2-(Trimethylsilyl)phenyl Trimethylsilyl Ethers as Stable and Readily Accessible Benzyne Precursors

Article abstract of DOI:10.1021/acs.joc.7b00238

Stable 2-(trimethylsilyl)phenyl trimethylsilyl ethers, readily obtained from the corresponding halogenated phenols in two steps, were identified as novel benzyne precursors. These species were converted to benzynes by a domino reaction of O-desilylation,

Full text of DOI:10.1021/acs.joc.7b00238

Subscriber access provided by UNIV OF REGINA
Article
2-(Trimethylsilyl)phenyl Trimethylsilyl Ethers as
Stable and Readily Accessible Benzyne Precursors
Takashi Ikawa, Shigeaki Masuda, Hiroki Nakajima, and Shuji Akai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00238 • Publication Date (Web): 01 Mar 2017
Downloaded from http://pubs.acs.org on March 1, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 33
The Journal of Organic Chemistry
1
1
2
3
4
5
6
7
8
9
2ꢀ(Trimethylsilyl)phenyl Trimethylsilyl Ethers as Stable
and Readily Accessible Benzyne Precursors
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
Takashi Ikawa,*,†,ID Shigeaki Masuda,† Hiroki Nakajima and Shuji Akai*,ID
Graduate School of Pharmaceutical Sciences, Osaka University, 1ꢀ6 Yamadaoka, Suita, Osaka, Japan
Eꢀmail: ikawa@phs.osakaꢀu.ac.jp, akai@phs.osakaꢀu.ac.jp
ABSTRACT: Stable 2ꢀ(trimethylsilyl)phenyl trimethylsilyl ethers, readily obtained from the
corresponding halogenated phenols in two steps, were identified as novel benzyne precursors. These
species were converted to benzynes by a domino reaction of O-desilylation, Oꢀnonaflylation, and βꢀ
elimination under mild conditions using nonafluorobutanesulfonyl fluoride (NfF) and
tetrabutylammonium triphenyldifluorosilicate (TBAT). The generated benzynes were trapped by various
arynophiles to afford a wide variety of benzoꢀfused heterocycles.
■ INTRODUCTION
Benzynes have been long known as attractive reactive intermediates for the synthesis of complex
polysubstituted and/or fused aromatic compounds.1 In the last two decades, a wide variety of new
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 33
2
1
2
3
4
5
6
7
8
benzyne reactions including transitionꢀmetalꢀcatalyzed multiꢀcomponent coupling reactions have been
developed, probably due to the conditions of benzyne generation becoming milder than before. In
particular, 2ꢀ(trimethylsilyl)phenyl triflates2 have greatly contributed to the prosperous benzyne
chemistry field, currently remaining the most widely used benzyne precursors, although a number of
other precursors has also been reported.3
9
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
Several 2ꢀsilylaryl triflates are now commercially available, and numerous other ones can be
synthesized in a few steps from readily accessible starting materials. However, the diversity of
substituted benzynes available from 2ꢀsilylaryl triflates has been limited by the use of relatively harsh
reagents such as nꢀBuLi and trifluoromethanesulfonic anhydride (Tf2O) for the synthesis of these species.
Recently, we have developed 2ꢀborylphenyl triflates as novel benzyne precursors that can be prepared
without using nꢀBuLi and generate benzynes under fluorideꢀmediated mild conditions.3g Additionally,
we have developed a novel method of benzyne generation from 2ꢀ(trimethylsilyl)phenols 1 using
benchtopꢀstable nonafluorobutanesulfonyl fluoride (NfF), featuring a domino reaction relying on in situ
formation of nonaflates 2 and benzyne generation by the attack of the produced fluoride ion on the
silicon atom (Scheme 1).3a This method provides some advantages over the use of 2ꢀsilylaryl triflates,
because it does not require the use of moistureꢀsensitive Tf2O that often causes decomposition of acidꢀ
labile compounds, and also because 1 is the precursor of 2ꢀsilylaryl triflates. However, this method has
some limitations. (1) Some 2ꢀsilylphenols 1 are too unstable to be isolated (vide infra). (2) Scrupulous
attention is required when handling hygroscopic Cs2CO3 and 18ꢀcrownꢀ6. (3) The specific solvent
usability restricts synthetic applications. (4) A strong base (NaH) is required for the generation of 3ꢀ
silylbenzyne.4 Therefore, the development of an alternative efficient method for benzyne generation is
required to overcome these limitations and open new possibilities for benzyne chemistry.
Herein, we report the use of 2ꢀ(trimethylsilyl)phenyl trimethylsilyl ethers 4 as new precursors for
generating various benzynes 3, including 3ꢀsilylbenzynes.4 The advantages of this method include twoꢀ
step preparations of 4 from halogenated phenols, high stability of 4, direct generation of 3 via a domino
ACS Paragon Plus Environment

Page 3 of 33
The Journal of Organic Chemistry
3
1
2
3
4
5
6
7
8
of O-desilylation, O-nonaflylation, and βꢀelimination, and the use of easyꢀtoꢀhandle NfF and nonꢀ
hygroscopic tetrabutylammonium triphenyldifluorosilicate (TBAT) as a fluoride source in various
solvents (Scheme 1). The generated benzynes are trapped by various arynophiles to afford a wide variety
of benzoꢀfused heterocycles.
9
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
Scheme 1. Previously Reported Benzyne Generation and
the Novel Method Used in This Work
■ RESULTS AND DISCUSSION
Initially, we synthesized 2ꢀ(trimethylsilyl)phenyl trimethylsilyl ethers 4a–4c from 2ꢀ
bromophenols 5a–5c in 72–84% overall yields via Oꢀsilylation, retroꢀBrook rearrangement in the
reaction with nꢀBuLi, and workꢀup with Me3SiCl (Table 1, entries 3, 6, and 9). The obtained 4a–4c were
stable for purification by silica gel column chromatography and could be stored for several months
without decomposition. On the other hand, the corresponding phenols 1a–1c and triflates 2a’–2c’ could
hardly be isolated after workꢀup of 2ꢀtrimethylsilylphenolates 1’ with Tf2O (entries 2, 5, and 8) or
aqueous NH4Cl (entries 1, 4, and 7) at –78 °C. The previously reported synthesis of 2a’–2c’ by trapping
phenolates 1’ by Tf2O at lower temperature (e.g. –100 °C) resulted in only moderate yields.5–7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 33
4
1
2
3
4
Table 1. Preparation of 2ꢀ(Trimethylsilyl)phenyl
Trimethylsilyl Ethers 4 from 2ꢀBromophenols 5a
5
6
7
8
9
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
We also synthesized other 2ꢀ(trimethylsilyl)phenyl trimethylsilyl ethers 4 from 2ꢀchlorophenols 6
(Table 2).2,8 After trimethylsilylation of the phenolic hydroxyl groups of 6 using hexamethyldisilazane
(HMDS), further Cꢀsilylation was achieved by using an excess of sodium metal and Me3SiCl to produce
4 (entries 1–4). In particular, two or three chlorine atoms attached to the benzene rings of 6b–6d could
be simultaneously replaced with the trimethylsilyl group, furnishing bisꢀ and tris(trimethylsilyl)phenyl
trimethylsilyl ethers 4e–4g (entries 2–4). Interestingly, one of the chlorine atoms of 4ꢀaminoꢀ2,6ꢀ
dichlorophenol 6e was selectively removed during silylation using sodium metal/Me3SiCl to give 4ꢀ
aminoꢀ2ꢀ(trimethylsilyl)phenyl trimethylsilyl ether 4h in 88% yield (entry 5). Compounds 4d–4h were
stable for purification by silica gel chromatography and could be stored under ambient conditions. It
should be noted that 2ꢀchlorophenol derivatives such as 6a–6e are commercially available at much
lower prices compared to the corresponding bromoꢀ or iodophenols.
ACS Paragon Plus Environment

Page 5 of 33
The Journal of Organic Chemistry
5
1
2
Table 2. Preparation of 2ꢀ(Trimethylsilyl)phenyl
Trimethylsilyl Ethers 4 from 2ꢀChlorophenols 6a
3
4
5
6
7
8
9
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
In contrast, 2,4ꢀbis(trimethylsilyl)phenyl triflate 2d’,4d,4e,4g which corresponds to 4f (Table 2,
entry 3) and generated 3ꢀ(trimethylsilyl)benzyne 3f under mild fluoride ion conditions, was prepared in
4ꢀstep in lower yield (49%) from a far more expensive raw material, 2,6ꢀdibromophenol 5d (Scheme 2).
Scheme 2. Reported Route for the Synthesis of 2,6ꢀ
Bis(trimethylsilyl)phenyl Triflate 2d’
Br
SiMe3
OSiMe3
SiMe3
OR
1) Me3SiCl, Et3N
2) n-BuLi, THF;
3) n-BuLi, THF; H3O+
4-step overall 49%
OH
Br
Me3SiCl
Br
SiMe3
5d
4i, 69%
1d, 99% (R = H)
2d', 72% (R = OTf)
10 g: $175.50 (Aldrich)
4) n-BuLi, Et2O; Tf2O
Cl
OH
3) n-BuLi, Et2O; Tf2O
1d (48%) + 2d' (26%)
6c
100 g: $78.30
(Aldrich)
difficult to separate
3-step overall 18%
Cl
Next, the conditions for generating benzyne 3d from 4d using fluoride ions and NfF (1.5 equiv)
were optimized in the presence of 3.0 equiv of nitrone 7a to trap 3d (Table 3). By using 3.0 equiv of
either KF/18ꢀcrownꢀ6 or TBAT in THF at room temperature, the product of a (3+2) cycloaddition
reaction between 3d and 7a, 8da was obtained in 95 and 99% yield, respectively (entries 2 and 3), while
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 33
6
1
2
3
4
5
6
7
8
the use of 3.0 equiv of Bu4NF (TBAF) resulted in a lower yield (53%) due to the significant hydrolysis
of 4d (entry 1). The use of CsF (3.0 equiv) gave an excellent yield in MeCN (99%, entry 5) but not in
THF (18%, entry 4). When less CsF was used (2.0 equiv), a hydrolyzed product [2ꢀ
(trimethylsilyl)phenol 1e] was observed, accounting for the lower yield of 8da (77%, entry 6). The
reactions utilizing CsF (3.0 equiv) seem to be sensitive to temperature (entries 7 and 8), with the best
yield observed at room temperature (entry 5). On the other hand, reactions utilizing TBAT (1.0–3.0
equiv) at 60 °C gave almost equal yields (92–98%) in THF, MeCN, and toluene (entries 3, 10–14). To
sum up these results, the best conditions for benzyne generation correspond to using 1.0–1.5 equiv of
anhydrous and nonꢀhygroscopic fluoride sources such as TBAT. In addition, hygroscopic CsF and KF
can also be used when present in excess in appropriate solvents.
9
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
Table 3. Optimization of Benzyne Generation from 2ꢀ(Trimethylsilyl)phenyl
Trimethylsilyl Ether 4da
yield (%)b
temp.
entry
F– (equiv)
Bu4NF
solv.
(°C)
8da
1e
2e
1
3.0
3.0
3.0
3.0
3.0
2.0
3.0
3.0
2.0
2.0
1.5
1.5
1.5
1.0
THF
THF
rt
rt
53
95 (91)c
99 (96)c
18
15
0
0
2
KF, 18ꢀcꢀ6
TBATd
CsF
0
3
THF
rt
0
0
4
THF
rt
0
82
5
CsF
MeCN
MeCN
MeCN
MeCN
THF
rt
99 (93)c
0
0
6
CsF
rt
77
17
7
0
7
CsF
60
0
87
0
8
CsF
20
0
78
9
TBATd
TBATd
TBATd
TBATd
TBATd
TBATd
TBATd
rt
89
0
11
10
11
12
13
14
15
THF
60
60
60
60
60
60
97 (93)c
98 (91)c
92 (94)c
98 (93)c
96
0
0
THF
0
0
toluene
MeCN
MeCN
0
0
0
0
0
0
5 mol% MeCN
5
0
93 (90)
aConditions: 4d (0.10 mmol), 7a (0.30 mmol), NfF (0.15 mmol), and F– (given in the Table) in solvent
(0.1 M) for 24 h. bGC yield (%) of 8da. Isolated yield (%) of 8da is shown in parenthesis. dTBAT:
c
Bu4NPh3SiF2.
ACS Paragon Plus Environment

