One-Pot Twofold Unsymmetrical C-Si Bond 2,6-Bifunctionalization of Arenes via Sequential [1,4]-Csp2 to O-Silyl Migration

Article abstract of DOI:10.1021/acs.joc.9b02014

Twofold unsymmetrical C-Si bond bifunctionalization of 2,6-di(trimethylsilyl) benzyl alcohols has been achieved in one pot via sequential [1,4]-Csp² to O-silyl migration. The hydroxyl group functions as an "on-off-on" switch to control two successive silyl migrations, and 4,7-dimethyl-o-phenanthroline ligand favors cleavage of the endocyclic C-Si bond. Diverse Csp³/Csp³ or Csp²/Csp³ electrophiles can be installed at the 2- and 6-positions. This approach was used to chemoselectively functionalize the three C-Si bonds of 2,4,6-tri(trimethylsilyl) benzyl alcohol, transforming it into isochroman derivatives. The approach even works as a five-component reaction to construct complex symmetric structures.

Full text of DOI:10.1021/acs.joc.9b02014

Subscriber access provided by University of Texas Libraries
Article
One-Pot Two-fold Unsymmetrical C-Si bond 2,6-Bifunctionalization
of Arenes via Sequential [1,4]-Csp2 to O-Silyl Migration
Kai Wang, Linjie Li, Tianbao Hu, Lu Gao, and Zhenlei Song
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02014 • Publication Date (Web): 09 Sep 2019
Downloaded from pubs.acs.org on September 14, 2019
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 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 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.
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 15
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
One-Pot Two-fold Unsymmetrical C-Si bond 2,6-Bifunctionalization of
Arenes via Sequential [1,4]-Csp2 to O-Silyl Migration
Kai Wang,a Linjie Li,a Tianbao Hu,a Lu Gao*a and Zhenlei Song *a, b
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
a Sichuan Engineering Laboratory for Plant-Sourced Drug and Research Center for Drug Industrial Technology, Key
Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy,
Sichuan University, Chengdu, 610041 (China); b State Key Laboratory of Elemento-organic Chemistry, Nankai Univer-
sity, Tianjin, 300071 (China)
KEYWORDS: bifunctionalization, cross-coupling, organosilane, catalysis, silyl migration
ABSTRACT: Two-fold unsymmetrical C-Si bond bifunctionalization of 2,6-di(trimethylsilyl) benzyl alcohols has been
achieved in one pot via sequential [1,4]-Csp2 to O-silyl migration. The hydroxyl group functions as an "on-off-on" switch to
control two successive silyl migrations, and 4,7-dimethyl-o-phenanthroline ligand favors cleavage of the endo-cyclic C-Si
bond. Diverse Csp3/Csp3 or Csp2/Csp3 electrophiles can be installed at the 2- and 6-positions. This approach was used to
chemoselectively functionalize the three C-Si bonds of 2,4,6-tri(trimethylsilyl) benzyl alcohol, transforming it into isochro-
man derivatives. The approach even works as a five-component reaction to construct complex symmetric structures.
INTRODUCTION
Takeda’s,8 our own9 and others’10 progress in cross-cou-
Two-fold unsymmetrical 2,6-bifunctionalization of 1-
pling based on Brook rearrangement involving Csp2 to O-si-
substituted arenes provides a useful access to polyfunction-
lyl migration,11 as well as our recent synthesis of
alized aromatic compounds, which are widely applied in or-
ganic chemistry, pharmaceuticals and materials. 1 A highly
step-efficient reaction in which different groups A and B are
(a) General profile of one-pot twofold unsymmetrical 2,6-functionalization
added at the 2- and 6-position of arenes in one pot is quite
FG
FG
one-pot catalysis
unsymmetrical
H ref.[3a, b]
1
1
desirable (Scheme 1a), but challenging for the following
reasons. (1) The A group introduced in the first C-Y bond
functionalization might inhibit subsequent functionaliza-
tion with the B group. (2) Competitive 2,6-homo-disubstitu-
tion2 with two A groups may be a problem to give the unde-
sired symmetric product. This would lead to a complex mix-
ture containing bi-functionalized chemoisomers (A/A, B/B,
A/B), mono-functionalized isomers (A/Y, B/Y), and recov-
ered substrate. (3) Finding one or two compatible catalytic
systems that efficiently control the reactivity and selectivity
of each functionality is difficult. Given these difficulties, it is
no surprise that only a handful of one-pot two-fold unsym-
metrical 2,6-bifunctionalizations of arenes have been re-
ported. One involves C-H functionalization to introduce ac-
etyl and pivaloxy groups,3a, b another involves 2,6-diboro
arenes, in which hydrazone differentiates two symmetric C-
B bonds,4 resulting in a sequential one-pot Suzuki-Miyaura
cross-coupling with two different aryl bromides. Another
promising substrate is 2,6-disilyl arene, yet we are aware of
only separated multi-step functionalization of 2,6-silyl
groups as demonstrated by Knochel.5 To the best of our
knowledge, it appears that two-fold unsymmetrical C-Si
bond bifunctionalization of 2,6-disilyl arenes in one pot has
still remained unexplored.
R =
R =
A
B
Y
Y
B ref.[4]
6
6
2
2
(
=
(
A B
/
A
B
)
R = Si
unexplored
)
R
R
(b) This work: one-pot 2,6-functionalization via sequential silyl migrations
HO
Si
OSi
Si
OH
E2
t-BuOLi/[Cu]
1-X1
TBAF/[Cu]
2-X2
Si-migration
E
E
E1
E1
Si
Si-migration
1st
2nd
Cu
O
Cu
O
R
R
R
1
2
3
(Si = SiMe3)
Me
3Si
Si
(not isolated) E1
SiMe3
"OFF"
"ON"
= allyl, aryl or vinyl;
"ON"
R
R
= allyl; R = H or SiMe
E1
E2
3
SCHEME 1. General form of two-fold unsymmetrical 2,6-
functionalization of arenes in one pot (a); two-fold un-
symmetrical C-Si bond 2,6-functionalization of arenes
via sequential [1,4]-Csp2 to O-silyl migrations in one pot
(b).
2,6-di(trimethylsilyl) benzaldehyde,12 we wished to test the
scenario in Scheme 1b. In this pathway, the hydroxyl group
in 1 acts as an "on-off-on" switch to control each step in the
sequential [1,4]-Csp2 to O-silyl migration. Deprotonation
under basic conditions turns the hydroxyl group on, and the
We have already demonstrated the power of geminal
bis(silanes) in organic synthesis by bifunctionalizing the
two C-Si bonds.6 Inspired by these studies, and Smith’,7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 15
first silyl migration occurs, in which one of the C-Si bonds is further transformation of 6 into 2a failed with longer reac-
cleaved to facilitate Cu-catalyzed cross-coupling with E1-X1.
In this process, the hydroxyl group turns off by forming the
silyl ether 2. This implies that a second C-Si bond in 2 would
remain untouched and no second cross-coupling would oc-
cur with the extra E1-X1. After complete conversion of 1 to
2, the hydroxyl group is turned on by selective O-Si bond
cleavage promoted by TBAF, paving the way for the second
silyl migration and cross-coupling with E2-X2, giving the
two-fold unsymmetrically functionalized product 3. Here
we report the realization of the approach in Scheme 1b.
tion time (entry 2). Switching the catalyst from CuI to other
copper salts such as CuCl, CuBr or CuCN did not improve the
ratio or only led to complex mixtures (entries 3-5).
Inspired by the ability of N, N-bidentate ligands to facili-
tate copper-catalyzed aryl or vinyl cross-coupling,15 we hy-
pothesized that this type of ligand might favor the genera-
tion of the desired aryl
1
2
3
4
5
6
7
8
TABLE 1. Screening of Reaction Conditions of Cross-
coupling with Csp3-electrophile E1-X1a
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
Cu(I)
t-BuOLi (1.2 equiv.)
HO
O
OSiMe3
SiMe3
RESULTS AND DISCUSSION
(0.5 equiv.)
Ligand
Me2Si
SiMe3
Me3Si
SiMe3
+
Cl
Syntheses of 1a and 1b The required 2,6-di(trimethylsilyl)
benzyl alcohol 1a was synthesized from the known N, N-di-
ethyl benzylamide 4a (Scheme 2).13 The approach we devel-
oped to reduce steric demanding amides allowed us to
transform 4a into the aldehyde 5a in73%.12 The reaction
was initiated by activation of amide with EtOTf to form im-
idate, which was reduced with LiAlH(OEt)3 to give aldehyde
by hydrolysis of the resulting hemiaminals. Reduction of al-
dehyde 5a with NaBH4 afforded the alcohol 1a in 83% yield.
Similar two-step operation on 2,4,6-tri(trimethylsilyl) ben-
zylamide 4b gave the corresponding alcohol 1b in an over-
all yield of 50%.
(1. 0 equiv.)
DMF, 0 oC to rt
1a
2a
6
Cu
O
a:
Me
Me
Me
endo-cyclic
exo-cyclic
b:
Si
b
Si
2a
6
a
C-Si bond
cleavage
C-Si bond
cleavage
7
Entry
Cu(I)
Ligand
t (h)
2a:4b
2a (%)c
1
2
3
4
5
6
7
8
CuI
CuI
CuCl
CuBr
CuCN
CuI
CuI
CuI
CuI
CuI
—
—
—
—
—
L1
L2
L3
L4
L5
L6
L7
1
10
1
1
1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
5.4:1
N.D.
N.D.
75
N.D.
N.D.
62
65
78
71
85
72
93
91
80
3.0:1
3.6:1
7.0:1
4.2:1
9.0:1
4.8:1
20:1
20:1
7.0:1
NEt2
SiMe3
O
H
OH
SiMe3
O
a
b
Me3Si
Me3Si
Me3Si
SiMe3
73%
83%
9
4a
5a
1a
10
11
12
CuI
CuI
NEt2
SiMe3
O
H
OH
SiMe3
O
a
b
Me3Si
Me3Si
Me3Si
SiMe3
aReaction conditions: Cu(I) (0.05 mmol), t-BuOLi (0.12 mmol) in
DMF, 0 C to rt, 10 min; then ligand (0.05 mmol), 1a (0.1 mmol),
allylchloride (0.1 mmol), rt, 30 min. bRatios were determined by 1H
NMR of the crude products. cIsolated yields.
62%
80%
o
SiMe3
SiMe3
SiMe3
4b
5b
1b
2, 45 o
, THF, 0
C, 4 h, then LiAlH(OEt)3
Cl
oC to rt, overnight (73% for
(a) EtOTf, CH2
5a 5b
t-Bu
t-Bu
1a
1b
).
; 62% for
, MeOH, rt, 2 h (83% for ; 80% for
). (b) NaBH4
SCHEME 2. Syntheses of 1a and 1b.
