146.21, 146.09, 143.24, 143.20,
143.01 (2), 136.84, 136.73, 133.31, 133.27, 121.57, 121.52,
119.62, 119.60, 118.0 (2), 82.58, 82.55, 82.36, 82.28, 65.5 (2),
64.8 (2), 49.61, 49.57, 46.34, 46.32, 44.47, 44.39, 39.18, 39.13,
34.4 (2), 31.0 (2), 30.1 (2), 27.11, 27.09, 26.44, 26.30, 22.6 (2),
and 14.5 (2); IR (neat) 3061 (m), 2957 (m), 2873 (w), 1491
(m), 1205 (m), 1192 (s), 1041 (m), and 814 (m) (s) cm-1; TLC
Rf = 0.4 in 5:1 hexanes:EtOAc; HRMS (APCI/TOF) calcd for
(M+H)+ (C24H29O3)+: 365.2111. Found: 365.2085.
4.5. Procedure for Preparation of (8R,9S,13S,14S)-3-
[Diethyl(methyl)silyl)]-13-methyl-6,7,8,9,11,12,13,14,15,16-
decahydrospiro(cyclopenta[a]phenanthrene-17,2'-
[1,3]dioxolan)-2-yl trifluoromethanesulfonate (18)
4.7. Procedure for Preparation of (3aS,3bR,11bS,13aS)-13a-
Methyl-2,3,3a,3b,4,5,7,10,11b,12,13,13a-dodecahydro-1H-
7,10-epoxycyclopenta[c]tetraphen-1-one (20)
C2-silyl phenol 17 (414 mg, 1 mmol) and pyridine (0.12
mL, 1.5 mmol) in CH2Cl2 (2 mL, 1 M) were cooled to 0 °C
with an ice bath. Trifluoromethanesulfonyl anhydride (0.25
mL, 1.5 mmol) was added into the reaction mixture dropwise.
The reaction mixture was stirred at 0 °C for 1 h and an
additional 30 min at rt. The reaction was quenched by saturated
aqueous sodium bicarbonate and was extracted with diethyl
ether three times. The combined organic extracts were washed
with water two times and brine, and dried over anhydrous
sodium sulfate. The volatiles were removed in vacuo, and the
The crude mixture of 19 was dissolved in a mixture of
THF/H2O (0.5 mL, 1:1, 0.1 M). Hydrochloric acid (0.5 ml, 1
M) was added and the mixture was stirred at rt for 5 h. The
reaction was quenched by adding saturated aqueous sodium
bicarbonate. The reaction mixture was extracted with diethyl
ether three times and concentrated in vacuo to afford the crude
9

10
Tetrahedron
ACCEPTED MANUSCRIPT
Garg, N. K. J. Am. Chem. Soc. 2016, 138, 4948-4954; (p)
Karmakar, R.; Lee, D. Chem. Soc. Rev. 2016.
mixture, which was purified by MPLC (hexanes/EtOAc = 5:1,
5 mL/min, retention time 15 min) to provide 20. Yield (72%,
46 mg) (1.2:1 dr); White solid; 1H NMR (CDCl3, 500 MHz) δ
7.24 (s, 0.45H, Ar-H), 7.24 (s, 0.55H, Ar-H), 7.02-6.98 [m, 3H,
Ar-H and CH(O)CH=CH], 5.66 (app s, 2H, CHOCH), 2.86-
2.82 (m, 2H, Alkyl-H), 2.50 (ddd, J = 19.0, 8.7, 2.3 Hz, 1H,
Alkyl-H), 2.41-2.35 (m, 1H, Alkyl-H), 2.27-2.24 (m, 1H,
Alkyl-H), 2.18-2.10 (m, 1H, Alkyl-H), 2.07-1.94 (m, 3H,
Alkyl-H), 1.63-1.42 (m, 6H, Alkyl-H), 0.91 [s, 1.35H,
CH(18)3], and 0.89 [s, 1.65H, CH(18)3]; 13C NMR (CDCl3, 125
MHz) δ 221.1 (2), 146.60, 146.58, 146.44 (2), 143.25, 143.23,
142.99, 142.96, 136.17, 136.07, 133.08, 133.05, 121.58,
121.54, 117.9 (2), 82.57, 82.54, 82.35, 82.27, 50.6 (2), 48.21,
48.19, 44.81, 44.73, 38.51, 38.47, 36.1 (2), 31.8 (2), 30.0 (2),
26.7 (2), 26.23, 26.10, 21.8 (2), and 14.1 (2); IR (neat) 3053
(m), 2961 (m), 2874 (w), 1631 (w), 1442 (m), 1222 (m), 1191
(m), 1115 (m), 1001 (m), 851 (s), 706 (s), cm-1; TLC Rf = 0.5 in
3:1 hexanes:EtOAc; HRMS (APCI/TOF) calcd for (M+H)+
(22H25O2)+: 321.1849. Found: 321.1855.
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Acknowledgments
This work was supported by the National Institutes of
Health (GM116031) and the ACS Petroleum Research Fund
(PRF# 54831-DNI1) for support. The NSF (CHE- 0234811 and
CHE-0840509) is acknowledged for partial funding of the
purchases of the NMR spectrometers used in this work. This
paper is dedicated to the memory of his former colleague and
friend, Dr. James P. Bacci (1979-2015).
Supplementary Material
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Supplementary data related to this article can be found at
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