Page 7 of 33
The Journal of Organic Chemistry
7
It is also worth noting that 5% of 8da and 93% of 2ꢀ(trimethylsilyl)phenyl nonaflate 2e3a,9 were
1
2
3
4
5
6
7
8
9
produced using 5 mol% TBAT (entry 15), indicating that fluoride ions generated from NfF by
nonaflylation of phenolate 1’ were effectively used for the Oꢀdesilylation of another 4d to complete its
conversion into 2e, followed by benzyne generation.
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
Subsequently, we applied our new benzyne generation method to other silyl ethers (4a–4c, 4e,
and 4h) for performing various cycloaddition reactions with arynophiles 7, e.g., benzyl azide 7b (Table
4, entries 1 and 5), 2ꢀmethylfuran 7c (entry 2), sydnone 7d (entry 3), and nitrile oxide 7e (entry 4), with
the corresponding (3+2) and [4+2] cycloaddition products 8ab, 8bc, 8cd, 8ee, and 8hb produced in 52–
86% yields. These results clearly indicate that 3,5ꢀdimethoxybenzyne 3a (entry 1), 2,3ꢀnaphthalyne 3b
(entry 2), 9,10ꢀphenanthryne 3c (entry 3), 4ꢀsilylbenzyne 3e (entry 4), and 4ꢀaminobenzyne 3h (entry 5)
were successfully generated from the corresponding nonaflates 2 and were efficiently trapped by 7.
Table 4. Scope of Substituted Benzyne Generations
from Precursors
4 and Their Reactions with
Arynophiles 7a
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 33
8
1
2
3
4
5
6
7
8
Additionally, combinations of 2,6ꢀbisꢀ and 2,4,6ꢀtris(trimethylsilyl)phenyl trimethylsilyl ethers
(4f and 4g, respectively) as precursors of 3ꢀsilylbenzynes with various arynophiles 7 were tested under
the same reaction conditions (Table 5). To our delight, 3ꢀ(trimethylsilyl)benzynes 3f and 3g were
successfully generated from 4f and 4g, respectively, and their cycloadditions with nitrone 7a,
diazoacetate 7f, 1,1ꢀdimethoxyethylene 7g, 1,3ꢀdimethylꢀ2ꢀimidazolidinone 7h, and 4ꢀarylsydnone 7i
proceeded with perfect regioselectivity in most cases (entries 1, 2, and 4–7).4 These excellent results
indicated the pronounced effect of the C3 silyl group of benzyne on controlling the orientation of
9
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
Table 5. Scope of 3ꢀSilylbenzyne Generations from
Precursors 4 and Their Regioselective Reactions with
Arynophiles 7a
ACS Paragon Plus Environment

Page 9 of 33
The Journal of Organic Chemistry
9
1
2
3
4
cycloaddition reactions. The better yield of a cycloaddition product 8fb from silyl ether 4f (76%, entry
3) was observed than that from 2ꢀ(trimethylsilyl)phenyl triflate 2d’ (52%).4g
5
6
7
8
9
Our new method is also applicable to transitionꢀmetalꢀcatalyzed threeꢀcomponent coupling
reactions10 (Scheme 3). For example, a mixture of 4d, allyl chloride 9, and phenylacetylene 10 was
heated at 60 °C for 2 h in the presence of CuI, dppp, CsF, K2CO3, and NfF to give 11 in 63% yield. In
this case, CsF was found to be a suitable fluoride source, whereas TBAT produced a complex mixture.
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
Scheme 3. Application of Benzyne Precursor 4d to
TransitionꢀMetalꢀCatalyzed Coupling Reaction
a
CuI, dppp
Cl
OSiMe3
NfF, CsF, K2CO3
9
+
MeCN, 60 °C, 3 h
SiMe3
Ph
Ph
10
4d
11
, 63%
■ CONCLUSION
In summary, we have developed a new method for the direct generation of benzynes from 2ꢀ
(trimethylsilyl)phenyl trimethylsilyl ethers, which are stable during both preparation and storage. This
method
avoids
problematic
triflylation
by
using
easyꢀtoꢀhandle
nonꢀhygroscopic
nonafluorobutanesulfonyl fluoride (NfF) and tetrabutylammonium triphenyldifluorosilicate (TBAT).
The simple and convenient access to 3ꢀsilylbenzynes from readily available 2ꢀchloroꢀ or 2ꢀbromophenol
precursors is another advantage of this method. Our new benzyne precursors 4 would contribute to
benzyne chemistry and take over 2ꢀ(trimethylsilyl)phenyl triflates 2’ in the near future.
■ EXPERIMENTAL SECTION
General. All reactions were carried out under a nitrogen atmosphere. A roundꢀbottomed, two necked,
three necked, or sideꢀarm flasks containing a magnetic stirꢀbar with a threeꢀway stopcock were used as
reactors. 2.6 M solution of nꢀBuLi in hexane was purchased from Kanto Chemical. CsF was heated
under reduced pressure with a flame torch for each reaction. 18ꢀCrownꢀ6 was recrystallized from
anhydrous MeCN in a Schlenk flask. Anhydrous THF, Et2O and MeCN were purchased from Kanto
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 33
10
1
2
3
4
5
6
7
8
Chemical, and purified with a Glass Contour solvent dispensing system (Nikko Hansen) using two
packed columns of activated molecular sieves. Anhydrous toluene was purchased from Wako Pure
Chemical Industries. 2ꢀBromoꢀ3,5ꢀdimethoxyphenol (5a),5a 3ꢀbromonaphthol (5b),7a 10ꢀ
bromophenanthrol (5c),11 2ꢀ(trimethylsilyl)phenol (1e),3a,9 3ꢀphenylsydnone (7d),12 2,4,6ꢀ
trimethylbenzonitrile oxide (7e),13 1,1ꢀdimethoxyethylene (7g)14 and 4ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀ
phenylsydnone (7i)11 were prepared according to the literature. All other reagents were purchased from
Wako Pure Chemical Industries, Tokyo Chemical Industry, SigmaꢀAldrich, Kishida Chemical, Nacalai
Tesque, and CombiꢀBlocks and used without further purification. Flash chromatography15 was
performed with silica gel 60N, spherical neutral (40–50 ꢁm), purchased from Kanto Chemical. All
reactions were monitored by thinꢀlayer chromatography (TLC) on glassꢀbacked silica gel 60 F254, 0.2
mm plates (Merck), and compounds were visualized under UV light (254 nm). These TLC plates were
also used for preparative thinꢀlayer chromatography (PTLC).
9
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
Melting points were recorded on a Yanagimoto melting point apparatus and are uncorrected. IR spectra
1
were obtained on a SHIMADZU IRAffinityꢀ1S. H NMR and 13C NMR spectra were recorded on a
13
13
JEOL JMNꢀECAꢀ500 (1H: 500 MHz, C: 125 MHz), a JEOL JMNꢀECSꢀ400 (1H: 400 MHz, C: 100
13
MHz), or a JEOL JMNꢀALꢀ300 (1H: 300 MHz, C: 75 MHz) instrument with chemical shifts reported
in ppm relative to the residual undeuterated solvent. NOESY, HMBC, HMQC spectra were taken by a
JEOL JMNꢀECAꢀ500, a JEOL JMNꢀECSꢀ400, a JEOL JMNꢀALꢀ300. GC chromatograms were
recorded on a SHIMADZU GCꢀ2010 and nꢀdecane was used as an internal standard. The mass spectra
were recorded on a JEOL JMSꢀS3000 (MALDI, TOF), or a JEOL JMSꢀ700 (FAB, quadrupole). ‘Yield’
refers to the isolated yields of compounds showing at most only trace peaks in the 1H NMR spectra that
1
are not attributable to the assigned structure. H NMR and melting points (where applicable) of all
known compounds were taken. All new products were further characterized by 13C NMR, infrared (IR)
and high resolution mass (HRMS) spectra. The regiochemistry of distalꢀ8ff was confirmed by NOESY,
HMBC and HMQC spectra and all other regiochemistries of cycloaddition products distal-8ab, distal-
ACS Paragon Plus Environment