N
N
N
N
N
N
N
N
Me
Me
L1
L2
L3
L4
Sequential cross-coupling of 1a with Csp3/Csp3-electro-
philes E1-X1 and E2-X2 Allyl chloride was tested as the elec-
trophile for the first cross-coupling using Takeda’s proto-
col.8e The reaction provided mono-allylated silyl ether 2a in
75% yield, without the undesired further desilylation of O-
Si or C-Si bonds (turning off). Two silyl groups in 1a ap-
peared to sterically protect the hydroxyl group from oxida-
tion to the corresponding aldehyde, which has frequently
been observed in systems involving thermal degradation of
the copper(I).8e Cyclic silyl ether 6 was detected as the ma-
jor by-product: the ratio of products 2a:6 was 5.4:1 (Table
1, entry 1). Product 2a was generated from the endo-cyclic
Csp2-Si bond cleavage of 7 (path a), while 6 resulted from
exo-cyclic Csp3-Si bond cleavage (path b). Exo-cyclic C-Si
bond cleavage is very common, and even dominates in
Hiyama’s14 and Takeda’s8k studies using phosphine as lig-
and. In our case, this pathway should be minimized as much
as possible to ensure complete formation of 2a, because 6
would complicate the second cross-coupling. Unfortunately,
Me
Me
Me
Me
N
Me
Me
N
N
N
N
N
N
L5
L6
L7
copper species via endo-cyclic C-Si bond cleavage. Bipyri-
dine ligands L1and L2 afforded moderate ratios (entries 6
and 7), while more rigid o-phenanthroline L3 significantly
improved the ratio to 9:1 (entry 8). Substitution on o-phe-
nanthroline greatly affected selectivity. Introducing two
methyl groups at the 2- and 9-positions in L4 lowered the
ratio to 4.8:1 (entry 9), probably because the increased ste-
ric hindrance weakened the coordination of o-phenanthro-
line with copper. Conversely, the electron-donating effects
of the 4,7-dimethyl groups in L5 appeared to strengthen the
coordination with copper, increasing the ratio to 20:1 and
giving 2a in 93% yield (entry 10). Consistent with this idea,
ACS Paragon Plus Environment

Page 3 of 15
The Journal of Organic Chemistry
L6, containing two extra dimethyl groups at 3- and 8-posi-
MeI, BnBr or propargyl chloride cannot be cross-coupled
with 1a either as E1-X1 or E2-X2.
1
2
3
4
5
6
7
8
tions, led to a similarly high ratio as L5 (entry 11). Triden-
tate ligand L7 was also tested, but less effective than L5, af-
fording a ratio of 7:1 (entry 12).
With the optimal conditions for the first cross-coupling in
hand, we examined installation of the second Csp3-electro-
phile (E2-X2) in the same pot. Key for this step is that the O-
Si bond in 2 is cleaved selectively over the C-Si bond, thus
exposing the alkoxide required for the second silyl migra-
tion (turning on). Among several fluoride sources tested, KF,
CsF and TBAT were unable to remove O-trime
Sequential cross-coupling of 1a with Csp2/Csp3-electro-
philes Compared with one-pot installation of two Csp3-elec-
trophiles, sequential cross-coupling of 1a with Csp2/Csp3-
electrophiles proved more challenging because of potential
incompatibility of reaction conditions. 1-Methyl vinylbro-
mide was initially used to examine the reaction conditions
for the first cross-coupling. Typically, strong polar solvents
such as DMF8b or THF/HMPA 7d are required to facilitate the
silyl migration in Cu/Pd-catalyzed cross-coupling with aryl
or vinyl halides. In our case, these solvents indeed pro-
moted silyl
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 2. Screening of Reaction Conditions of Sequen-
tial cross-coupling with Csp3/Csp3-electrophiles E1-
X1/E2-X2a
TABLE 3. Scope of Csp3/Csp3-electrophiles E1-X1 and E2-
X2a
F-
(1.5 equiv.)
HO
OSiMe3
SiMe3
CuI, t-BuOLi
L5
t-BuOLi
Me
3Si
SiMe3
Cl
Me
L5
CuI, t-BuOLi,
HO
3Si
OH
E2
oC to rt, 0.5 h
Cl
1-X1
DMF, 0 o
E
, DMF, 0
C to rt, 0.5 h
Me
E1
SiMe3
1a
2a
Si-mig.
Si-mig.
E
1st
2nd
2-X2
then
, TBAF, t-BuOLi
(not isolated)
DMF, rt,1 h
1a
OH
3b
OH
c
3a
(%)
N.D.
Entry
F-
t-BuOLib
-
OH
OH
1
2
3
4
5
KF
Me
Me
-
-
-
N.D.
N.D.
41
CsF
TBAT
TBAF
TBAF
Me
Me
Me
Me
R
(R = Ph, 54%)
= Cl, 74%]
(65%)
3b
3c
3d
1, X2
3a
1, X2
[X
3a
2.0 equiv
74
(R = n-Pr, 57%)
= Br, X2 = Cl, 69%]
= OTs, X2 = Cl, 60%]
= Cl]
[X1
[X
[X
= Cl]
1, X2
[X1
aReaction conditions: 1st Si-migration: Cu(I) (0.05 mmol), t-BuOLi
OH
OH
OH
o
(0.12 mmol) in DMF, 0 C to rt, 10 min, then L5 (0.05 mmol), 1a
Me
Me
Me
(0.1 mmol), allylchloride (0.1 mmol), rt, 30 min; 2nd Si-migration:
2-methyl allylchloride (0.25 mmol), F-source. bt-BuOLi used in the
second cross-coupling. cIsolated yields.
Me
( 51%)
3e
(R = Cl, 64%)
(R = Me, 51%)
R
3f
3g
3h
(79%)
thylsilyl group even at 60 oC (Table 2, entries 1-3). We were
delighted to find that TABF functioned effectively for com-
pletely selective O-desilylation. However, the resulting
alkoxide intermediate only underwent the second silyl mi-
gration partially. The desired unsymmetrical two-fold dial-
lylated benzyl alcohol 3a was obtained in a moderate yield
of 41% through the second cross-coupling with 2-methyl al-
lylchloride followed by in situ O-desilylation (entry 4). To
solve this problem, another 2.0 equiv. of t-BuOLi were
added to complete the second silyl migration. The yield of
3a was improved to 74% yield (entry 5).
= Cl]
= Cl]
1, X2
1, X2
[X
[X
[X
= Cl]
1, X2
OH
OH
OH
Me
Me
Me
OBn
NBn
Boc
SBn
(68%)
(82%)
3i
3j
1, X2
3k
(62%)
= Cl]
= Cl]
= Cl]
1, X2
1, X2
[X
[X
[X
OH
OH
OH
Me
The scope of Csp3/Csp3-electrophiles E1-X1/E2-X2 were
tested and the results were shown in Table 3. The 2-methyl
allylic electrophile was fixed as E1 firstly, in which Cl, Br and
OTs were all compatible leaving groups. The reaction
worked well with various E2-X2, which were either (E)-3-
mono-substituted or 3,3′-disubstituted allylchlorides, lead-
ing to 3b-d via addition at the more accessible 1-position.
Substituents at the 2-position in E2-X2 varied from aryl
groups (3e-h) to methylene groups substituted with O, S, or
N (3i-k). The reaction of 1a with allyl dichloride afforded 3l
in 52% yield. The allylchloride moiety in 3l, which is steri-
cally more hindered than allyl dichloride, did not act as a
competitive electrophile to interfere with the second cross-
coupling. Similar to E2-X2, 2- or 3-mono-substituted or 3,3′-
disubstituted allylchlorides were also suitable for the first
cross-coupling, giving 3m-o in good yields. The approach
currently appears only working for allylic electrophiles, as
Cl
Ph
(52%)
(58%)
(57%)
3l
3m
1, X2
3n
1, X2
= Cl]
= Cl]
= Cl]
1, X2
[X
[X
[X
Me
OH
Me
unsuitable electrophiles
Me
Br
Cl
MeI
(56%)
Ph
3o
1, X2
= Cl]
[X
aReaction conditions: 1st Si-migration: Cu(I) (0.05 mmol), t-BuOLi
o
(0.12 mmol) in DMF, 0 C to rt, 10 min, then L5 (0.05 mmol), 1a
(0.1 mmol), E1-X1 (0.1 mmol), rt, 30 min; 2nd Si-migration: E2-X2
(0.25 mmol), TBAF (0.15 mmol), t-BuOLi (0.2 mmol), rt, 1 h. bI-
solated yields.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 15
migration, but they appeared to interfere with the step of
Sequential cross-coupling of 1b with Csp3/Csp3-electro-
philes E1-X1 and E2-X2 The 2,4,6-tri(trimethylsilyl) benzyl
alcohol 1b also served as a good substrate for one-pot cross-
coupling with Csp3/Csp3-electrophiles to give 3ab-3ad. Re-
action with Csp2/Csp3-electrophiles afforded 3ae and 3af in
higher yields than those obtained from disilylated 1a (Table
6). Again, TBAF desilylated the O-Si in 2 selectively, without
affecting the two other C-Si bonds. Once the alkoxide was
exposed, only the C-Si bond at the 6-position was cleaved by
the second silyl migration. Thus, the C-Si bond at the 4-po-
sition remained in 3 and enabled further functionalization
as shown in Scheme 3.
1
2
3
4
5
6
7
8
cross-coupling, only providing a complex mixture contain-
ing a trace amount of 2b (Table 4, entries 1 and 2). To our
surprise, we found that non-polar toluene, which barely ef-
fects C to O silyl migration, functioned efficiently for both
silyl migration and cross-coupling, giving 2b in 43% yield
after selective O-desilylation by acidic hydrolysis (entry 3).
We speculated that eliminating the steric repulsion be-
tween the alkoxide moiety and two silyl groups might drive
silyl migration in non-polar toluene. Increasing the loading
of t-BuOLi from 1.2 equiv. to 2.2 equiv. further favored com-
plete silyl migration to improve the yield of 2b to 85% (en-
try 4). Other solvents such as THF, Et2O or CH2Cl2 were less
effective, leading to much lower yields (entries 5-7). o-Phe-
nanthroline L5, which facilitated the cross-coupling of 1a
with Csp3-electrophiles, did not favor the cross-coupling
with Csp2-electrophile, instead, interfered with the reaction
to give a complex mixture (entry 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
Reaction of 3ae with 2.5 equiv. of NBS led to cyclization
together with bromination of arylsilane into arylbromide,
giving the isochroman18 derivative 8 in 82% yield. The ar-
ylbromide moiety was chemoselectively transformed into
9a by Suzuki cross-coupling with furylboronate, into 9b by
Kumada cross-coupling with aryl magnesium bromide and
into 9c by Sonogashira cross-coupling with terminal alkyne.
In this way, three C-Si bonds at 2-, 4- and 6-positions in 1b
were functionalized in a controlled, chemoselective man-
ner.
TABLE 4. Screening of Reaction Conditions of Cross-
coupling with Csp2-electrophile E1-X1a
CuI (0.5 equiv.), t-BuOLi
OH
SiMe3
OH
SiMe3
0 oC to rt
Me
3Si
TABLE 5. Scope of Csp2/Csp3-electrophiles E1-X1 and E2-
X2a
Me
Me
then
(1.2 equiv.)
Br
(5 mol %), solvent, rt, 0.5 h
1a
2b
Pd(PPh3 4
)
HO
OH
E2
CuI, t-BuOLi, Pd(PPh3
1-X1
)
4
then 1N HCl
, toluene, 0 oC to rt, 0.5 h
2-X2
E
E1
Me3Si
SiMe3
L5, E
then
2b (%)b
, TBAF, t-BuOLi
Entry
t-BuOLi (equiv.) solvent
Ligand
DMF/HMPA, rt,1 h
1a
OH
3b
1
2
3
4
5
6
7
8
1.2
1.2
1.2
2.2
2.2
2.2
2.2
2.2
DMF
—
—
—
—
—
—
—
L5
N.D.