Page 11 of 33
The Journal of Organic Chemistry
11
1
2
3
4
and proximalꢀ8ee, distal- and proximalꢀ8hb, distal- and proximalꢀ8fa, proximal-8fg, distal-8fh, distal-
8fi, distal-8gi, were confirmed by NOESY spectra.
5
6
7
8
9
Preparation of 2ꢀ(trimethylsilyl)phenols 1, 2ꢀ(trimethylsilyl)phenyl triflates 2, and 2ꢀ
(trimethylsilyl)phenyl trimethylsilyl ethers 4 from 2ꢀbromophenols 5 (Table 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
General Procedure A: An ovenꢀdried round bottom flask was charged with 5 (1.0 equiv) and a stirꢀbar.
The flask was equipped with a threeꢀway stopcock, and evacuated and backꢀfilled with N2 (This process
was repeated three times). Anhydrous THF (0.20 M), Me3SiCl (1.5 equiv), and Et3N (1.5 equiv) were
sequentially added into the flask via a syringe. The mixture was stirred at room temperature for 1 h. The
reaction mixture was evaporated under reduced pressure and the residue was filtrated through a celite
cake and washed with hexane to provide the 2ꢀbromophenyl trimethylsilyl ether which can be used
without further purification. The obtained silyl ether was dissolved in anhydrous THF (0.20 M, for
Workꢀup Methods I and III) or Et2O (0.10 M, for Workꢀup Method II) under N2. After the mixture was
cooled to –78 °C, 2.6 M solution of n-BuLi in hexane (1.2 equiv) was added dropwise into the mixture
and it was stirred for 1 h. The reaction was quenched by following Workꢀup Method I–III.
Workꢀup Method I: sat. aq NH4Cl (ca. 3–5 mL) was added to the reaction mixture at –78 °C. After the
mixture was warmed to room temperature, it was extracted with hexane three times. The combined
organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel (hexane/AcOEt) to afford 2ꢀ
(trimethylsilyl)phenol 1.
Workꢀup Method II: Tf2O (1.5 equiv) was added to the reaction mixture at –78 °C and the mixture
was stirred for 1 h at –78 °C. The reaction was quenched with sat. aq NaHCO3 (ca. 3–5 mL) at –78 °C.
After the mixture was warmed to room temperature, it was extracted with hexane three times. The
combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica gel (hexane/AcOEt) to afford 2ꢀ
(trimethylsilyl)aryl triflate 2’.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 33
12
1
2
3
4
5
6
7
8
Workꢀup Method III: Me3SiCl (1.5 equiv) was added to the reaction mixture at –78 °C and the
mixture was stirred for 1 h at –78 °C. The reaction was quenched with sat. aq NaHCO3 (ca. 3–5 mL) at –
78 °C. After the mixture was warmed to room temperature, it was extracted with hexane three times.
The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatography on silica gel (hexane/AcOEt) to
afford 2ꢀ(trimethylsilyl)aryl trimethylsilyl ether 4.
9
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
2ꢀ(Trimethylsilyl)ꢀ3,5ꢀdimethoxyphenol (1a) (Table 1, entry 1): Following General Procedure A, a
mixture of Me3SiCl (0.15 mL, 1.2 mmol), Et3N (0.17 mL, 1.2 mmol) and 2ꢀbromoꢀ3,5ꢀdimethoxyphenol
(5a)5a (0.19 g, 0.80 mmol) was stirred in THF (4.0 mL, 0.20 M) for 1 h at room temperature. To the
obtained silyl ether in THF (4.0 mL, 0.20 M) was added nꢀBuLi (1.6 M in hexane, 0.60 mL, 0.96 mmol)
at –78 °C and the mixture was stirred for 1 h. Following Workꢀup Method I, sat. aq NH4Cl (3 mL) was
added and stirred for 1 h at room temperature. However, the titled compound 1a could not be detected
by 1H NMR analysis of the crude mixture.
2ꢀ(Trimethylsilyl)ꢀ3,5ꢀdimethoxyphenyl trifluoromethanesulfonate (2a’) (Table 1, entry 2):5a
Following General Procedure A, a mixture of Me3SiCl (0.15 mL, 1.2 mmol), Et3N (0.17 mL, 0.80
mmol) and 2ꢀbromoꢀ3,5ꢀdimethoxyphenol (5a)5a (0.19 g, 0.80 mmol) was stirred in THF (4.0 mL, 0.20
M) for 1 h at room temperature. To the obtained silyl ether in Et2O (4.0 mL, 0.20 M) was added nꢀBuLi
(1.6 M in hexane, 0.60 mL, 0.96 mmol) at –78 °C and stirred for 1 h. Following Workꢀup Method II,
Tf2O (0.20 mL, 1.2 mmol) was added and stirred for 1 h at –78 °C. However, the titled compound 2a’
could not be detected by 1H NMR analysis of the crude mixture.
2ꢀ(Trimethylsilyl)ꢀ3,5ꢀdimethoxyphenyl trimethylsilyl ether (4a) (Table 1, entry 3): Following
General Procedure A, a mixture of Me3SiCl (0.82 mL, 6.4 mmol), Et3N (0.90 mL, 6.4 mmol) and 2ꢀ
bromoꢀ4,6ꢀdimethoxyphenol (5a)5a (1.0 g, 4.3 mmol) was stirred in THF (22 mL, 0.20 M) for 1 h at
room temperature. To the obtained silyl ether in THF (22 mL, 0.20 M) was added nꢀBuLi (2.6 M in
hexane, 2.0 mL, 5.2 mmol) at –78 °C and stirred for 1.5 h. Following Workꢀup Method III, Me3SiCl
ACS Paragon Plus Environment

Page 13 of 33
The Journal of Organic Chemistry
13
1
2
3
4
5
6
7
8
(0.82 mL, 6.5 mmol) was added and stirred for 1 h. The crude material was purified by flash column
chromatography on silica gel (hexane/EtOAc = 10:1) to provide the titled compound 4a as a colorless
oil (1.1 g, 84%). 1H NMR (300 MHz, CDCl3) δ: 0.26 (9 H, s), 0.32 (9 H, s), 3.73 (3 H, s), 3.78 (3 H, s),
6.00 (1 H, d, J = 2.0 Hz), 6.08 (1 H, d, J = 2.0 Hz). 13C NMR (75 MHz, CDCl3) δ: 0.7, 1.5, 54.99, 55.03,
90.9, 96.7, 108.3, 162.0, 162.3, 166.6. IR (neat): 1595, 1402 cm–1. HRMS (MALDI) Calcd for
C14H26O3Si2 [M]+: 298.1415, found 298.1393.
9
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
3ꢀ(Trimethylsilyl)ꢀ2ꢀnaphthol (1b) (Table 1, entry 4):16 Following General Procedure A, a mixture of
Me3SiCl (85 µL, 0.68 mmol), Et3N (94 µL, 0.68 mmol) and 3ꢀbromoꢀ2ꢀnaphthol (5b)7a (0.10 g, 0.45
mmol) was stirred in THF (2.3 mL, 0.20 M) for 1 h at room temperature. To the obtained silyl ether in
THF (4.5 mL, 0.10 M) was added nꢀBuLi (2.6 M in hexane, 0.25 mL, 0.52 mmol) at –78 °C and stirred
for 1 h. Following Workꢀup Method I, sat. aq NH4Cl (3 mL) was added and stirred for 1 h at room
temperature. The crude material was purified by flash column chromatography on silica gel
1
(hexane/EtOAc = 10:1) to provide the titled compound 1b as a colorless oil (23 mg, 25%). H NMR
(300 MHz, CDCl3) δ: 0.40 (9 H, s), 6.98 (1 H, s), 7.27–7.36 (1 H, m), 7.38–7.47 (1 H, m), 7.62 (1 H, d,
J = 8.0 Hz), 7.78 (1 H, d, J = 8.0 Hz), 7.88 (1 H, s).
3ꢀ(Trimethylsilyl)naphthaleneꢀ2ꢀyl trifluoromethanesulfonate (2b’) (Table 1, entry 5):7a Following
General Procedure A, a mixture of Me3SiCl (85 µL, 0.68 mmol), Et3N (94 µL, 0.68 mmol) and 3ꢀ
bromoꢀ2ꢀnaphthol (5b)7a (0.10 g, 0.45 mmol) was stirred in THF (2.3 mL, 0.20 M) for 1 h at room
temperature. To the obtained silyl ether in Et2O (4.5 mL, 0.10 M) was added nꢀBuLi (2.6 M in hexane,
0.25 mL, 5.2 mmol) at –78 °C and stirred for 1.5 h. Following Workꢀup Method II, Tf2O (0.16 mL, 0.66
mmol) was added and stirred for 1 h. The crude material was purified by flash column chromatography
on silica gel (hexane/EtOAc = 10:1) to provide the titled compound 2b’ as a colorless oil (18 mg, 12%).
1H NMR (300 MHz, CDCl3) δ: 0.44 (9 H, s), 7.51–7.60 (2 H, m), 7.80 (1 H, s), 7.82–7.90 (2 H, m), 8.01
(1 H, s).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 33
14
1
2
3
4
5
6
7
8
3ꢀ(Trimethylsilyl)naphthaleneꢀ2ꢀyl trimethylsilyl ether (4b) (Table 1, entry 6): Following General
Procedure A, a mixture of Me3SiCl (0.19 mL, 1.5 mmol), Et3N (0.21 mL, 1.5 mmol) and 3ꢀbromoꢀ2ꢀ
naphthol (5b)7a (0.22 g, 1.0 mmol) was stirred in THF (5.0 mL, 0.20 M) for 1 h at room temperature. To
the obtained silyl ether in THF (10 mL, 0.10 M) was added nꢀBuLi (2.6 M in hexane, 0.50 mL, 1.3
mmol) at –78 °C and stirred for 1.5 h. Following Workꢀup Method III, Me3SiCl (0.19 mL, 1.5 mmol)
was added and stirred for 1 h. The crude material was purified by flash column chromatography on silica
gel (hexane) to provide the titled compound 4b as a brown solid (0.23 g, 80%). Mp: 51–52 °C. 1H NMR
(400 MHz, CDCl3) δ: 0.34 (9 H, s), 0.40 (9 H, s), 7.06 (s, 1 H), 7.31 (1 H, dd, J = 8.0, 8.0 Hz), 7.41 (1 H,
dd, J = 8.0, 8.0 Hz), 7.66 (1 H, d, J = 8.0 Hz), 7.76 (1 H, d, J = 8.0 Hz), 7.86 (1 H, s). 13C NMR (100
MHz, CDCl3) δ: –0.8, 0.6, 110.7, 123.5, 126.2, 126.4, 127.8, 128.8, 132.9, 135.4, 136.2, 157.7. IR
(neat): 1587, 1445 cm–1. HRMS (MALDI) Calcd for C16H24OSi2 [M]+: 288.1360, found 288.1367.
10ꢀ(Trimethylsilyl)ꢀ9ꢀphenanthrol (1c) (Table 1, entry 7): Following General Procedure A, a mixture
of Me3SiCl (95 µL, 0.75 mmol), Et3N (105 µL, 0.75 mmol) and 10ꢀbromoꢀ9ꢀphenanthrol (5c)11 (0.14 g,
0.50 mmol) was stirred in THF (2.5 mL, 0.20 M) for 1 h at room temperature. To the obtained silyl ether
in THF (2.5 mL, 0.20 M) was added nꢀBuLi (2.1 M in hexane, 0.29 mL, 0.60 mmol) at –78 °C and the
mixture was stirred for 1 h. Following Workꢀup Method I, sat. aq NH4Cl (3 mL) was added and stirred
for 1 h at room temperature. 9ꢀPhenanthryl trimethylsilyl ether (12) (8% determined by 1H NMR which
was identical with alternatively synthesized compound 12 shown below) was observed in the crude
mixture. The crude material was purified by flash column chromatography on silica gel (hexane) to
provide 9ꢀphenanthrol17 (65 mg, 46 %) and 5c (17 mg, 6%). However, the titled compound 1c could not
be detected by 1H NMR analysis.
9
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
Alternative synthesis of 9ꢀphenanthryl trimethylsilyl ether (12) (Table 1, entry 7): A test tube (1.0
mL) was charged with 9ꢀphenanthrol17 (5.0 mg, 26 µmol) and a stirꢀbar. THF (ca. 0.50 mL, 0.050 M)
and Me3SiCl (1 drop), Et3N (1 drop) were sequentially added to the test tube using a Pasteur pipet. The
test tube was blown with N2 and equipped with a rubber septum. The mixture was stirred at room
ACS Paragon Plus Environment

Page 15 of 33
The Journal of Organic Chemistry
15
1
2
3
4
temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was
filtrated through a celite cake and washed with hexane. The resultant residue was concentrated under
5
6
7
1
reduced pressure to provide the titled compound 12 as a colorless oil (6.4 mg, 93%). H NMR (400
8
9
MHz, CDCl3) δ: 0.40 (9 H, s), 7.08 (s, 1 H), 7.49–7.47 (2 H, m), 7.63 (1 H, ddd, J = 8.0, 8.0, 1.5 Hz),
7.68 (1 H, ddd, J = 8.0, 8.0, 1.5 Hz), 7.75 (1 H, dd, J = 8.0, 1.5 Hz), 8.25 (1 H, dd, J = 8.0, 1.5 Hz), 8.61
(1 H, d, J = 8.0 Hz), 8.67 (1 H, d, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3) δ: 0.4, 110.9, 122.5, 122.6,
123.1, 124.5, 126.3, 126.7, 126.9, 127.2, 128.6, 131.6, 132.9, 149.5. IR (neat): 1450, 1317, 1229 cm–1.
HRMS (MALDI) Calcd for C17H18OSi [M]+: 266.1121, found 266.1128.
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
10ꢀ(Trimethylsilyl)ꢀ9ꢀphenanthryl trifluoromethanesulfonate (2c’) (Table 1, entry 8):11 Following
General Procedure A, a mixture of Me3SiCl (95 µL, 0.75 mmol), Et3N (105 µL, 0.75 mmol) and 10ꢀ
bromoꢀ9ꢀphenanthrol (5c)11 (0.14 g, 0.50 mmol) was stirred in THF (2.5 mL, 0.20 M) for 1 h at room
temperature. To the obtained silyl ether in Et2O (2.5 mL, 0.20 M) was added nꢀBuLi (2.1 M in hexane,
0.29 mL, 0.60 mmol) at –78 °C and stirred for 1 h. Following Workꢀup Method II, Tf2O (96 µL, 0.57
mmol) was added and stirred for 1 h at –78 °C. However, the titled compound 2c’ could not be detected
by 1H NMR analysis of the crude mixture.
10ꢀ(Trimethylsilyl)phenanthrenꢀ9ꢀyl trimethylsilyl ether (4c) (Table 1, entry 9): Following General
Procedure A, a mixture of Me3SiCl (0.19 mL, 1.5 mmol), Et3N (0.21 mL, 1.5 mmol) and 10ꢀbromoꢀ9ꢀ
phenanthrol (5c)11 (0.22 g, 1.0 mmol) was stirred in THF (5.0 mL, 0.20 M) for 1 h at room temperature.
To the obtained silyl ether in THF (10 mL, 0.10 M) was added nꢀBuLi (2.6 M in hexane, 0.50 mL, 1.3
mmol) at –78 °C and stirred for 1.5 h. Following Workꢀup Method III, Me3SiCl (0.19 mL, 1.5 mmol)
was added and stirred for 1 h. The crude material was purified by flash column chromatography on silica
1
gel (hexane) to provide the titled compound 4c as a white solid (0.24 g, 72%). Mp: 103–105 °C. H
NMR (400 MHz, CDCl3) δ: 0.24 (9 H, s), 0.52 (9 H, s), 7.47–7.67 (4 H, m), 8.02–8.08 (1 H, m), 8.14 (1
H, dd, J = 8.0, 1.5 Hz), 8.58–8.65 (2 H, m). 13C NMR (125 MHz, CDCl3) δ: 1.2, 2.8, 120.3, 122.5, 122.9,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 33
16
124.0, 124.2, 125.8, 125.9, 128.4, 128.5, 132.6, 136.6, 155.8. IR (neat): 1560, 1445, 1310 cm–1. HRMS
(MALDI) Calcd for C20H26OSi2 [M]+: 338.1517, found 338.1519.
1
2
3
4
5
6
7
8
9
Preparation of 2ꢀ(trimethylsilyl)phenyl trimethylsilyl ethers 4 from 2ꢀchlorophenols 6 (Table 2):
General Procedure B: An ovenꢀdried round bottom flask was charged with 2ꢀchlorophenol 6 (1.0
equiv) and a stirꢀbar. The flask was equipped with a threeꢀway stopcock, and evacuated and backꢀfilled
with N2 (This process was repeated three times). Anhydrous THF (1.0 M) and hexamethyldisilazane
(HMDS) (1.0 equiv) were added into the flask via a syringe. The mixture was stirred at 60 °C for 1 h
and evaporated under reduced pressure to provide 2ꢀchlorophenyl trimethylsilyl ether which can be used
in the next step without further purification. Another ovenꢀdried three necked flask was charged with a
glass coated stirꢀbar and equipped with two septum caps and a reflux condenser which has a threeꢀway
stopcock on the top. The flask was evacuated and backꢀfilled with N2 (This process was repeated three
times). Anhydrous toluene (0.50 M) was added to the flask via a syringe and sodium metal (Na metal)
(7.5 equiv for each chlorine atom) was quickly added under N2 flow. The mixture was refluxed for 15
min. A mixture of the above obtained 2ꢀchlorophenyl trimethylsilyl ether and Me3SiCl (8.0 equiv for
each chlorine atom) was added dropwise to the flask via a cannula at reflux temperature and continued
to be refluxed for 18 h. After the reaction mixture was cooled to room temperature, the mixture was
filtrated through a celite cake and washed with hexane. The filtrate was evaporated and the resultant
residue was purified by flash column chromatography on silica gel (hexane/CH2Cl2 or hexane/EtOAc) to
afford 2ꢀ(trimethylsilyl)phenyl trimethylsilyl ether 4.
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
2ꢀ(Trimethylsilyl)phenyl trimethylsilyl ether (4d) (Table 2, entry 1):18 Following General Procedure
B, a mixture of HMDS (10 mL, 50 mmol) and 2ꢀchlorophenol (6a) (6.4 g, 50 mmol) was stirred in THF
(50 mL, 1.0 M) for 1 h at 60 °C, and the mixture was evaporated to provide the 2ꢀchlorophenyl
trimethylsilyl ether. A mixture of the obtained silyl ether and Me3SiCl (50 mL, 0.40 mol) was added into
Na metal (9.2 g, 0.40 mol) in toluene (0.10 L, 0.50 M) and refluxed for 18 h. The crude material was
purified by flash column chromatography on silica gel (hexane/CH2Cl2 = 100:1) to provide the titled
ACS Paragon Plus Environment

Page 17 of 33
The Journal of Organic Chemistry
17
compound 4d as a colorless oil (10 g, 86%). 1H NMR (300 MHz, CDCl3) δ: 0.26 (9 H, s), 0.33 (9 H, s),
6.76 (1 H, dd, J = 8.0, 1.0 Hz), 6.93 (1 H, ddd, J = 7.5, 7.5, 1.0 Hz), 7.24 (1 H, ddd, J = 8.0, 7.5, 2.0 Hz),
7.37 (1 H, dd, J = 7.5, 2.0 Hz). 13C NMR (100 MHz, CDCl3) δ: –1.0, 0.6, 116.4, 120.5, 129.9, 130.5,
135.3, 160.3. IR (neat): 1470, 1435, 1238 cm–1. HRMS (MALDI) Calcd for C12H22OSi2 [M]+: 238.1204,
found 238.1206.
1
2
3
4
5
6
7
8
9
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
2,4ꢀBis(trimethylsilyl)phenyl trimethylsilyl ether (4e) (Table 2, entry 2):19 Following General
Procedure B, a mixture of HMDS (2.1 mL, 10 mmol) and 2,4ꢀdichlorophenol (6b) (1.6 g, 10 mmol) was
stirred in THF (10 mL, 1.0 M) for 1 h at 60 °C, and the mixture was evaporated to provide the 2,4ꢀ
dichlorophenyl trimethylsilyl ether. A mixture of the obtained silyl ether and Me3SiCl (20 mL, 0.16 mol)
was added into Na metal (3.4 g, 0.15 mol) in toluene (20 mL, 0.50 M) and refluxed for 18 h. The crude
material was purified by flash column chromatography on silica gel (hexane/CH2Cl2 = 100:1) to provide
the titled compound 4e as a colorless oil (2.5 g, 78%). 1H NMR (400 MHz, CDCl3) δ: 0.18 (9 H, s), 0.31
(9 H, s), 0.37 (9 H, s), 6.79 (1 H, d, J = 8.0 Hz), 7.44 (1 H, d, J = 8.0 Hz), 7.56 (1 H, s). 13C NMR (100
MHz, CDCl3) δ: –0.95, –0.86, 0.6, 115.8, 129.1, 130.7, 135.9, 140.5, 161.2. IR (neat): 1574, 1474, 1246
cm–1. HRMS (MALDI) Calcd for C15H30OSi3 [M]+: 310.1599, found 310.1590.
2,6ꢀBis(trimethylsilyl)phenyl trimethylsilyl ether (4f) (Table 2, entry 3): Following General
Procedure B, a mixture of HMDS (2.1 mL, 10 mmol) and 2,6ꢀdichlorophenol (6c) (1.6 g, 10 mmol) was
stirred in THF (10 mL, 1.0 M) for 1 h at 60 °C, and the mixture was evaporated to provide the 2,6ꢀ
dichlorophenyl trimethylsilyl ether. A mixture of the obtained silyl ether and Me3SiCl (20 mL, 0.16 mol)
was added into Na metal (3.4 g, 0.15 mol) in toluene (20 mL, 0.50 M) and refluxed for 18 h. The crude
material was purified by flash column chromatography on silica gel (hexane/CH2Cl2 = 100:1) to provide
1
the titled compound 4f as a white solid (2.4 g, 76%). Mp: 54–56 °C. H NMR (300 MHz, CDCl3) δ:
0.24 (9 H, s), 0.32 (18 H, s), 6.99 (1 H, t, J = 7.0 Hz), 7.41 (2 H, d, J = 7.0 Hz). 13C NMR (75 MHz,
CDCl3) δ: 1.0, 1.9, 121.0, 130.0, 137.3, 164.7. IR (neat): 1558, 1377 cm–1. HRMS (MALDI) Calcd for
C15H30OSi3 [M]+: 310.1599, found 310.1574.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 33
18
1
2
3
4
5
6
7
8
2,4,6ꢀTris(trimethylsilyl)phenyl trimethylsilyl ether (4g) (Table 2, entry 4): Following General
Procedure B, a mixture of HMDS (2.1 mL, 10 mmol) and 2,4,6ꢀtrichlorophenol (6d) (2.0 g, 10 mmol)
was stirred in THF (10 mL, 1.0 M) for 1 h at 60 °C, and the mixture was evaporated to provide the
2,4,6ꢀtrichlorophenyl trimethylsilyl ether. A mixture of the obtained silyl ether and Me3SiCl (30 mL,
0.24 mol) was added into Na metal (5.2 g, 0.23 mol) in toluene (20 mL, 0.50 M) and refluxed for 18 h.
The crude material was purified by flash column chromatography on silica gel (hexane/CH2Cl2 = 100:1)
9
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
to provide the titled compound 4g as a white solid (2.4 g, 68%). Mp: 47–50 °C. H NMR (400 MHz,
CDCl3) δ: 0.250 (9 H, s), 0.252 (9 H, s), 0.33 (18 H, s), 7.55 (2 H, s). 13C NMR (100 MHz, CDCl3) δ: –
0.9, 1.0, 2.0, 128.9, 130.9, 142.8, 165.8. IR (neat): 1557, 1385, 1248 cm–1. HRMS (FAB, NBA) Calcd
for C18H38OSi4 [M]+: 382.2000, found 382.2000.
4ꢀAminoꢀ2ꢀ(trimethylsilyl)phenyl trimethylsilyl ether (4h) (Table 2, entry 5): An oven dried round
bottom flask was charged with 4ꢀaminoꢀ2,6ꢀdichlorophenol (6e) (1.8 g, 10 mmol) and a stirꢀbar. The
flask was equipped with a threeꢀway stopcock, and evacuated and backꢀfilled with N2 (This process was
repeated three times). Then, anhydrous THF (50 mL, 0.20 M), Me3SiCl (3.8 mL, 30 mmol), and Et3N
(4.2 mL, 30 mmol) were sequentially added into the flask via a syringe at room temperature. The
mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated under reduced
pressure and the residue was filtered through a celite pad and washed with hexane to provide the 4ꢀ
[(trimethylsilyl)amino]ꢀ2,6ꢀdichlorophenyl trimethylsilyl ether which can be used in the next step
without further purification. Another ovenꢀdried three necked flask was charged with a glass coated stirꢀ
bar and equipped with two septums and a reflux condenser having a threeꢀway stopcock on the top. The
flask was evacuated and backꢀfilled with N2 (This process was repeated three times). Anhydrous toluene
(20 mL, 0.50 M) was added to the flask via a syringe and Na metal (3.4 g, 0.15 mol) was quickly added
under N2 flow. The mixture was refluxed for 15 min. A mixture of the above obtained trimethylsilyl
ether and Me3SiCl (20 mL, 0.16 mol) was added dropwise to the flask via a cannula at reflux
temperature and continued to be refluxed for 18 h. After the reaction mixture was cooled to room
ACS Paragon Plus Environment