N.D.
43%
85%
71%
34%
31%
N.D.
THF/HMPA
toluene
toluene
THF
Et2O
CH2Cl2
toluene
OH
OH
Ph
Me
Me
Me
(59%)
(45%)
(51%)
3p
= Br, X2 = Cl]
3q
3r
= Br, X2 = Cl]
= I, X2 = Cl]
[X1
[X1
Me
[X1
OH
OH
OH
REDG
REWG
aReaction conditions: Cu(I) (0.05 mmol), t-BuOLi, 0 oC to rt, 10 min;
then Pd(PPh3)4 (5 mol %), 1a (0.1 mmol), 1-methyl vinylbromide
(0.12 mmol), rt, 30 min. bIsolated yields.
Me
Me
(R = Me, 60%)
(54%)
3s
3v
= I, X2 = Cl]
3w
3x
[X1
, 40%)
(R = CF3
(R = NO
(R = t-Bu, 55%)
(R = OMe, 56%)
= I, X2 = Cl]
[X1
3t
2, 46%)
= I, X2 = Cl]
The solvent also has a great impact on the second cross-
coupling with Csp3-electrophile 2-methyl allylchloride in
the same pot. Toluene or a co-solvent of toluene/DMF only
afforded a complex mixture. Thus, toluene was removed un-
der reduced pressure followed by adding DMF/HMPA (3:1)
as the co-solvent for the second cross-coupling.16 TABF,
which is required to turn on the second silyl migration, was
added slowly to minimize formation of the O-allylated by-
product. A range of vinyl bromides and aryl iodides were
tolerated to give styrene derivatives 3p and 3q17 and biaryl
compounds 3r-w in generally good yields (Table 5). The
electronic nature of the substituents on the phenyl ring in
E1-X1 showed little impact on the efficiency. But, 2-methyl
iodobenzene, which is sterically demanding, cannot be in-
stalled in the first cross-coupling to give 3z. In addition, we
have been unable to expand the process to Csp2/Csp2-elec-
trophiles to form 3aa: only protodesilylation occurred at
the 6- position under all the conditions we tried. We suspect
that steric hindrance during cross-coupling with the second
Csp2-electrophile inhibits the desired reaction.
3u
[X1
OMe
Me
Me
MeO
MeO
OH
OH
OH
Me
Me
(40%)
(N.D.)
(N.D.)
3y
= I, X2 = Cl]
3z
= I, X2 = Cl]
3aa
= I, X2 = Cl]
[X1
[X1
[X1
aReaction conditions: 1st Si-migration: Cu(I) (0.05 mmol), t-BuOLi
(0.22 mmol) in toluene, 0 oC to rt, 10 min, then Pd(PPh3)4 (5 mol %),
1a (0.1 mmol), E1-X1 (0.12 mmol), rt, 30 min; 2nd Si-migration: E2-
X2 (0.25 mmol), t-BuOLi (0.22 mmol), TBAF (0.2 mmol), L5 (0.05
mmol) in DMF/HMPA (3:1), rt, 1 h. bIsolated yields.
TABLE 6. Reaction of 1b with Csp3/Csp3- and Csp2/Csp3-
electrophiles E1-X1 and E2-X2a
ACS Paragon Plus Environment

Page 5 of 15
The Journal of Organic Chemistry
HO
OH
Sequential five-component cross-coupling The three-
Si-mig.
(
E
1st
1-X1
)
E1
E2
Me3Si
SiMe3
1
2
3
4
5
6
7
8
9
component reaction was not limited to cross-coupling of 1a
with two electrophiles: we were also able to connect allyl
dichloride with 2.0 equiv. of 1a (Scheme 4a). The first two-
fold silyl migration generated 10 in 50% yield. The second
two-fold silyl migration of 10 initiated cross-coupling with
2.0 equiv. of allyl monochloride, giving 11 in 43% yield. Fol-
lowing the similar operation, using the first electrophile in
which two allylchlorides were tethered by a phenyl ring af-
forded 12 and 13 with high density of aryl and allyl moie-
ties. In this way, we were able to use this two-step sequence
to rapidly assemble five components into complex symmet-
ric structures.19
2-X2
E
then
Si-mig.
2nd
(
)
SiMe3
1b
SiMe3
3b
HO
OH
OH
Me
Me
Me
Me
Me
Ph
SiMe3
SiMe3
(51%)
SiMe3
(66%)
(79%, 73%c
3ab
3ac
1, X2
3ad
1, X2
[X
)
= Cl]
1, X2
= Cl]
= Cl]
[X
[X
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
Me
MeO
OH
OH
Me
Me
CONCLUSION
SiMe3
(68%)
SiMe3
(62%)
In summary, we have developed a sequential [1,4]-Csp2
to O-silyl migration that enables two-fold unsymmetrical
2,6-bifunctionalization of arenes in one pot. The hydroxyl
group acts as an "on-off-on" switch to cleave successively
two C-Si bonds at the 2- and 6-positions, installing
Csp3/Csp3 or Csp2/Csp3 electrophiles in a well-controlled
manner. The approach allows chemoselective functionaliza-
tion of three C-Si bonds in 2,4,6-tri(trimethylsilyl) benzyl al-
cohol to give isochroman derivatives. A two-step five-com-
ponent cross-coupling was developed to construct complex
symmetric structures. More applications of this reaction in
organic synthesis are under development.
3ae
[X1
3af
[X1
= I, X2 = Cl]
= I, X2 = Cl]
a3ab-3ad were synthesized following the reaction conditions in
Table 2; 3ae and 3af were synthesized following the conditions in
Table 5. Isolated yields. The yield was obtained by on the scale
b
c
using 0.3 mmol of 1b.
Ar
NBS (2.5 equiv.)
O
3ae
O
CH3CN, rt, 3.0 h
Br
Br
82%
isochroman
Me
8
H4-4-Me)
(Ar = -C6
MeO
a
b
c
EXPERIMENTAL SECTION
Ph
H
O
B(OH)2
MgBr
Br
Commercial reagents were used without any purification.
All reactions were performed using common anhydrous, in-
ert atmosphere techniques. Reactions were monitored by
TLC which was performed on glass-backed silica plates and
visualized using UV, KMnO4 stains, H3PO4·12MoO3/EtOH
stains, H2SO4 (conc.)/ anisaldehyde/ EtOH stains. Column
chromatography was performed using silica gel (200-300
mesh) eluting with EtOAc/petroleum ether. 1H NMR spectra
were recorded at 400 MHz (Varian and Bruker) and 600
MHz (Agilent), 13C NMR spectra were recorded at 100 MHz
(Bruker) and 150 MHz (Agilent) using CDCl3 (except where
noted) with TMS as standard. Infrared spectra were ob-
tained using KCl plates on a VECTOR22. High-resolution
mass spectral analyses performed on Waters Q-TOF. CH2Cl2,
TMEDA, DMF, Et2NH and Et3N were distilled from CaH2. THF
and PhMe were distilled from sodium. The heat source of
reactions that require heating is oil bath. All spectral data
obtained for new compounds are reported here.
Ar
Ar
Ar
O
O
O
Br
Br
Me
Me
Me
O
Ph
MeO
9a
9b
9c
(93%)
(76%)
(10 mol %), Cs
(60%)
(1.1 equiv.), toluene/MeOH, 100 o
oC, 3 h; (c) Pd(PPh3
)4 (5 mol %), CuI (10
2CO3
C, 4 h; (b) Pd
(a) Pd(PPh3)4
2(dba)3
(4 mol %), IprHCl (10 mol %), 1,4-dioxane, 80
mol %), piperidine, 80 o
C, 5 h.
SCHEME 3. Dibromination of 3ae and its cross-coupling
reactions to form 9a-c.
1st
Si-mig.
2nd
Si-mig.
1a
(a)
Me
50%
Cl Cl
43%
Me Cl
Me
O
O
Me3Si
OH OH SiMe3
Me3Si
SiMe3
10
11
Preparation of allyl chloride: S1, S6, S7, S8 are known
compounds, and S2, S3, S4 and S5 are new compounds.
Other electrophiles used in this work are commercially
available. Please see Scheme S1 in supporting information
for chemical structures of S1-S8 see Scheme 1 in supporting
information)
Me
Me3Si
HO
HO
two-fold Si-mig.
two-fold Si-mig.
1st
2nd
(b)
1a
12
13
HO
58%
30%
Me Cl
HO
(3-Chloroprop-1-en-2-yl)benzene (S1). A solution of 2-
phenyl-1-propene (1.18 g, 10 mmol), NCS (1.6 g, 12 mmol),
Yb(OTf)3 (310 mg, 0.5 mmol) and TMSCl (54 mg, 0.5 mmol)
in CH2Cl2 (40 mL) and THF (10 mL) was stirred at room tem-
perature for 30 min. The reaction was quenched with sat. aq.
NaCl (20 mL) and extracted with CH2Cl2 (3 × 20 mL). The
Cl
Cl
Me3Si
Me
SCHEME 4. Five-component cross-coupling to construct
complex symmetric compounds 11 and 13.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 15
combined organic layers were then dried over Na2SO4, fil- (((2-(Chloromethyl)allyl)oxy)methyl)benzene (S6). To a
1
2
3
4
5
6
7
8
tered and concentrated under reduced pressure. The resi-
due was purified by silica gel flash column chromatography
(petroleum ether) to afford S1 (0.7 g, 46% yield) as a color-
less liquid. Please see Scheme S2 in supporting information
suspension of NaH (120 mg, 5.00 mmol) in THF (5.0 mL)
was added benzyl alcohol (0.572 mL, 5.50 mmol) at room
temperature. The reaction mixture was stirred for 1 h and
then slowly transferred to a solution of 3-chloro-2-(chloro-
methyl)prop-1-ene (656 mg, 5.25 mmol) in THF at 0 °C. The
reaction mixture was stirred for 12 h at room temperature,
then quenched with 1N HCl and extracted with EtOAc (3 ×10
mL). The combined organic layers were then dried over
Na2SO4, filtered and concentrated under reduced pressure.
The residue was purified by silica gel flash column chroma-
tography (gradient eluent: petroleum ether/EtOAc =
200:1→50:1) to afford S6 (0.46 g, 47% yield) as a colorless
liquid. Please see Scheme S4 in supporting information for
1
for the synthesis of S1. H NMR (400 MHz, CDCl3) δ 7.51 –
7.44 (m, 2H), 7.42 – 7.27 (m, 3H), 5.56 (s, 1H), 5.45 (s, 1H),
4.46 (s, 2H). The physical and spectral data were consistent
with those previously reported.20
1-(3-Chloroprop-1-en-2-yl)-4-methylbenzene (S2). Using
the same procedure as that used for S1: 1-(3-chloroprop-1-
en-2-yl)-4-methylbenzene (0.331g, 2.5 mmol), NCS (0.40 g,
3 mmol), Yb(OTf)3 (77.5 mg, 0.125 mmol), TMSCl (13.5 mg,
0.125 mmol) in CH2Cl2 (20 mL) and THF (5 mL) at room
temperature for 30 min afforded S2 (0.21 g, 50% yield) as a
colorless liquid. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.3
Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 5.52 (s, 1H), 5.43 – 5.35 (m,
1H), 4.45 (d, J = 0.9 Hz, 2H), 2.36 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 143.8, 138.1, 134.8, 129.2, 126.0, 115.9, 46.6,
21.1. IR (neat) cm-1 3050, 2961, 2866, 1566, 1513, 1213,
903, 822; HRMS (ESI-TOF), m/z: (M+Na)+ calcd for
C10H11ClNa 189.0441; found 189.0442.