Page 19 of 33
The Journal of Organic Chemistry
19
1
2
3
4
5
6
7
8
temperature, the mixture was filtrated through a celite cake and washed with hexane. The filtrate was
evaporated and the resultant residue was purified by flash column chromatography on silica gel
(hexane/EtOAc = 4:1) to provide the titled compound 4h as a brown solid (2.1 g, 88%). Mp: 83–85 °C.
1H NMR (300 MHz, CDCl3) δ: 0.23 (9 H, s), 0.28 (9 H, s), 3.36 (2 H, brs), 6.58–6.60 (2 H, m), 6.71–
6.73 (1 H, m). 13C NMR (100 MHz, CDCl3) δ: –0.9, 0.6, 117.0, 117.3, 122.3, 130.6, 139.4, 153.2. IR
(neat): 3308, 3215, 1473 cm–1. HRMS (MALDI) Calcd for C12H23NOSi2 [M]+: 253.1313, found
253.1309.
9
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
Synthesis of 2,6ꢀbis(trimethylsilyl)phenyl triflate 2d’ from 2,6ꢀdibromophenol 5d (Scheme 2):
2ꢀ(Trimethylsilyl)ꢀ6ꢀbromophenyl trimethylsilyl ether (4i) (Scheme 2): Following General Procedure
A, a mixture of Me3SiCl (1.9 mL, 15 mmol) and Et3N (2.1 mL, 15 mmol) and 2,6ꢀdibromophenol (5d)
(2.6 g, 10 mmol) was stirred in THF (50 mL, 0.20 M) for 1 h at room temperature. To the obtained silyl
ether in THF (50 mL, 0.20 M) was added nꢀBuLi (2.6 M in hexane, 4.6 mL, 12 mmol) at –78 °C and
stirred for 1 h. Following Workꢀup Method III, Me3SiCl (1.9 mL, 15 mmol) was added and stirred for 1
h. The crude material was purified by flash column chromatography on silica gel (hexane) to provide the
titled compound 4i as a colorless oil (2.2 g, 69%). 1H NMR (400 MHz, CDCl3) δ: 0.31 (9 H, s), 0.41 (9
H, s), 6.83 (1 H, dd, J = 8.0, 7.5 Hz), 7.31 (1 H, dd, J = 7.5, 1.5 Hz), 7.53 (1 H, dd, J = 8.0, 1.5 Hz). 13C
NMR (100 MHz, CDCl3) δ: –0.2, 2.5, 114.0, 122.5, 133.0, 134.5, 135.0, 157.0. IR (neat): 1570, 1416,
1246 cm–1. HRMS (FAB, NBA) Calcd for C12H21BrOSi2 [M] +: 316.0309, found 316.0315.
2,6ꢀBis(trimethylsilyl)phenol (1d) (Scheme 2): Anhydrous THF (34 mL, 0.20 M) was added to 2ꢀ
(trimethylsilyl)ꢀ6ꢀbromophenyl trimethylsilyl ether (4i) (2.2 g, 6.8 mmol) in a round bottom flask
equipped with a stirꢀbar and a threeꢀway stopcock. After the mixture was cooled to –78 °C, nꢀBuLi (2.6
M in hexane, 3.1 mL, 8.2 mmol) was added dropwise into the mixture and it was stirred for 1 h. sat. aq
NH4Cl (5 mL) was added to the reaction mixture at –78 °C. After the mixture was warmed to room
temperature, it was extracted with hexane three times. The combined organic extracts were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 33
20
1
2
3
4
chromatography on silica gel (hexane) to provide the titled compound 1d as a colorless oil (1.6 g, 99%).
1H NMR (400 MHz, CDCl3) δ: 0.34 (18 H, s), 5.00 (1 H, brs), 6.94 (1 H, t, J = 7.5 Hz), 7.38 (2 H, d, J =
5
6
7
13
7.5 Hz). C NMR (100 MHz, CDCl3) δ: –0.6, 120.4, 124.0, 136.7, 165.2. IR (neat): 3614, 1580, 1389
cm–1. HRMS (FAB, NBA) Calcd for C12H22OSi2 [M]+: 238.1204, found 238.1203.
8
9
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
2,6ꢀBis(trimethylsilyl)phenyl trifluoromethanesulfonate (2d’) (Scheme 2):4g
[Stepwise method] Anhydrous Et2O (65 mL, 0.10 M) was added to 2,6ꢀbis(trimethylsilyl)phenol (1d)
(1.6 g, 6.5 mmol) in a round bottom flask equipped with a stirꢀbar and a threeꢀway stopcock. After the
mixture was cooled to –78 °C, nꢀBuLi (2.6 M in hexane, 3.0 mL, 7.8 mmol) was added dropwise into
the mixture and it was stirred for 10 min. Tf2O (1.6 mL, 9.8 mmol) was added to the reaction mixture at
–78 °C and the mixture was stirred for 5 h at room temperature. The reaction was quenched with sat. aq
NaHCO3 (10 mL). And it was extracted with hexane three times. The combined organic extracts were
dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (hexane) to provide the titled compound 2d’ as a colorless oil (1.7
1
g, 72%). H NMR (400 MHz, CDCl3) δ: 0.37 (18 H, s), 7.37 (1 H, t, J = 8.0 Hz), 7.58 (1 H, d, J = 8.0
13
19
Hz). C NMR (100 MHz, CDCl3) δ: 0.33, 118.4 (CF3, q, J = 318 Hz), 127.3, 134.9, 138.2, 154.8. F
NMR (376 MHz, CDCl3) δ: –72.3. IR (neat): 1578, 1397, 1213 cm–1. HRMS (FAB, NBA) Calcd for
C13H21O3SF3Si2Na [M+Na]+: 393.0594, found 393.0608.
[Direct method] Anhydrous Et2O (10 mL, 0.10 M) was added to 2ꢀ(trimethylsilyl)ꢀ6ꢀbromophenyl
trimethylsilyl ether (4i) (0.32 g, 1.0 mmol) in a round bottom flask equipped with a stirꢀbar and a threeꢀ
way stopcock. After the mixture was cooled to –78 °C, nꢀBuLi (2.5 M in hexane, 0.48 mL, 1.2 mmol)
was added dropwise into the mixture and it was stirred for 1 h. Tf2O (0.25 mL, 1.5 mmol) was added to
the reaction mixture at –78 °C and the mixture was stirred for 5 h at room temperature. The reaction was
quenched with sat. aq NaHCO3 (5 mL). And it was extracted with hexane three times. The combined
organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel (hexane) to provide the titled compound 1d
ACS Paragon Plus Environment

Page 21 of 33
The Journal of Organic Chemistry
21
1
2
3
4
with 2d’ as a mixture (colorless oil, 0.21 g, 48% of 1d and 26% of 2d’). These two compounds (1d and
2d’) were hard to separate completely by silica gel column chromatography.
5
6
7
Optimization of benzyne generation in detail (Table 3):
8
9
Procedures for Table 3, entries 1–3, and 9–15: An ovenꢀdried sideꢀarm flask was charged with 4d (24
mg, 0.10 mmol), Nꢀtertꢀbutylꢀαꢀphenylnitrone (7a) (53 mg, 0.30 mmol) and a stirꢀbar. The flask was
equipped with a septum, and evacuated and backꢀfilled with N2 (This process was repeated three times).
Anhydrous THF (1.0 mL, 0.10 M) and NfF (26 µL, 0.15 mmol) were added into the flask via a syringe
through the septum. Then, a fluoride source (0.050–3.0 equiv) was quickly added to the flask at room
temperature with N2 flow [A solution of Bu4NF (3.0 equiv) was added via a syringe through the septum].
The mixture was [warmed to 60 °C and (for entries 10–15)] stirred for 5 h. The reaction mixture was
filtered through a short pad of silica gel and washed with EtOAc. nꢀDecane (19 µL, 0.10 mmol) was
added to the filtrate and the crude mixture (1.0 µL) was injected to a gas chromatograph (GC) to
determine yields of 8da,20 1e,3a,9 and 2e.3a,9 The mixture was evaporated under reduced pressure and the
resultant residue was purified by flash column chromatography on silica gel (hexane/EtOAc = 8:1) to
provide 8da.
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
Procedures for Table 3, entries 4–8: A sideꢀarm flask was charged with CsF [46 mg, 0.30 mmol (for
entries 4, 5, 7 and 8) or 30 mg, 0.20 mmol (for entry 6)] and a stirꢀbar. The flask was equipped with a
septum and heated under reduced pressure with a flame torch. After cooling to room temperature under
reduced pressure, the flask was backꢀfilled with N2. The solution of 4d (23 mg, 0.10 mmol) and Nꢀtertꢀ
Butylꢀαꢀphenylnitrone (7a) (53 mg, 0.30 mmol) in solvent (1.0 mL) was added to the flask via a cannula
at room temperature [or at 0 °C (for entry 8)] and the mixture was [warmed to 60 °C and (for entry 7)]
stirred at the indicated temperature for 5 h. Then, the reaction mixture was filtered through a short pad
of silica gel and washed with EtOAc. nꢀDecane (19 µL, 0.10 mmol) was added to the filtrate and the
crude mixture (1.0 µL) was injected to a gas chromatograph (GC) to determine yields of 8da,20 1e,3a,9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 33
22
and 2e.3a,9 The mixture was evaporated under reduced pressure and the resultant residue was purified by
1
2
3
4
flash column chromatography on silica gel (hexane/EtOAc = 8:1) to provide 8da.
5
6
7
8
2ꢀ(tertꢀButyl)ꢀ3ꢀphenylꢀ2,3ꢀdihydrobenzo[d]isoxazole (8da) (Table 3, entry 11):20 An ovenꢀdried
sideꢀarm flask was charged with 2ꢀ(trimethylsilyl)phenyl trimethylsilyl ether 4d (24 mg, 0.10 mmol) and
Nꢀtertꢀbutylꢀαꢀphenylnitrone (7a) (53 mg, 0.30 mmol) and a stirꢀbar. The flask was equipped with a
septum, and evacuated and backꢀfilled with N2 (This process was repeated three times). Anhydrous THF
(1.0 mL, 0.10 M) and NfF (27 µL, 0.15 mmol) were added into the flask via a syringe through the
septum. Then, Bu4NPh3SiF2 (TBAT) (81 mg, 0.15 mmol) was quickly added to the flask at room
temperature with N2 flow. The mixture was warmed to 60 °C and stirred at for 5 h. After cooling to
room temperature, the reaction mixture was filtered through a short pad of silica gel using EtOAc and
solvents were removed under reduced pressure. The crude product was purified by flash column
chromatography on silica gel (hexane/EtOAc = 8:1) to afford the titled compound 8da as a white solid
(21 mg, 91%). Mp: 92–94 °C (lit. 93–95 °C). 1H NMR (400 MHz, CDCl3) δ: 1.18 (9 H, s), 5.59 (1 H, s),
6.77–6.82 (2 H, m), 6.88 (1 H, d, J = 7.5 Hz), 7.14 (1 H, dd, J = 8.0, 8.0 Hz), 7.22–7.26 (1 H, m), 7.32
(2 H, dd, J = 7.5, 7.5 Hz), 7.39 (2 H, d, J = 7.5 Hz).
9
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
2ꢀ(Trimethylsilyl)phenyl perfluorobutaneslufonate (2d) (Table 3, entry 15):3a,9 An ovenꢀdried sideꢀ
arm flask was charged with 2ꢀ(trimethylsilyl)phenyl trimethylsilyl ether (4d) (23 mg, 0.10 mmol) and a
stirꢀbar. The flask was equipped with a septum, and evacuated and backꢀfilled with N2 (This process was
repeated three times). Anhydrous THF (1.0 mL, 0.10 M) and NfF (26 mL, 0.15 mmol) were added into
the flask via a syringe. Then, TBAT (2.7 mg, 5.0 µmol) was quickly added to the flask with N2 flow.
The mixture was stirred at 60 °C for 24 h. After cooling to room temperature, the reaction mixture was
filtered through a short pad of silica gel and washed with EtOAc and solvents were removed under
reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane) to
provide the titled compound 2d as a colorless oil (13 mg, 90%). 1H NMR (400 MHz, CDCl3) δ: 0.40 (9
H, s), 7.34–7.37 (2 H, m), 7.46 (1 H, ddd, J = 2.5, 7.5, 7.5 Hz), 7.56 (1 H, dd, J = 2.5, 7.5 Hz).
ACS Paragon Plus Environment

Page 23 of 33
The Journal of Organic Chemistry
23
1
2
Reactions of 2ꢀ(trimethylsilyl)phenyl trimethylsilyl ethers 4 with arynophiles 7 (Tables 4 and 5):
3
4
5
6
7
8
9
General Procedure C: An ovenꢀdried sideꢀarm flask was charged with 4 (1.0 equiv) [and arynophile 7
(3.0 equiv) in cases where the 7 was solid] and a stirꢀbar. The flask was equipped with a septum, and
evacuated and backꢀfilled with N2 (This process was repeated three times). Anhydrous THF and NfF
(1.5 equiv) [and arynophile 7 (3.0 equiv) in cases where the 7 was liquid] was added into the flask via a
syringe through the septum. Then, TBAT (Bu4NPh3SiF2) (1.5 equiv) was quickly added to the flask at
room temperature with N2 flow. The mixture was warmed to 60 °C and stirred at for 5 h. After cooling
to room temperature, the reaction mixture was filtered through a short pad of silica gel using EtOAc, and
solvents were removed under reduced pressure. The resultant residue was filtered through a short pad of
silica gel using hexane/EtOAc (10:1) to remove Ph3SiF and then other products were washed out using
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
hexane/EtOAc (1:1). The crude mixture was subjected to H NMR analysis for calculating the ratio of
the two regioisomers (distal- and proximalꢀ8). The crude product was purified by flash column
chromatography on silica gel or PTLC (hexane or CH2Cl2 or a mixture of hexane and EtOAc, hexane
and toluene) to afford distalꢀ and proximal-8.
1ꢀBenzylꢀ4,6ꢀdimethoxyꢀ1Hꢀbenzo[d][1,2,3]triazole (distalꢀ8ab) (Table 4, entry 1): Following
General Procedure C, a mixture of TBAT (161 mg, 0.30 mmol), NfF (53 µL, 0.30 mmol), benzylazide
(7b) (75 µL, 0.45 mmol) and 3,5ꢀdimethoxyꢀ2ꢀ(trimethylsilyl)phenyl trimethylsilyl ether (4a) (60 mg,
0.20 mmol) was stirred in THF (2.0 mL, 0.10 M) for 20 h at 60 °C. The crude product (distalꢀ
1
8ab/proximalꢀ8ab = >98:2, determined by 400 MHz H NMR analysis) was purified by column
chromatography on silica gel (hexane/EtOAc = 2:1) to provide the titled compound distalꢀ8ab as a pale
yellow solid (47 mg, 86%) and its regiochemistry was determined by NOESY spectra. Mp: 167–169 °C.
1H NMR (400 MHz, CDCl3) δ: 3.76 (3 H, s), 4.04 (3 H, s), 5.74 (2 H, s), 6.16 (1 H, d, J = 1.5 Hz), 6.30
(1 H, d, J = 1.5 Hz), 7.23 (2 H, d, J = 7.0 Hz), 7.27–7.35 (3 H, m). 13C NMR (125 MHz, CDCl3) δ: 51.8,
55.7, 56.1, 82.2, 96.1, 127.3, 128.2, 128.8, 134.3, 134.8, 135.3, 151.9, 161.3. IR (neat): 1620, 1516 cm–1.
HRMS (MALDI) Calcd for C15H16N3O2 [M+H]+: 270.1237, found 270.1240.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 33
24
1
2
3
4
5
6
7
8
1ꢀMethylꢀ1,4ꢀdihydroꢀ1,4ꢀepoxyanthracene (8bc) (Table 4, entry 2): Following General Procedure C,
a mixture of TBAT (161 mg, 0.30 mmol), NfF (53 µL, 0.30 mmol), 2ꢀmethylfuran (7c) (53 µL, 0.45
mmol) and 3ꢀ(trimethylsilyl)ꢀ2ꢀnaphthyl trimethylsilyl ether (4b) (58 mg, 0.20 mmol) was stirred in
THF (2.0 mL, 0.10 M) for 16 h at 60 °C. The crude product was purified by column chromatography on
silica gel (hexane/EtOAc = 8:1) to provide the titled compound 8bc as a colorless oil (35 mg, 85%). Mp:
71–73 °C. 1H NMR (500 MHz, CDCl3) δ: 2.00 (3 H, s), 5.72 (1 H, d, J = 1.5 Hz), 6.71 (1 H, d, J = 5.0
Hz), 6.96 (1 H, dd, J = 5.0 , 1.5 Hz), 7.41–7.45 (2 H, m), 7.48 (1 H, s), 7.54 (1 H, s), 7.69–7.75 (2 H,
m). 13C NMR (125 MHz, CDCl3) δ: 15.3, 81.3, 88.7, 117.1, 118.2, 126.0, 128.0, 128.1, 131.7, 131.9,
142.8, 144.3, 145.8, 147.0. IR (neat): 1662, 1307 cm–1. HRMS (MALDI) Calcd for C15H12O [M]+:
208.0883, found 208.0881.
9
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
2ꢀPhenylꢀ2Hꢀdibenzo[e,g]indazole (8cd) (Table 4, entry 3): Following General Procedure C, a
mixture of TBAT (161 mg, 0.30 mmol), NfF (53 µL, 0.30 mmol), 3ꢀphenylsydnone (7d)13 (97 mg, 0.45
mmol) and 10ꢀ(trimethylsilyl)ꢀ9ꢀphenanthoryl trimethylsilyl ether (4c) (68 mg, 0.20 mmol) was stirred
in THF (2.0 mL, 0.10 M) for 5 h at 60 °C. The crude product was purified by column chromatography
on silica gel (hexane/EtOAc = 8:1) to provide the titled compound 8cd as a white solid (37 mg, 63%).
1
Mp: 104–106 °C. H NMR (500 MHz, CDCl3) δ: 7.39 (1 H, dd, J = 7.5, 7.5 Hz), 7.53–7.59 (4 H, m),
7.61–7.67 (2 H, m), 7.98 (2 H, m), 8.10 (1 H, m), 8.56 (2 H, m), 8.68–8.72 (2 H, m). 13C NMR (100
MHz, CDCl3) δ: 118.7, 120.1, 120.7, 123.3, 123.5, 123.9, 124.1, 125.8, 126.0, 126.8, 127.1, 127.3,
127.4, 127.6, 129.0, 129.6, 130.8, 140.5, 147.0. IR (neat): 1599, 1504 cm–1. HRMS (MALDI) Calcd for
C21H14N2 [M]+: 294.1151, found 294.1146.
3ꢀ(2,4,6ꢀTrimethylphenyl)ꢀ6ꢀ(trimethylsilyl)benzo[d]isoxazole and 3ꢀ(2,4,6ꢀtrimethylphenyl)ꢀ5ꢀ
(trimethylsilyl)benzo[d]isoxazole (distal- and proximal-8ee) (Table 4, entry 4): Following General
Procedure C, a mixture of TBAT (162 mg, 0.30 mmol), NfF (53 µL, 0.30 mmol), 2,4,6ꢀ
trimethylphenylnitriloxide (7e)12 (48 mg, 0.45 mmol) and 2,4ꢀbis(trimethylsilyl)phenyl trimethylsilyl
ether (4e) (63 mg, 0.10 mmol) was stirred in THF (2.0 mL, 0.10 M) for 24 h at 60 °C. The crude product
ACS Paragon Plus Environment