1-Chloro-4-(3-chloroprop-1-en-2-yl)benzene (S3). Using
the same procedure as that used for S1: 1-chloro-4-(3-chlo-
roprop-1-en-2-yl)benzene (0.381g, 2.5 mmol), NCS (0.40 g,
3 mmol), Yb(OTf)3 (77.5 mg, 0.125 mmol), TMSCl (13.5 mg,
0.125 mmol) in CH2Cl2 (20 mL) and THF (5 mL) at room
temperature for 30 min afforded S3 (0.21 g, 45% yield) as a
colorless liquid. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.7
Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 5.55 (s, 1H), 5.47 (s, 1H),
4.44 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 142.9, 128.7,
128.5, 127.9, 127.5, 117.4, 46.4. IR (neat) cm-12926, 1625,
1595, 1492, 1451, 1397, 1100, 1012, 912, 832; HRMS (ESI-
TOF), m/z: (M+H)+ calcd for C9H9Cl2 187.0076; found
187.0078.
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
the synthesis of S6. H NMR (400 MHz, CDCl3) δ 7.39 – 7.28
(m, 5H), 5.33 (s, 1H), 5.28 (d, J = 1.3 Hz, 1H), 4.54 (s, 2H),
4.15 (d, J = 1.0 Hz, 2H), 4.13 (s, 2H). The physical and spec-
tral data were consistent with those previously reported.21
Benzyl(2-(chloromethyl)allyl)sulfane (S7). To a suspen-
sion of Cs2CO3 (1.295 g, 5.8 mmol) in DMF (15 mL) was
added 3-chloro-2-chloromethyl-1-propene (0.50 mL, 4.3
mmol) and benzyl mercaptan (0.55 mL 4.73 mmol). The
suspension was heated to 60 °C and stirred for 16 h. The re-
action was quenched with H2O (20 mL) and extracted with
EtOAc (3 × 20 mL). The combined organic layers were
washed with H2O (2 x 10 mL), dried with Na2SO4, filtered
and concentrated under reduced pressure. The residue was
purified by silica gel flash column chromatography (gradi-
ent eluent: petroleum ether/EtOAc = 200:1→100:1) to af-
ford S7 (0.584 g, 64% yield) as a colorless liquid. Please see
Scheme S5 in supporting information for the synthesis of
S7. 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.23 (m, 5H), 5.29 –
5.24 (d, J = 1.3 Hz, 1H), 5.07 (d, J = 1.3 Hz, 1H), 4.21 (d, J =
0.9 Hz, 2H), 3.62 (s, 2H), 3.20 (d, J = 1.1 Hz, 2H). The physical
and spectral data were consistent with those previously re-
ported.22
1-(3-Chloroprop-1-en-2-yl)-3-(prop-1-en-2-yl)benzene
(S4) AND 1,3-bis(3-chloroprop-1-en-2-yl)benzene (S5). A so-
lution of 1, 3-di(prop-1-en-2-yl)benzene (0.79 g, 5 mmol),
NCS (1.6 g, 12 mmol), Yb(OTf)3 (310 mg, 0.25 mmol), TMSCl
(54 mg, 0.25 mmol) was stirred in CH2Cl2 (40 mL) and THF
(10 mL) at room temperature for 3 h. The reaction was
quenched with sat. aq. NaCl (20 mL) and extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were then
dried over Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by silica gel flash column
chromatography (petroleum ether) to afford S4 (0.451 g,
47% yield) as a colorless liquid and S5 (0.227 g, 20% yield)
as a colorless liquid. Please see Scheme S3 in supporting in-
formation for the syntheses of S4 and S5. S4: 1H NMR (400
MHz, CDCl3) δ 7.57 (s, 1H), 7.50 – 7.30 (m, 3H), 5.59 (s, 1H),
5.49 (s, 1H), 5.40 (s, 1H), 5.13 (s, 1H), 4.50 (s, 2H), 2.19 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.1, 143.1, 141.6,
137.7, 128.4, 125.4, 125.2, 123.4, 116.8, 112.9, 46.6, 21.8. IR
(neat) cm-1 3087, 2931, 1803, 1628, 1596, 1574, 1447, 1375,
1259, 1050, 1003, 892, 801; HRMS (ESI-TOF) m/z: (M+H)+
tert-Butyl benzyl(2-(chloromethyl)allyl)carbamate (S8).
To a solution of tert-butyl benzylcarbamate (0.5 g, 2.41
mmol) and 3-chloro-2-(chloromethyl) prop-1-ene (0.335
mL, 2.89 mmol) in DMF (2.5 mL) was added NaH (0.145 g,
3.62 mmol). After stirring for 6 h, the reaction was quenched
with dropwise addition of water (10 mL), and extracted
with EtOAc (3 × 10 mL). The combined organic layers were
washed with H2O (2 × 5 mL), dried with Na2SO4, filtered and
concentrated under reduced pressure. The residue was pu-
rified by silica gel flash column chromatography (gradient
eluent: petroleum ether/EtOAc = 200:1→50:1) to afford S8
(0.403 g, 57% yield) as a colorless liquid. Please see Scheme
1
S6 in supporting information for the synthesis of S8. H
NMR (400 MHz, CDCl3) δ 7.36 – 7.19 (m, 5H), 5.28 (s, 1H),
5.04 (s, 1H), 4.42 (s, 2H), 4.01 (s, 2H), 3.91 (d, 2H), 1.48 (s,
9H). The physical and spectral data were consistent with
those previously reported.23
Preparation of 1a (Please see Scheme S7 in supporting in-
formation for the synthesis of 1a.) N,N-Diethyl-2-(trime-
thylsilyl)benzamide (S9). To a solution of TMEDA (0.5 mL,
3.3 mmol) and N, N-diethylbenzamide (0.53 g, 3 mmol) in
anhydrous THF (50 mL) was added s-BuLi (4.5 mL, 1.0 M in
pentane) dropwise at -78 °C under Ar atmosphere. TMSCl
(0.5 mL, 3.9 mmol) was added before the reaction was stir-
ring for 1 h at -78 °C. The resulted mixture was allowed to
1
calcd for C12H14Cl 193.0779; found 193.0779. S5: H NMR
(400 MHz, CDCl3) δ 7.59 (d, J = 1.8 Hz, 1H), 7.48 – 7.39 (m,
2H), 5.60 (s, 2H), 5.50 (s, 2H), 4.49 (s, 4H).13C{1H} NMR (150
MHz, CDCl3) δ 143.7, 138.0, 128.6, 126.0, 124.1, 117.2, 46.5.
IR (neat) cm-1 2924, 2852, 1834, 1626, 1449, 1259, 1050,
907, 801; HRMS (ESI-TOF) m/z: (M+Na)+ calcd for
C12H12Cl2Na 249.0208; found 249.0217.
ACS Paragon Plus Environment

Page 7 of 15
The Journal of Organic Chemistry
warm to room temperature with stirring for additional 4 h. Preparation of 1b (Please see Scheme S8 in supporting in-
1
2
3
4
5
6
7
8
The reaction was quenched with sat. aq. NH4Cl (15 mL) and
extracted with EtOAc (3 × 20 mL). The combined organic
layers were then dried over Na2SO4, filtered and concen-
trated under reduced pressure. The residue was prfied by
silica gel flash column chromatography (gradient eluent: pe-
troleum ether/EtOAc = 200:1→30:1) to afford S9 (0.6 g, 80%
yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.57 (t, J
= 3.6 Hz, 1H), 7.31 -7.26 (m, 2H), δ 7.17 (d, J = 3.6 Hz, 1H),
3.53 (q, J = 7.2 Hz, 2H), 3.15 (q, J = 7.2 Hz, 2H), 1.26 (q, J =
7.2 Hz, 3H), 1.06 (t, J = 7.2 Hz, 3H), 0.26 (s, 9 H). The physical
and spectral data were consistent with those previously re-
ported.24
N,N-Diethyl-2,6-bis(trimethylsilyl)benzamide (4a). Using
the same procedure as that used for S9 (0.75 g, 3 mmol), s-
BuLi (4.5 mL, 1.0 M in pentane), TMEDA (0.5 mL, 3.3 mmol)
and TMSCl (0.5 mL, 3.9 mmol) in THF (50 mL) at -78 °C to
room temperature for 4 h afforded 4a (0.89 g, 92% yield) as
a colorless viscous liquid. 1H NMR (400 MHz, CDCl3) δ 7.57
(d, J = 7.5 Hz, 2H), 7.38 – 7.24 (m, 1H), 3.57 (q, J = 7.2 Hz, 2H),
3.07 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H), 0.98 (t, J = 7.2
Hz, 3H), 0.25 (s, 18H) 13CNMR (150 MHz, CDCl3) δ 172.2,
147.6, 135.8, 135.5, 126.4, 43.2, 38.5, 13.2, 12.8, 0.4. The
physical and spectral data were consistent with those pre-
viously reported.12
formation for the synthesis of 1b.) N,N-Diethyl-4-(trime-
thylsilyl)benzamide (S10).To a solution of (4-bromo-
phenyl)trimethylsilane (2.06 g, 0.9 mmol) in THF (24 mL)
was added dropwise a solution of n-BuLi (3.6 mL, 2.5 M in
hexanes) at -78 °C under Ar atmosphere. The reaction was
stirred at -78 °C for 25 min before transferring via cannula
to a solution of diethylcarbamic chloride (3.64 g, 2.7 mmol)
in THF (24 mL) at -78 °C. After stirring for 2 h at -78 °C, the
mixture was allowed to warm to room temperature over-
night. The reaction was quenched with sat. aq. NaHCO3 (20
mL) and extracted with EtOAc (3 × 30 mL). The combined
organic layers were then dried over Na2SO4, filtered and
concentrated under reduced pressure. The residue was pu-
rified by silica gel flash column chromatography (gradient
eluent: petroleum ether/EtOAc = 200:1→50:1) to afford
S10 (2.16 g, 96% yield) as a white solid. 1H NMR (400 MHz,
CDCl3) δ 7.52 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 3.54
(s, 2H), 3.26 (s, 2H), 1.25 (s, 3H), 1.11 (s, 3H), 0.26 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3) δ 171.3, 141.7, 137.5, 133.3,
125.4, 43.2, 39.1, 14.2, 12.9, -1.2. IR (neat) cm-1 2956, 1628,
1545, 1499, 1423, 1286, 1116, 838, 836; HRMS (ESI-TOF)
m/z: (M+Na)+ calcd for C14H23NOSiNa 272.1441; found
272.1441; mp: 56.9-58.7 oC.