Page 25 of 33
The Journal of Organic Chemistry
25
1
1
2
3
4
5
6
7
(distalꢀ8ee/proximalꢀ8ee = 76:24, determined by 400 MHz H NMR analysis) was purified by column
chromatography on silica gel (hexane/EtOAc = 15:1) and PTLC (hexane/toluene = 1:1) to provide the
titled compound distal- and proximal-8ee (65:35) as a colorless oil (50 mg, 88%) and its regiochemistry
1
8
9
was determined by NOESY spectra. H NMR (500 MHz, CDCl3) δ: 0.29 (9/3 H, s), 0.37 (18/3 H, s),
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
2.10 (12/3 H, s), 2.11 (6/3 H, s), 2.36 (6/3 H, s), 2.40 (3/3 H, s), 7.02 (4/3 H, s), 7.04 (2/3 H, s), 7.39
(2/3 H, d, J = 8.0 Hz), 7.43 (2/3 H, d, J = 8.0 Hz), 7.52 (1/3 H, s), 7.66 (1/3 H, d, J = 8.5 Hz), 7.73 (1/3
H, d, J = 8.5 Hz), 7.83 (2/3 H, s). 13C NMR (75 MHz, CDCl3) δ: –1.1, –0.9, 20.06, 20.13, 21.2, 109.5,
114.5, 121.2, 122.0, 122.5, 124.3, 124.4, 127.1, 128.0, 128.46, 128.53, 134.5, 135.6, 137.65, 137.73,
139.20, 139.24, 143.6, 157.6, 157.7, 163.0, 163.7. IR (neat): 1612, 1449, 1250 cm–1. HRMS (MALDI)
Calcd for C19H24NOSi [M+H]+: 310.1622, found 310.1617.
5ꢀAminoꢀ1ꢀbenzylꢀ1Hꢀbenzo[d][1,2,3]triazol (distalꢀ8hb) (Table 4, entry 5): Following General
Procedure C, a mixture of TBAT (0.40 g, 0.50 mmol), benzylazide (7b) (0.19 mL, 1.5 mmol), and 4ꢀ
aminoꢀ2,6ꢀbis(trimethylsilyl)phenyl trimethylsilyl ether (4h) (0.12 g, 67 µmol) was stirred in THF (5.0
1
mL) for 6 h at 60 °C. The crude product (distalꢀ8hb/proximalꢀ8hb = 50:50, determined by 400 MHz H
NMR analysis) was purified by column chromatography on silica gel (hexane/EtOAc = 1:2) to provide
the titled compound distalꢀ8hb as a brown solid (12 mg, 26%) and its regiochemistry was determined by
NOESY spectra. Mp: 169–171 °C. 1H NMR (400 MHz, CDCl3) δ: 3.78 (2 H, brs), 5.75 (2 H, s), 6.82 (1
H, d, J = 8.5, 2.5 Hz), 7.10 (1 H, d, J = 8.5 Hz), 7.18 (1 H, d, J = 2.5 Hz), 7.21–7.27 (2 H, m), 7.28–7.34
(3 H, m). 13C NMR (100 MHz, CDCl3) δ: 52.3, 101.4, 110.4, 119.3, 127.5, 127.7, 128.3, 128.9, 134.9,
143.4, 147.8. IR (neat): 3433, 3341, 1506 cm–1. HRMS (MALDI) Calcd for C13H13N4 [M+H]+:
225.1135, found 225.1127.
5ꢀAminoꢀ1ꢀbenzylꢀ1Hꢀbenzo[d][1,2,3]triazol (proximalꢀ8hb) (Table 4, entry 5) was obtained from
the aboveꢀmentioned reaction mixture as a brown solid (12 mg, 26%) and its regiochemistry was
1
determined by NOESY spectra. Mp: 158–160 °C. H NMR (500 MHz, CDCl3) δ: 3.91 (2 H, brs), 5.70
(2 H, s), 6.40 (1 H, d, J = 2.5 Hz), 6.71 (1 H, dd, J = 8.5, 2.5 Hz), 7.22–7.26 (2 H, m), 7.28–7.35 (3 H,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 33
26
m), 7.81 (1 H, d, J = 8.5 Hz). 13C NMR (125 MHz, CDCl3) δ:51.7, 91.1, 115.6, 120.8, 127.4, 128.2,
128.9, 134.5, 135.1, 141.1, 146.5. IR (neat): 3325, 3217, 1624 cm–1. HRMS (MALDI) Calcd for
C13H13N4 [M+H]+: 225.1135, found 225.1134.
1
2
3
4
5
6
7
8
9
2ꢀ(tertꢀButyl)ꢀ3ꢀphenylꢀ7ꢀ(trimethylsilyl)ꢀ2,3ꢀdihydrobenzo[d]isoxazole (distal-8fa) (Table 5, entry
1): Following General Procedure C, a mixture of TBAT (57 mg, 0.30 mmol), NfF (26 µL, 0.15 mmol),
Nꢀtertꢀbutylꢀαꢀphenylnitrone (7a) (57 mg, 0.30 mmol), and 2,6ꢀbis(trimethylsilyl)phenyl trimethylsilyl
ether (4f)13 (31 mg, 0.10 mol) was stirred in THF (1.0 mL) for 24 h at 60 °C. The crude product (distalꢀ
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
8fa/proximalꢀ8fa = 95:5, determined by 400 MHz H NMR analysis) was purified by column
chromatography on silica gel (hexane/EtOAc = 1:20) and PTLC (hexane/EtOAc = 1:15) to provide the
titled compound distal-8fa as a yellow solid (27 mg, 80%) and its regiochemistry was determined by
1
NOESY spectra. Mp: 60–62 °C. H NMR (500 MHz, CDCl3) δ: 0.34 (9 H, s), 1.18 (9 H, s), 5.56 (1 H,
s), 6.81 (1 H, dd, J = 7.5, 7.0 Hz), 6.90 (1 H, dd, J = 7.5, 1.0 Hz), 7.21–7.26 (2 H, m), 7.32 (2 H, dd, J =
8.5, 8.5 Hz) 7.37 (2 H, d, J = 8.5 Hz). 13C NMR (125 MHz, CDCl3) δ:–1.2, 25.4, 61.0, 66.7, 117.2,
120.4, 124.7, 127.3, 127.4, 128.0, 128.6, 133.7, 144.0, 161.1. IR (neat): 1416, 1364 cm–1. HRMS
(MALDI) Calcd for C20H27NOSi [M]+: 325.1856, found 325.1857.
2ꢀ(tertꢀButyl)ꢀ3ꢀphenylꢀ4ꢀ(trimethylsilyl)ꢀ2,3ꢀdihydrobenzo[d]isoxazole (proximal-8fa) (Table 5,
entry 1) was obtained from the aboveꢀmentioned reaction mixture as a white solid (1.3 mg, 4%) and its
1
regiochemistry was determined by NOESY spectra. Mp: 67–70 °C. H NMR (300 MHz, CDCl3) δ: –
0.03 (9 H, s), 1.18 (9 H, s), 5.63 (1 H, s), 6.91 (1 H, d, J = 8.0 Hz), 7.00–7.07 (2 H, m), 7.20–7.30 (5 H,
m). 13C NMR (125 MHz, CDCl3) δ: –1.0, 25.6, 61.3, 66.6, 107.5, 127.0, 127.6, 128.2, 128.4, 128.7,
133.3, 135.6, 143.3, 157.3. IR (neat): 1730, 1562, 1250 cm–1HRMS (MALDI) Calcd for C20H27NOSi
[M]+: 325.1856, found 325.1854.
Ethyl 7ꢀ(trimethylsilyl)ꢀ1Hꢀindazoleꢀ3ꢀcarboxylate (distalꢀ8ff) (Table 5, entry 2): Following General
Procedure C, a mixture of TBAT (0.40 g, 1.5 mmol), NfF (0.13 mL, 0.75 mmol), ethyl diazoacetate (7f)
(contain 13% of CH2Cl2 181 µL, 1.5 mmol), and 2,6ꢀbis(trimethylsilyl)phenyl trimethylsilyl ether (4f)
ACS Paragon Plus Environment