N,N-Diethyl-2,4-bis(trimethylsilyl)benzamide (S11): Using
the same procedure as that used for S9. S10 (0.75 g, 3
mmol), s-BuLi (4.5 mL, 1.0 M in pentane), TMEDA (0.5 mL,
3.3 mmol) and TMSCl (0.5 mL, 3.9 mmol) in THF (50 mL) at
-78 °C to room temperature for 4 h afforded S11 (0.59 g,
61% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.72
(s, 1H), 7.60 – 7.42 (m, 1H), 7.15 (d, J = 7.5 Hz, 1H), 3.56 (q,
J = 7.1 Hz, 2H), 3.19 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H),
1.10 (t, J = 7.1 Hz, 3H), 0.29 (s, 9H), 0.27 (s, 9H); 13C{1H} NMR
(100 MHz, CDCl3) δ 172.4, 143.2, 139.9, 139.8, 136.1, 133.4,
124.6, 43.4, 38.9, 13.8, 12.8, 0.1, -1.1. IR (neat) cm-1 2954,
2897, 1630, 1577, 1530, 1423, 1276, 1260, 1061, 943, 830;
HRMS (ESI-TOF) m/z: (M+Na)+ calcd for C17H31NOSi2Na
344.1836; found 344.1841; mp: 37.1-39.7 oC
N,N-Diethyl-2,4,6-tris(trimethylsilyl)benzamide (4b). Us-
ing the same procedure as that used for S9. S11 (0.97 g, 3
mmol), s-BuLi (4.5 mL, 1.0 M in pentane), TMEDA (0.5 mL,
3.3 mmol) and TMSCl (0.5 mL, 3.9 mmol) in THF (50 mL) at
-78 °C to room temperature for 4 h afforded 4b (0.8 g, 67%
yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J
= 1.3 Hz, 1H), 3.66 – 3.46 (m, 2H), 3.25 – 2.96 (m, 2H), 1.33
– 1.18 (m, 3H), 1.18 – 0.87 (m, 3H), 0.27 (s, 27H); 13C{1H}
NMR (100 MHz, CDCl3) δ 172.4, 148.2, 140.6, 137.7, 134.4,
43.4, 38.6, 13.3, 12.9, 0.6, -1.0; IR (neat) cm-1 2953, 2897,
1621, 1482, 1406, 1379, 1320, 1246, 1086, 942, 823, 764,
690; HRMS (ESI-TOF) m/z: (M+Na)+ calcd for
C20H39NOSi3Na: 416.2232, found 416.2229; mp: 100.1-
103.9 oC
2,4,6-Tris(trimethylsilyl)benzaldehyde (5b). Using the
same procedure as that used for 5a. 4b (0.96 g, 3.0 mmol),
EtOTf (1.07 g, 6.0 mmol) in CH2Cl2 (20 mL) at 45 °C for 4 h.
Then remove CH2Cl2, the mixture and LiAlH(OEt)3 (18 mL,
1.0 M in THF) in THF (10 mL) at room temperature over-
night afforded 5b (0.6 g, 62% yield) as a colorless liquid.1H
NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 7.91 (s, 2H), 0.38 (s,
18H), 0.31 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ 194.2,
146.2, 144.9, 142.4, 141.2, 0.9, -1.1; IR (neat) cm-1 2954,
2898, 2856, 1694, 1520, 1406, 1247, 854, 831; HRMS (ESI-
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
2,6-Bis(trimethylsilyl)benzaldehyde (5a).To a solution of
4a (0.96 g, 3.0 mmol) in CH2Cl2 (20 mL) was added EtOTf
(1.07 g, 6.0 mmol). The reaction was stirred at 45 °C for 4 h
before removing CH2Cl2 and adding THF (10 mL) as solvent.
The mixture was cooled to 0 °C and stirred for 20 min. To
the resulting mixture was added LiAlH(OEt)3 (18 mL, 1.0 M
in THF) dropwise at 0 °C. The reaction was stirred overnight
at room temperature before quenching with aq. NaOH (15
o
mL, 1.0 M) at 0 C. The mixture was filtered and the white
solid was washed with EtOAc (3 × 10 mL). The combined
organic layers were then dried over Na2SO4, filtered and co-
centrated under reduced pressure. The residue was purified
by silica gel flash column chromatography (petroleum
ether/EtOAc = 200:1) to afford 5a (0.55 g, 73% yield) as a
colorless liquid. 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H),
7.75 (d, J = 7.6 Hz, 2H), 7.52 (t, J = 7.2 Hz, 1H), 0.38 (s, 18H);
13C{1H} NMR (150 MHz, CDCl3) δ 193.8, 145.8, 144.1, 136.2,
131.4, 0.7. The physical and spectral data were consistent
with those previously reported.12
(2,6-Bis(trimethylsilyl)phenyl)methanol (1a).To a solu-
tion of 5a (1.2 g, 4.8 mmol) in MeOH (15 mL) was added
NaBH4 (0.363 g, 9.6 mmol). The reaction was stirred at
room temperature for 2 h before quenching with sat. aq.
NH4Cl (10 mL) and extracted with EtOAc (3 × 20 mL). The
combined organic layers were then dried over Na2SO4, fil-
tered and concentrated under reduced pressure. The resi-
due was purified by silica gel flash column chromatography
(gradient eluent: petroleum ether/EtOAc = 200:1→50:1) to
1
afford 1a (1.0 g, 83% yield) as a white solid. H NMR (400
MHz, CDCl3) δ 7.60 (d, J = 7.4 Hz, 2H), 7.29 (dd, J = 7.4 Hz,
1H), 4.83 (d, J = 5.7 Hz, 2H), 1.33 (t, J = 5.7 Hz, 1H), 0.38 (s,
18H). 13C{1H} NMR (100 MHz, CDCl3) δ 151.3, 140.1, 136.3,
126.7, 65.3, 1.0; IR (neat) cm-1 3337, 3043, 2952, 2899, 1557,
1245, 1021, 830; HRMS (ESI-TOF) m/z: (M+Na)+ calcd for
C13H24OSi2Na 275.1258, found 275.1263; mp: 74.1 -77.5 oC.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 15
TOF) m/z: (M+Na)+ calcd for C16H30OSi3Na 345.1497, found
345.1501.
1H), 4.64 (s, 2H), 4.48 (s, 1H), 3.56 (d, J = 6.0 Hz, 2H), 3.47
(s, 2H), 1.79 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3) δ 147.0,
139.4, 139.0, 138.3, 137.0, 129.2, 128.7, 128.1, 115.6, 111.6,
58.7, 41.6, 37.3, 22.9; IR (neat) cm-1 3318, 3074, 2915, 1641,
1589, 1442, 1276, 996, 892, 838; HRMS (ESI-TOF) m/z:
(M+Na)+ calcd for C14H18ONa 225.1250; found 225.1252.
(2-Cinnamyl-6-(2-methylallyl)phenyl)methanol (3b): Us-
ing the same procedure as that used for 3a afforded 3b (15
1
2
3
4
5
6
7
8
(2,4,6-Tris(trimethylsilyl)phenyl)methanol (1b). Using the
same procedure as that used for 1a. 5b (1.2 g, 3.7 mmol)
and NaBH4 (0.28 g, 7.4 mmol) in MeOH (15 mL) at room
temperature for 2 h afforded 1b (0.96 g, 80% yield) as a
1
white solid. H NMR (400 MHz, CDCl3) δ 7.76 (s, 2H), 4.81
(d, J = 5.6 Hz, 2H), 0.37 (s, 18H), 0.22 (s, 9H); 13C{1H} NMR
(150 MHz, CDCl3) δ 151.7, 141.2, 138.6, 137.8, 65.2, 1.0, -1.1.
IR (neat) cm-1 3393, 2953, 2897, 1528, 1398, 1375, 1309,
1246, 1004, 874, 827. HRMS (ESI-TOF) m/z: (M+Na)+ calcd
for C16H32OSi3Na 347.1653; found 347.1656; mp: 94.5-96.2
oC.
1
mg, 54% yield) as a colorless liquid. H NMR (400 MHz,
CDCl3) δ 7.41-7.01 (m, 7H), 7.09 (dd, J = 7.4, 1.6 Hz, 1H),
6.51- 6.27 (m, 2H), 4.85 (s, 1H), 4.70 (s, 2H), 4.50 (s, 1H),
3.71 (d, J = 5.6 Hz, 2H), 3.47 (s, 2H), 1.79 (s, 3H).13C{1H} NMR
(150 MHz, CDCl3) δ 147.1, 139.8, 139.0, 137.3, 137.0, 130.8,
129.8, 129.3, 128.7, 128.4, 128.2, 127.1, 126.0, 111.7, 58.8,
41.7, 36.4, 22.9. IR (neat) cm-1 3329, 2922, 1648, 1446,
1276, 1261,996, 891; HRMS (ESI-TOF) m/z: (M+Na)+ calcd
for C20H22ONa 301.1563; found 301.1572.
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
Preparation of Intermediate 2a. 3-Allyl-2-(((trimethylsi-
lyl)oxy)methyl)phenyl)trimethylsilane (2a): To a solution of
CuI (10 mg, 0.05 mmol) in DMF (3.0 mL) was added t-BuOLi
(0.12 mL, 1.0 M in THF) at 0 °C under argon atmosphere.
The reaction mixture was stirred at room temperature for
10 min. Then L5 (0.05 mmol), 1a (25.2 mg, 0.1 mmol) and
3-chloroprop-1-ene (7 mg, 0.11 mmol) was added succes-
sively and kept stirring at room temperature for 0.5 h. The
reaction was quenched with 2 mL of saturated NaCl solu-
tion, extracted with EtOAc (3 × 5 mL) and washed with H2O
(3 × 2 mL). The combined organic layers were then dried
over Na2SO4, filtered and concentrated under reduced pres-
sure. The residue was purified by silica gel flash column
chromatography (gradient eluent: petroleum ether/EtOAc
= 200:1→100:1) to afford 2a (27.3 mg, 93% yield) as a col-
orless liquid.1H NMR (400 MHz, CDCl3) δ 7.39 (t, J = 4.4 Hz,
1H), 7.31 – 7.21 (d, J = 4.4 Hz, 2H), 6.01 (m, 1H), 5.14 – 4.95
(m, 2H), 4.72 (s, 2H), 3.52 (dt, J = 6.4, 1.6 Hz, 2H), 0.34 (s,
9H), 0.21 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 142.9,
140.2, 139.6, 137.8, 133.0, 131.3, 127.6, 115.6, 61.9, 37.0,
1.0, 0.3; IR (neat) cm-1 3059, 2955, 1637, 1429, 1249, 1146,
836, 687, 635; HRMS (ESI-TOF) m/z: (M+Na)+ calcd for
C16H28OSi2Na 315.1578; found 315.1571. Because the by-
product 6 was unstable on the silica gel column, we were
(E)-(2-(Hex-2-en-1-yl)-6-(2-methylallyl)phenyl)methanol
(3c): Using the same procedure as that used for 3a afforded
1
3c (14 mg, 57% yield) as a colorless liquid. H NMR (400
MHz, CDCl3) δ 7.19 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 7.4 Hz, 1H),
7.05 (d, J = 7.5 Hz, 1H), 5.67 – 5.56 (m, 1H), 5.46 – 5.34 (m,
1H), 4.82 (s, 1H), 4.65 (d, J = 6.1 Hz, 2H), 4.46 (s, 1H), 3.48
(d, J = 6.2 Hz, 2H), 3.45 (s, 2H), 1.96 (m, 2H), 1.77 (s, 3H),
1.35 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 147.0, 140.5, 138.9, 137.0, 131.7, 129.8, 129.0,
128.5, 128.1, 111.8, 58.7, 41.6, 36.3, 34.6, 22.9, 22.5, 13.6. IR
(neat) cm-1 3321, 3070, 2958, 2924, 2856, 1649, 1586, 1444,
1375, 1260, 1174, 996, 970, 890; HRMS (ESI-TOF) m/z:
(M+Na)+ calcd for C17H24ONa 267.1719; found 267.1724.
(2-(2-Methylallyl)-6-(3-methylbut-2-en-1-yl)phenyl)meth-
anol (3d): Using the same procedure as that used for 3a af-
forded 3d (15 mg, 65% yield) as a colorless liquid. 1H NMR
(400 MHz, CDCl3) δ 7.19 (t, J = 6.8 Hz, 1H), 7.13 – 7.09 (m,
1H), 7.04 (dd, J = 7.4, 1.2 Hz, 1H), 5.26 (m, 1H), 4.84 (dd, J =
1.9, 1.3 Hz, 1H), 4.65 (s, 2H), 4.50 (d, J = 1.0 Hz, 1H), 3.49 (d,
J = 7.0 Hz, 2H), 3.46 (s, 2H), 1.79 (d, J = 1.1 Hz, 3H), 1.76 (d,
J = 1.2 Hz, 3H), 1.73 (d, J = 1.1 Hz, 3H). 13C{1H} NMR (150
MHz, CDCl3) δ 147.0 , 141.6 , 138.9 , 136.9, 132.4, 128.8,
128.2, 128.1, 123.8, 111.6, 58.8, 41.6, 32.0, 25.7, 22.9, 17.9.
IR (neat) cm-1 3312, 2967, 2919, 2854, 1649, 1587, 1444,
1375, 1276, 1261, 1100, 997, 890. HRMS (ESI-TOF) m/z:
(M+Na)+ calcd for C16H22ONa 253.1563; found 253.1573.
(2-(2-Methylallyl)-6-(2-phenylallyl)phenyl)methanol (3e):
Using the same procedure as that used for 3a afforded 3e
(14 mg, 51% yield) as a colorless liquid. 1H NMR (400 MHz,
CDCl3) δ 7.54 – 7.44 (m, 2H), 7.38 – 7.27 (m, 3H), 7.20 (t, J =
7.5 Hz, 1H), 7.10 (t, J = 7.3 Hz, 2H), 5.44 (s, 1H), 4.83 (s, 1H),
4.65 (s, 1H), 4.62 (d, J = 5.7 Hz, 2H), 4.46 (s, 1H), 3.95 (s, 2H),
3.47 (s, 2H), 1.78 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3)
δ148.3, 147.0, 141.1, 139.0, 138.9, 137.34, 129.4, 129.3,
128.3, 128.1, 127.6, 125.9, 114.0, 111.6, 59.0, 41.6, 38.4,
23.0. IR (neat) cm-1 3333, 3068, 3022, 2917, 2850, 1648,
1592, 1442, 1223, 1079, 994, 892, 838, 803 HRMS (ESI-TOF)
m/z: (M+Na)+ calcd for C20H22ONa 301.1563, found
301.1564.
1
not able to isolate and characterize 6. The mixed H NMR
spetra (Table 1, entry 5) was provided in Supporting Infor-
mation.
Synthesis of 3a – 3o. 2-Allyl-6-(2-methylallyl)phenyl)meth-
anol (3a): To a solution of CuI (10 mg, 0.05 mmol) in DMF
(0.8 mL) was added t-BuOLi (0.12 mL, 1.0 M in THF) at 0 °C
under Ar atmosphere. The reaction was stirred at room tem-
perature for 10 min. L5 (10.5 mg, 0.05 mmol), 1a (25.2 mg,
0.1 mmol) and 3-chloro-2-methylprop-1-ene (9.6 mg, 0.1
mmol) was added successively. The resulted mixture was
stirred at room temperature for 0.5 h. Then 3-chloroprop-1-
ene (19 mg, 0.25 mmol), TBAF (0.15 mL, 1.0 M in THF) and
t-BuOLi (0. 2 mL, 1.0 M in THF) was added successively. The
resulted mixture was stirred at room temperature for 1 h.
The reaction was quenched with sat. aq. NaCl (2 mL), ex-
tracted with EtOAc (3 × 5 mL) and washed with H2O (3 × 3
mL). The combined organic layers were then dried over
Na2SO4, filtered and concentrated under reduced pressure.
The residue was purified by silica gel flash column chroma-
tography (gradient eluent: petroleum ether/EtOAc =
200:1→30:1) to afford 3a (15 mg, 74% yield) as a colorless
(2-(2-(4-Chlorophenyl)allyl)-6-(2-methylallyl)phe-
nyl)methanol (3f): Using the same procedure as that used
for 3a afforded 3f (20 mg, 64% yield) as a colorless liquid.
1H NMR (400 MHz, CDCl3) δ 7.44 – 7.38 (m, 2H), 7.32 – 7.25
(m, 2H), 7.20 (t, J = 7.5 Hz, 1H), 7.10 (dt, J = 7.3, 3.1 Hz, 2H),
5.51 – 5.41 (m, 1H), 4.85 (t, J = 1.5 Hz, 1H), 4.72 (q, J = 1.5
1
liquid. H NMR (400 MHz, CDCl3) δ 7.21 (t, J = 7.5 Hz, 1H),
7.09 (m, 2H), 6.06 (ddt, J = 16.5, 10.2, 6.1 Hz, 1H), 5.07 (dd,
J = 10.1, 1.0 Hz, 1H), 4.97 (dd, J = 17.1, 1.4 Hz, 1H), 4.84 (s,
ACS Paragon Plus Environment

Page 9 of 15
The Journal of Organic Chemistry
Hz, 1H), 4.62 (d, J = 4.4 Hz, 2H), 4.46 (s, 1H), 3.94 (d, J = 1.9 tert-Butyl
benzyl(2-(2-(hydroxymethyl)-3-(2-methylal-
Hz, 2H), 3.48 (s, 2H), 1.80 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 146.7, 139.1, 138.7, 138.4, 136.9, 134.3, 133.1,
129.2, 128.8, 128.1, 127.8, 126.9, 114.3, 111.3, 58.6, 41.3,
38.0, 22.6. IR (neat) cm-1 3343, 3073, 2920, 2852, 1626,
1492, 1395, 1098, 1010, 895, 834; HRMS (ESI-TOF) m/z:
(M+Na)+ calcd for C20H21ClONa 335.1173, found 335.1180.
(2-(2-Methylallyl)-6-(2-(p-tolyl)allyl)phenyl)methanol
lyl)benzyl)allyl)carbamate (3k): Using the same procedure
as that used for 3a afforded 3k (27 mg, 62% yield) as a col-
orless liquid. 1H NMR (400 MHz, CDCl3) δ 7.29 (q, J = 8.8, 8.0
Hz, 3H), 7.18 (d, J = 8.1 Hz, 3H), 7.05 (m, 2H), 4.92 (m, 1H),
4.81 (s, 1H), 4.71 (m, 1H), 4.58 (s, 2H), 4.42 (m, 2H), 3.76 (s,
2H), 3.44 (m, 4H), 1.79 (s, 3H), 1.43 (s, 9H). 13C{1H} NMR
(100 MHz, CDCl3) δ 155.9, 146.5, 145.6, 144.9, 138.0, 137.6,
130.5, 129.4, 128.8, 128.4, 127.9, 127.4, 127.2, 113.4, 111.6,
80.2, 77.2, 58.6, 50.6, 41.4, 37.7, 28.3, 22.9. IR (neat) cm-1
3433, 3068, 2974, 2925, 1691, 1674, 1453, 1246, 1163,
1003, 889, 766; HRMS (ESI-TOF) m/z: (M+Na)+ calcd for
C27H35NO3Na 444.2509; found 444.2512.
(2-(2-(Chloromethyl)allyl)-6-(2-methylallyl)phenyl)meth-
anol (3l): Using the same procedure as that used for 3a af-
forded 3l (13 mg, 52% yield) as a colorless liquid. 1H NMR
(400 MHz, CDCl3) δ 7.21 (t, J = 7.5 Hz, 1H), 7.10 (t, J = 7.4 Hz,
2H), 5.20 (s, 1H), 4.82 (s, 1H), 4.72 (s, 1H), 4.61 (s, 2H), 4.45
(s, 1H), 4.04 (s, 2H), 3.65 (s, 2H), 3.46 (s, 2H), 1.77 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 145.9, 144.6, 138.3, 136.8,
136.5, 128.7, 128.3, 127.2, 115.2, 110.6, 57.5, 47.0, 40.6,
35.7, 21.9. IR (neat) cm-1 3346, 2923, 1648, 1443, 1276,
1261, 998, 893, 843; HRMS (ESI-TOF) m/z: (M+Na)+ calcd
for C15H19ClONa 273.1017; found 273.1025.
1
2
3
4
5
6
7
8
(3g): Using the same procedure as that used for 3a afforded
1
3g (15 mg, 51% yield) as a colorless liquid. H NMR (400
9
MHz, CDCl3) δ 7.43 – 7.36 (m, 2H), 7.25 – 7.06 (m, 5H), 5.43
(d, J = 1.6 Hz, 1H), 4.87 – 4.81 (m, 1H), 4.62 (m, 3H), 4.50 –
4.45 (m, 1H), 3.94 (d, J = 1.6 Hz, 2H), 3.48 (s, 2H), 2.35 (s,
3H), 1.79 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 148.2,
147.0, 139.1, 139.0, 138.2, 137.5, 137.4, 129.4, 129.4, 129.0,
128.1, 125.8, 113.3, 111.6, 59.0, 41.6, 38.4, 23.0, 21.1. IR
(neat) cm-13351, 3073, 2921, 2853, 1624, 1442, 1375, 1260,
1091, 995, 891; HRMS (ESI-TOF) m/z: (M+Na)+ calcd for
C21H24ONa 315.1719; found 315.1721.
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-(2-Methylallyl)-6-(2-(3-(prop-1-en-2-yl)phenyl)al-
lyl)phenyl)methanol (3h): Using the same procedure as that
used for 3a afforded 3h (25 mg, 79% yield) as a colorless
1
liquid. H NMR (400 MHz, CDCl3) δ 7.57 (t, J = 1.9 Hz, 1H),
7.43 – 7.38 (m, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.5 Hz,
1H), 7.15 (d, J = 7.9 Hz, 1H), 7.12 – 7.07 (m, 1H), 5.47 (s, 1H),
5.37 (s, 1H), 5.10 (t, J = 1.7 Hz, 1H), 4.85 (s, 1H), 4.70 (t, J =
1.6 Hz, 1H), 4.65 (d, J = 5.0 Hz, 2H), 4.48 (s, 1H), 3.98 (s, 2H),
3.49 (s, 2H), 2.16 (s, 3H), 1.80 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 148.2, 146.6, 143.0, 141.0, 140.8, 138.7,
138.6, 137.0, 129.1, 129.0, 127.8, 127.8, 124.7, 124.5, 122.9,
113.8, 112.3, 111.3, 58.7, 41.3, 38.3, 22.6, 21.5. IR (neat) cm-
1 3349, 3073, 2921, 1628, 1593, 1441, 1375, 1247, 996, 891,
840; HRMS (ESI-TOF) m/z: (M+Na)+ calcd for C23H26ONa
341.1876; found 341.1884.