Page 27 of 33
The Journal of Organic Chemistry
27
1
2
(0.16 g, 0.50 mmol) was stirred in THF (5.0 mL) for 5 h at 60 °C. The crude product (distalꢀ
3
4
1
8ff/proximalꢀ8ff = >98:2, determined by 400 MHz H NMR analysis) was purified by column
5
6
7
8
9
chromatography on silica gel (hexane/EtOAc = 1:8 to 1:2) to provide the titled compound distalꢀ8ff as a
white solid (0.10 g, 79%) and its regiochemistry was determined by NOESY, HMQC and HMBC
spectra. Mp: 128–130 °C. 1H NMR (500 MHz, CDCl3) δ: 0.46 (9 H, s), 1.49 (3 H, t, J = 7.0 Hz), 4.53 (2
H, q, J = 7.0 Hz), 7.33 (1 H, dd, J = 8.0, 8.0 Hz), 7.55 (1 H, d, J = 8.0 Hz), 8.26 (1 H, d, J = 8.0 Hz),
10.48 (1 H, brs). 13C NMR (100 MHz, CDCl3) δ: –0.7, 14.4, 61.0, 121.4, 121.7, 122.9, 123.1, 133.4,
136.8, 145.0, 162.6. IR (neat): 3294, 1737, 1454 cm–1. HRMS (MALDI) Calcd for C13H19N2O2Si
[M+H]+: 263.1210, found 263.1219.
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
1ꢀBenzylꢀ4ꢀ(trimethylsilyl)ꢀ1Hꢀbenzo[d][1,2,3]triazole (distal-8fb) (Table 5, entry 3):4g Following
General Procedure C, a mixture of TBAT (81 mg, 0.15 mmol), NfF (26 µL, 0.15 mmol), benzylazide
(7b) (37 µL, 0.30 mmol) and 2,6ꢀbis(trimethylsilyl)phenyl trimethylsilyl ether (4f) (31 mg, 0.10 mmol)
was stirred in THF (1.0 mL, 0.10 M) for 7 h at 60 °C. The crude product (distalꢀ8fb/proximalꢀ8fb =
75:25, determined by 400 MHz 1H NMR analysis) was purified by column chromatography on silica gel
1
(hexane/EtOAc = 8:1) to provide the titled compound distalꢀ8fb as a colorless oil (16 mg, 57%). H
NMR (300 MHz, CDCl3) δ: 0.49 (9 H, s), 5.83 (2 H, s), 7.27–7.44 (8 H, m).
1ꢀBenzylꢀ7ꢀ(trimethylsilyl)ꢀ1Hꢀbenzo[d][1,2,3]triazole (proximal-8fb) (Table 5, entry 3)4g was
obtained from the aboveꢀmentioned reaction mixture as a yellow oil (5.4 mg, 19%). 1H NMR (400 MHz,
CDCl3) δ: 0.36 (9 H, s), 6.05 (2 H, s), 6.89 (2 H, d, J = 8.0 Hz), 7.27–7.42 (4 H, m), 7.64 (1 H, dd, J =
8.0, 1.5 Hz), 8.15 (1 H, d, J = 8.0 Hz).
3ꢀ(Trimethylsilyl)ꢀbenzocyclobuteneꢀ1ꢀone (proximalꢀ8fg) (Table 5, entry 4): Following General
Procedure C, a mixture of TBAT (0.40 g, 1.5 mmol), NfF (0.13 mL, 0.75 mmol), 1,1ꢀdimethoxyethylene
(7g) (0.14 µL, 1.5 mmol) and 2,6ꢀbis(trimethylsilyl)phenyl trimethylsilyl ether (4f) (0.16 mg, 0.50
mmol) was stirred in THF (5.0 mL, 0.10 M) for 5 h at 60 °C. The crude product (distalꢀ8fg/proximalꢀ
1
8fg = 2:>98, determined by 400 MHz H NMR analysis) was purified by column chromatography on
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 33
28
1
2
silica gel (hexane/EtOAc = 8:1) to provide the titled compound proximalꢀ8fg as a colorless oil (62 mg,
3
4
1
65%). and its regiochemistry was determined by NOESY spectra. H NMR (500 MHz, acetoneꢀd6) δ:
5
6
7
8
9
0.27 (9 H, s), 3.30 (6 H, s), 3.32 (2 H, s), 7.18 (1 H, d, J = 7.5 Hz), 7.27 (1 H, dd, J = 7.5, 7.5 Hz), 7.38
13
(1 H, d, J = 7.5 Hz). C NMR (125 MHz, acetoneꢀd6) δ: –0.5, 39.9, 52.1, 108.3, 124.4, 130.2, 133.6,
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
136.5, 141.6, 151.7. IR (neat): 1765, 1562, 1250 cm–1. HRMS (MALDI) Calcd for C13H21O2Si [M+H]+:
237.1305, found 237.1305.
1,4ꢀDimethylꢀ6ꢀ(trimethylsilyl)ꢀ1,2,3,4ꢀtetrahydroꢀ5Hꢀbenzo[e][1,4]diazepinꢀ5ꢀone
(distalꢀ8fh)
(Table 5, entry 5): Following General Procedure C, TBAT (0.40 g, 1.5 mmol), 2,5ꢀ
dimethylinidazolidinone (7h) (0.16 mL, 1.5 mmol), and 2,6ꢀbis(trimethylsilyl)phenyl trimethylsilyl ether
(4f) (0.16 g, 0.50 mmol) was stirred in THF (5.0 mL) for 3 h at 60 °C. The crude product (distalꢀ
1
8fh/proximalꢀ8fh = >98:2, determined by 300 MHz H NMR analysis) was purified by column
chromatography on silica gel (hexane/EtOAc = 2:1) to provide the titled compound distalꢀ8fh as a white
1
solid (20 mg, 77%) and its regiochemistry was determined by NOESY spectra. Mp: 122–125 °C. H
NMR (500 MHz, CDCl3) δ: 0.28 (9 H, s), 2.79 (3 H, s), 3.17 (2 H, d, J = 6.5 Hz), 3.20 (3 H, s), 3.40 (2
H, d, J = 6.5 Hz), 6.91 (1 H, dd, J = 8.0, 1.0 Hz), 7.23–7.26 (1 H, m), 7.32 (1 H, dd, J = 8.0, 8.0 Hz). 13C
NMR (125 MHz, CDCl3) δ: –0.03, 33.9, 40.1, 48.2, 57.6, 118.4, 128.8, 130.0, 136.3, 141.2, 146.0,
171.5. IR (neat): 1645, 1394 cm–1. HRMS (MALDI) Calcd for C14H23N2OSi [M+H]+: 263.1574, found
263.1573.
3ꢀ(4ꢀMethoxyphenyl)ꢀ2ꢀphenylꢀ7ꢀ(trimethylsilyl)ꢀ2Hꢀindazole (distalꢀ8fi) (Table 5, entry 6):
Following General Procedure C, a mixture of TBAT (0.16 g, 0.30 mmol), NfF (53 µL, 0.30 mmol), 4ꢀ
(4ꢀmethoxyphenyl)ꢀ3ꢀphenylsydnone (7i)13 (80 mg, 0.30 mmol) and 2,6ꢀbis(trimethylsilyl)phenyl
trimethylsilyl ether (4f) (62 mg, 0.20 mmol) was stirred in THF (2.0 mL, 0.10 M) for 10 h at 60 °C. The
crude product (distalꢀ8fi/proximalꢀ8fi = >98:2, determined by 400 MHz 1H NMR analysis) was purified
by column chromatography on silica gel (hexane/EtOAc = 8:1) to provide the titled compound distalꢀ8fi
as a white solid (50 mg, 82%) and its regiochemistry was determined by NOESY spectra. Mp: 145–
ACS Paragon Plus Environment

Page 29 of 33
The Journal of Organic Chemistry
29
146 °C. 1H NMR (500 MHz, CDCl3) δ: 0.47 (9 H, s), 3.81 (3 H, s), 6.92 (2 H, d, J = 8.5 Hz), 7.09 (1 H,
dd, J = 8.5, 6.5 Hz), 7.25–7.28 (2 H, m), 7.31–7.40 (3 H, m), 7.44–7.48 (3 H, m), 7.66 (1 H, d, J = 8.5
Hz). 13C NMR (125 MHz, CDCl3) δ: –0.9, 55.3, 114.2, 120.7, 121.4, 121.9, 122.7, 125.8, 127.6, 128.7,
129.8, 131.0, 132.7, 134.5, 140.6, 152.3, 159.4. IR (neat): 1504, 1250 cm–1. HRMS (MALDI) Calcd for
C23H24N2OSi [M]+: 372.1652, found 372.1657.
1
2
3
4
5
6
7
8
9
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
3ꢀ(4ꢀMethoxyphenyl)ꢀ2ꢀphenylꢀ5,7ꢀbis(trimethylsilyl)ꢀ2Hꢀindazole (distalꢀ8gi) (Table 5, entry 7):
Following General Procedure C, a mixture of TBAT (0.16 g, 0.30 mmol), NfF (53 µL, 0.30 mmol), 4ꢀ
(4ꢀmethoxyphenyl)ꢀ3ꢀphenylsydnone (7i)13 (0.16 g , 0.21 mmol) and 2,4,6ꢀtris(trimethylsilyl)phenyl
trimethylsilyl ether (4g) (76 mg, 0.20 mmol) was stirred in THF (2.0 mL) for 13 h at 60 °C. The crude
1
product (distalꢀ8gi/proximalꢀ8gi = >98:2, determined by 300 MHz H NMR analysis) was purified by
column chromatography on silica gel (hexane/EtOAc = 16:1) to provide the titled compound distalꢀ8gi
as a white solid (74 mg, 58%) and its regiochemistry was determined by NOESY spectra. Mp: 208–
209 °C. 1H NMR (500 MHz, CDCl3) δ: 0.31 (9 H, s), 0.49 (9 H, s), 3.86 (3 H, s), 6.96 (2 H, d, J = 8.5
Hz), 7.28 (2 H, d, J = 8.5 Hz), 7.32–7.40 (3 H, m), 7.45 (2 H, d, J = 7.5 Hz), 7.58 (1 H, s), 7.84 (1 H, s).
13C NMR (125 MHz, CDCl3) δ: –0.9, –0.8, 55.3, 144.3, 120.5, 122.7, 125.9, 127.5, 127.6, 128.6, 128.7,
131.0, 132.7, 134.5, 136.4, 140.6, 152.6, 159.4. IR (neat): 1593, 1248 cm–1. HRMS (MALDI) Calcd for
C26H32N2OSi2 [M] +: 444.2048, found 444.2057.
Application to transitionꢀmetal catalyzed reaction (Scheme 3):
1ꢀ(2ꢀAllylphenyl)ꢀ2ꢀphenylacetylene (11) (Scheme 3):10 An ovenꢀdried sideꢀarm flask was charged
with CuI (5.7 mg, 30 µmol), 1,2ꢀbis(diphenylphosphino)propane (12 mg, 30 µmol), CsF (68 mg, 0.45
mmol), K2CO3 (83 mg, 0.60 mmol) and a stirꢀbar. The flask was equipped with a septum, and evacuated
and backꢀfilled with N2 (This process was repeated three times). Anhydrous MeCN (1.0 mL) was added
to the flask. Then, the mixture of 2ꢀ(trimethylsilyl)phenyl trimethylsilyl ether (4d) (72 mg, 0.30 mmol),
phenylacetylene (10) (33 µL, 0.30 mmol), allylchloride (9) (98 µL, 1.2 mmol) and NfF (80 µL, 0.45
mmol) in anhydrous MeCN (2.0 mL) were added into the flask via a cannula through the septum and it
ACS Paragon Plus Environment