(2-(2-((Benzyloxy)methyl)allyl)-6-(2-methylallyl)phe-
nyl)methanol (3i): Using the same procedure as that used
for 3a afforded 3i (22 mg, 68% yield) as a colorless liquid.
1H NMR (400 MHz, CDCl3) δ 7.37 – 7.27 (m, 5H), 7.19 (t, J =
7.5 Hz, 1H), 7.08 (td, J = 7.9, 1.5 Hz, 2H), 5.12 (q, J = 1.4 Hz,
1H), 4.82 (d, J = 1.9 Hz, 2H), 4.62 (d, J = 5.2 Hz, 2H), 4.46 (s,
3H), 3.95 (s, 2H), 3.58(s, 2H), 3.58(s, 2H),1.77 (s, 3H).13C{1H}
NMR (100 MHz, CDCl3) δ 146.6, 146.4, 139.2, 138.3, 137.9,
137.6, 129.3, 129.0, 128.4, 128.0, 127.8, 127.7, 114.3, 111.6,
72.8, 71.8, 58.6, 41.5, 36.8, 23.0. IR (neat) cm-1 3405, 3068,
3028, 2910, 2852, 1648, 1588, 1448, 1373, 1067, 997, 894;
HRMS (ESI-TOF) m/z: (M+Na)+ calcd for C22H26O2Na
345.1825; found 345.1831.
(2-(2-((Benzylthio)methyl)allyl)-6-(2-methylallyl)phe-
nyl)methanol (3j): Using the same procedure as that used
for 3a afforded 3j (28 mg, 82% yield) as a colorless liquid.
1H NMR (400 MHz, CDCl3) δ 7.30 (m, 5H), 7.22 – 7.16 (m,
1H), 7.08 (d, J = 7.6 Hz, 2H), 4.95 (d, J = 1.3 Hz, 1H), 4.83 (t, J
= 1.6 Hz, 1H), 4.66 (d, J = 1.6 Hz, 1H), 4.64 (m, 4H), 4.46 (d, J
= 2.2 Hz, 1H), 3.66 (s, 2H), 3.64 (d, J = 1.4 Hz, 2H), 3.47 (s,
2H), 3.06 (s, 2H), 1.78 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ 146.8, 145.5, 139.2, 138.4, 138.1, 137.6, 129.4, 129.3,
129.0, 128.5, 128.1, 127.0, 114.7, 111.7, 58.8, 41.5, 37.7,
37.2, 35.4, 23.0. IR (neat) cm-1 3390, 3068, 3026, 2909,
1644, 1590, 1447, 1226, 1174, 1071, 994, 892; HRMS (ESI-
TOF) m/z: (M+Na)+ calcd for C22H26OSNa 361.1597; found
361.1599.
(2-Allyl-6-(2-(p-tolyl)allyl)phenyl)methanol (3m): Using
the same procedure as that used for 3a afforded 3m (16 mg,
58% yield) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ
7.40 (d, J = 8.2 Hz, 2H), 7.25 – 7.18 (m, 1H), 7.14 (m, 4H),
6.14 – 5.99 (m, 1H), 5.49 – 5.39 (m, 1H), 5.08 (dd, J = 10.1,
1.7 Hz, 1H), 4.98 (dd, J = 17.1, 1.8 Hz, 1H), 4.67 (d, J = 4.1 Hz,
2H), 4.65 – 4.60 (m, 1H), 3.94 (s, 2H), 3.64 – 3.50 (m, 3H),
2.36 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3) δ 148.4, 139.4,
139.0, 138.4, 138.1, 137.5, 136.9, 129.3, 129.0, 128.8, 128.3,
125.7, 115.7, 113.3, 58.9, 38.5, 37.4, 37.4, 21.1. IR (neat) cm-
1
3339, 3076, 2854, 1636, 1598, 1513, 1464, 1405, 1276,
1176, 995, 905, 823, 750; HRMS (ESI-TOF) m/z: (M+Na)+
calcd for C20H22ONa 301.1563; found 301.1566.
(2-Allyl-6-cinnamylphenyl)methanol (3n): Using the same
procedure as that used for 3a afforded 3n (15 mg, 57%
yield) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 7.48
– 7.04 (m, 8H), 6.54 – 6.27 (m, 2H), 6.19 – 5.99 (m, 1H), 5.04
(m, 2H), 4.75 (s, 2H), 3.71 (d, J = 5.1 Hz, 2H), 3.56 (d, J = 6.0
Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 139.7, 139.4,
138.5, 137.3, 136.7, 130.8, 129.9, 128.7, 128.7, 128.5, 128.5,
127.2, 126.1, 115.7, 58.7, 37.5, 36.6. IR (neat) cm-1 3322,
2922, 1638, 1447, 1276, 913, 751; HRMS (ESI-TOF) m/z:
(M+Na)+ calcd for C19H20ONa 287.1406; found 287.1409.
(2-Allyl-6-(3-methylbut-2-en-1-yl)phenyl)methanol (3o):
Using the same procedure as that used for 3a afforded 3o
(12 mg, 56% yield) as a colorless liquid. 1H NMR (400 MHz,
CDCl3) δ 7.20 (t, J = 7.5 Hz, 1H), 7.09 (dd, J = 12.3, 7.5 Hz, 2H),
6.05 (ddt, J = 16.5, 10.2, 6.2 Hz, 1H), 5.26 (t, J = 6.9 Hz, 1H),
5.03 (ddd, J = 18.5, 13.6, 1.3 Hz, 2H), 3.54 (d, J = 6.1 Hz, 2H),
3.48 (d, J = 6.9 Hz, 2H), 1.76 (s, 3H), 1.73 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 141.6, 139.3, 138.5, 136.5, 132.5,
128.4, 128.2, 128.2, 123.9, 115.6, 58.7, 37.5, 32.2, 29.7, 25.7,
17.9; IR (neat) cm-1 3302, 2921, 1637, 1441, 1377, 996, 911;
HRMS (ESI-TOF) m/z: (M+Na)+ calcd for C15H20ONa
239.1406, found 239.1413.
Preparation of Intermediate 2b. (2-(Prop-1-en-2-yl)-6-
(trimethylsilyl)phenyl)methanol (2b): H NMR (400 MHz,
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 15
CDCl3) δ 7.48 (dd, J = 7.4, 1.5 Hz, 1H), 7.29 – 7.23 (m, 1H), MHz, CDCl3) δ 7.36 – 7.15 (m, 7H), 4.89 (s, 1H), 4.59 (s, 1H),
1
2
3
4
5
6
7
8
7.17 (dd, J = 7.6, 1.5 Hz, 1H), 5.26 (dd, J = 2.2, 1.5 Hz, 1H),
4.94 (dd, J = 2.2, 1.0 Hz, 1H), 4.78 – 4.68 (m, 2H), 2.12 (d, J =
0.5 Hz, 3H), 0.38 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3) δ
146.5, 144.7, 142.2, 140.6, 134.0, 129.6, 127.2, 115.4, 62.7,
26.0, 0.9; IR (neat) cm-1 3310, 3056, 2923, 1269, 1248, 1008,
852, 798, 617. HRMS (ESI-TOF) m/z: (M+Na)+ calcd for
C13H20OSiNa 243.1176, found 243.1178.
4.55 (d, J = 4.3 Hz, 2H), 3.56 (s, 2H), 2.41 (s, 3H), 1.83 (s, 3H),
1.70 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 146.9, 143.5,
139.2, 138.5, 136.7, 136.3, 129.9, 129.2, 128.8, 128.8, 127.7,
112.0, 59.8, 41.6, 22.9, 21.1. IR (neat) cm-1 3335, 2921, 1648,
1586, 1514, 1451, 1261, 1189, 999, 822, 818, 754; HRMS
(ESI-TOF) m/z: (M+Na)+ calcd for C18H20ONa 275.1406;
found 275.1412; mp: 63.9-65.3 oC.
(4'-(tert-Butyl)-3-(2-methylallyl)-[1,1'-biphenyl]-2-
Synthesis of 3p
–
3y. (2-(2-Methylallyl)-6-vi-
yl)methanol (3t): Using the same procedure as that used for
3p afforded 3t (16 mg, 55% yield) as a white solid. 1H NMR
(400 MHz, CDCl3) δ 7.43 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.1
Hz, 2H), 7.28 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 7.5 Hz, 2H), 4.88
(s, 1H), 4.58 (s, 1H), 4.55 (d, J = 5.6 Hz, 2H), 3.55 (s, 2H), 1.82
(s, 3H), 1.74 – 1.70 (t, J = 5.6 Hz, 1H), 1.36 (s, 9H). 13C{1H}
NMR (150 MHz, CDCl3) δ 149.8, 147.0, 143.4, 139.1, 138.4,
136.2, 129.9, 129.0, 128.9, 127.7, 125.0, 111.9, 59.8, 41.5,
34.5, 31.4, 23.0. IR (neat) cm-1 3357, 2960, 1726, 1649, 1585,
1461, 1363, 1270, 1194, 1001, 890, 839, 764, 750; HRMS
(ESI-TOF) m/z: (M+Na)+ calcd for C21H26ONa 317.1876;
found 317.1877; mp: 103.1-104.5 oC.
(4'-Methoxy-3-(2-methylallyl)-[1,1'-biphenyl]-2-yl)metha-
nol (3u): Using the same procedure as that used for 3p af-
forded 3u (15 mg, 56% yield) as a white solid. 1H NMR (400
MHz, CDCl3) δ 7.37 (d, J = 8.4 Hz, 2H), 7.31 – 7.26 (m, 1H),
7.18 (d, J = 7.5 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 4.88 (s, 1H),
4.58 (s, 1H), 4.54 (d, J = 4.6 Hz, 2H), 3.85 (s, 3H), 3.54 (s, 2H),
1.82 (s, 3H), 1.75 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ
158.8, 147.08, 143.2, 139.2, 136.3, 133.8, 130.5, 129.8,
128.9, 127.7, 113.5, 112.0, 59.8, 55.3, 41.6, 22.9. IR (neat)
cm-1 3355, 2924, 1609, 1513, 1461, 1245, 1179, 1035, 1001,
891, 835, 781; HRMS (ESI-TOF) m/z: (M+Na)+ calcd for
C18H20O2Na 291.1357; found 291.1356; mp: 49.6-51.9 oC.
(3-Allyl-4'-methyl-[1,1'-biphenyl]-2-yl)methanol (3v): Us-
ing the same procedure as that used for 3p afforded 3v (12
mg, 54% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ
7.36 – 7.13 (m, 7H), 6.10 (ddt, J = 16.5, 10.3, 6.2 Hz, 1H), 5.08
(m, 2H), 4.58 (d, J = 3.7 Hz, 2H), 3.63 (d, J = 6.1 Hz, 2H), 2.40
(s, 3H).13C{1H} NMR (100 MHz, CDCl3) δ 143.5, 139.6, 138.5,
138.4, 136.8, 135.8, 129.3, 129.2, 128.8, 128.7, 127.9,
115.94, 59.69, 37.44, 21.15; IR (neat) cm-1 3322, 2922,
1460, 999, 911, 824, 779, 754; HRMS (ESI-TOF) m/z:
(M+Na)+ calcd for C17H18ONa 261.1250; found 261.1251;
mp: 70.8-72.8 oC.
9
nylphenyl)methanol (3p): To a solution of CuI (10 mg, 0.05
mmol) in toluene (1.0 mL) was added t-BuOLi (0.1 mL, 2.2
M in THF) at 0 °C under Ar atmosphere. The reaction was
stirred at room temperature for 10 min. Pd(PPh3)4 (6 mg, 5
mol %), 1a (25.2 mg, 0.1 mmol) and bromoethene (0.12 mg,
1.0 M in THF) was added successively. The resulted mixture
was stirred at room temperature for 0.5 h. Toluene was re-
moved under reduced pressure before adding DMF (0.6
mL), HMPA (0.2 mL), 3-chloro-2-methylprop-1-ene (22.5
mg, 0.25 mmol) and t-BuOLi (0. 1 mL, 2.2 M in THF) succes-
sively. TBAF (0.2 mL, 1.0 M in THF) was then added slowly
over 10 min. The reaction was stirred at room temperature
for 1 h before quenching with sat. aq. NaCl (2 mL), extract-
ing with EtOAc (3 × 5 mL) and washing with H2O (3 × 3 mL).
The combined organic layers were then dried over Na2SO4,
filtered and concentrated under reduced pressure. The res-
idue was purified by silica gel flash column chromatography
(gradient eluent: petroleum ether/EtOAc = 200:1→25:1) to
afford 3p (11 mg, 59% yield) as a colorless viscous liquid.1H
NMR (400 MHz, CDCl3) δ 7.51 – 7.30 (m, 1H), 7.28 – 6.97 (m,
3H), 5.68 (d, J = 17.3 Hz, 1H), 5.36 (d, J = 10.9 Hz, 1H), 4.84
(s, 1H), 4.69 (s, 2H), 4.48 (s, 1H), 3.45 (s, 2H), 1.78 (s, 3H).
13C{1H} NMR (150 MHz, CDCl3) δ 146.9, 138.6, 138.5, 135.9,
134.8, 130.4, 128.2, 125.0, 116.9, 111.7, 58.7, 41.6, 22.9. IR
(neat) cm-1 3328, 3074, 2968, 2919, 1649, 1581, 1444,
1375, 1291, 1223, 1173, 997, 891, 762; HRMS (ESI-TOF)
m/z: (M+Na)+ calcd for C13H16ONa 211.1093; found
211.1098.
(E)-(2-(2-Methylallyl)-6-styrylphenyl)methanol (3q): Us-
ing the same procedure as that used for 3p afforded 3q (12
mg, 45% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ
7.59 – 7.47 (m, 3H), 7.35 (d, J = 7.6 Hz, 2H), 7.31 – 7.18 (m,
2H), 7.16 – 6.95 (m, 3H), 4.86 (s, 1H), 4.77 (s, 2H), 4.51 (d, J
= 2.2 Hz, 1H), 3.47 (s, 2H), 1.80 (s, 2H). 13C{1H} NMR (150
MHz, CDCl3) δ 147.0, 138.7, 138.3, 137.4, 136.2, 131.7,
130.3, 128.6, 128.3, 127.7, 126.7, 126.3, 125.1, 111.8, 58.9,
41.7, 22.9. IR (neat) cm-1 3356, 2924, 2853, 1649, 1446,
1265, 997, 764, 749 HRMS (ESI-TOF) m/z: (M+Na)+ calcd for
C19H20ONa 287.1406; found 287.1411; mp: 77.7-79.9 oC
(3-(2-Methylallyl)-[1,1'-biphenyl]-2-yl)methanol (3r): Us-
ing the same procedure as that used for 3p afforded 3r (12
mg, 51% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ
7.53 – 7.10 (m, 8H), 4.88 (s, 1H), 4.58 (s, 1H), 4.53 (d, J = 3.1
Hz, 2H), 3.55 (s, 2H), 1.82 (s, 3H), 1.71 (s, 1H). 13C{1H} NMR
(100 MHz, CDCl3) δ 146.9, 143.5, 141.5, 139.2, 136.2, 130.1,
129.4, 128.8, 128.0, 127.7, 127.0, 112.0, 59.7, 41.6, 22.9. IR
(neat) cm-13355, 2918, 1442, 1277, 1002, 877, 757; HRMS
(ESI-TOF) m/z: (M+Na)+ calcd for C17H18ONa 261.1250;
found 261.1252; mp: 80.4-82.0 oC
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
(3-(2-Methylallyl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-
yl)methanol (3w): Using the same procedure as that used
1
for 3p afforded 3w (12 mg, 40% yield) as a white solid. H
NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.0 Hz, 2H), 7.57 (d, J =
7.9 Hz, 2H), 7.33 (t, J = 7.5 Hz, 1H), 7.26 (d, J = 6.0 Hz, 1H),
7.18 (d, J = 7.4 Hz, 1H), 4.90 (s, 1H), 4.59 (s, 1H), 4.49 (s, 2H),
3.56 (s, 2H), 1.83 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ147.1, 145.1, 142.3, 139.5, 136.1, 130.8, 129.8, 129.5,
128.7, 128.0, 125.0 (q, J = 3.8 Hz), 124.3 (q, J = 270.2 Hz),
112.1, 59.6, 41.6, 22.9. IR (neat) cm-1 3335, 2919, 1618,
1403, 1325, 1275, 1166, 1125, 1066, 896, 848; HRMS (ESI-
TOF) m/z: (M+Na)+ calcd for C18H17F3ONa 329.1124; found
329.1131; mp: 89.9-92.1 oC.
(3-(2-Methylallyl)-4'-nitro-[1,1'-biphenyl]-2-yl)methanol
(3x): Using the same procedure as that used for 3p afforded
3x (13 mg, 46% yield) as a colorless viscous liquid. 1H NMR
(400 MHz, CDCl3) δ 8.28 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5
Hz, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 7.4 Hz, 1H), 7.19
(4'-Methyl-3-(2-methylallyl)-[1,1'-biphenyl]-2-yl)metha-
nol (3s): Using the same procedure as that used for 3p af-
forded 3s (15 mg, 60% yield) as a white solid. 1H NMR (400
ACS Paragon Plus Environment

Page 11 of 15
The Journal of Organic Chemistry
(d, J = 7.4 Hz, 1H), 4.90 (s, 1H), 4.59 (s, 1H), 4.48 (d, J = 4.1 (m, 4H), 7.25 (s, 1H), 7.23 (s, 1H), 4.88 (d, J = 1.8 Hz, 1H),
Hz, 2H), 3.53 (s, 2H), 1.83 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 148.2 , 147.1, 147.1, 141.5, 139.7, 135.9, 131.3,
130.4, 128.5, 128.2, 123.2, 112.2, 59.5, 41.6, 22.9; IR (neat)
cm-1 3374, 3074, 2917, 2850, 1648, 1597, 1515, 1460, 1445,
1345, 1187, 1002, 857, 755. HRMS (ESI-TOF) m/z: (M+Na)+
calcd for C17H17NO3Na 306.1101; found 306.1108.
(3',4',5'-Trimethoxy-3-(2-methylallyl)-[1,1'-biphenyl]-2-
yl)methanol (3y): Using the same procedure as that used for
3p afforded 3y (13 mg, 40% yield) as a colorless viscous liq-
uid. 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.16 (m, 3H), 6.68 (s,
2H), 4.89 (s, 1H), 4.61 (s, 1H), 4.56 (d, J = 4.1 Hz, 2H), 3.89
(s, 3H), 3.86 (s, 6H), 3.55 (s, 2H), 1.82 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 152.7, 147.0, 143.6, 139.3, 137.1, 136.9,
136.2, 130.1, 128.6, 127.8, 112.1, 106.8, 60.9, 59.8, 56.1,
41.7, 22.9. IR (neat) cm-1 3460, 2927, 1648, 1579, 1507,
1463, 1408, 1345, 1174, 893, 754, 667; HRMS (ESI-TOF,
m/z) calcd for C20H24O4 (M+Na)+: 351.1567; found
351.1575.
4.59 (s, 1H), 4.54 (d, J = 5.4 Hz, 2H), 3.56 (s, 2H), 2.41 (s, 3H),
1.83 (s, 3H), 0.26 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ
147.2, 142.6, 140.2, 138.7, 138.1, 136.8, 136.7, 135.1, 133.9,
129.3, 128.8, 111.9, 59.8, 41.7, 23.0, 21.1, -1.12. IR (neat)
cm-1 3334, 2954, 2924, 1648, 1521, 1444, 1248, 1117, 1000,
888, 857, 834, 753; HRMS (ESI-TOF) m/z: (M+Na)+ calcd for
C21H28OSNa 347.1802; found 347.1805.
(4'-Methoxy-3-(2-methylallyl)-5-(trimethylsilyl)-[1,1'-bi-
phenyl]-2-yl)methanol (3af): Using the same procedure as
that used for 3p afforded 3af (21 mg, 62% yield) as a yellow
liquid. 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.36 (m, 2H), 7.35
– 7.30 (m, 2H), 7.02 – 6.88 (m, 2H), 4.94 – 4.84 (m, 1H), 4.59
(s, 1H), 4.54 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.56 (s, 2H), 1.84
(s, 3H), 1.73 (t, J = 6.0 Hz, 1H), 0.27 (s, 9H).13C{1H} NMR (100
MHz, CDCl3) δ 158.8, 147.3, 142.3, 140.2, 138.1, 136.8,
135.0, 134.0, 133.9, 130.6, 113.5, 111.9, 59.9, 55.3, 41.7,
23.0, -1.1. IR (neat) cm-1 3356, 2924, 2852, 1609, 1453,
1376, 1246, 1287, 1037, 834, 754; HRMS (ESI-TOF) m/z:
(M+Na)+ calcd for C21H28O2SiNa 363.1751; found 363.1759.
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
Synthesis of 3ab – 3af. (2-allyl-6-(2-methylallyl)-4-(trime-
thylsilyl)phenyl)methanol (3ab): Using the same procedure
as that used for 3a afforded 3ab (22 mg, 79% yield) as a
colorless liquid. 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.15 (m,
2H), 6.06 (m, 1H), 5.02 (m, 2H), 4.82 (s, 1H), 4.63 (d, J = 5.9
Hz, 2H), 4.45 (s, 1H), 3.55 (d, J = 6.0 Hz, 2H), 3.46 (s, 2H),
1.79 (s,3H), 0.24 (s, 9H). 13C{1H} NMR (150 MHz, CDCl3) δ
147.4, 140.6, 138.7, 138.6, 138.1, 137.7, 134.5, 133.9, 115.7,
111.7, 59.0, 41.8, 37.6, 23.1, -0.9; IR (neat) cm-1 3393, 2953,
2897, 1528, 1398, 1375, 1309, 1246, 1004, 874, 827, 784;
HRMS (ESI-TOF) m/z: (M+Na)+ calcd for C17H26OSiNa
297.1645; found 297.1650.
Synthesis of 8 and 9a-9c. 6-Bromo-3-(bromomethyl)-3-me-
thyl-8-(p-tolyl)isochromane (8): To a solution of 3ae (120
mg, 0.37 mmol) in MeCN (3 mL) was added NBS (166 mg,
0.93 mmol). The mixture was stirred at room temperature
for 3 h before quenching with sat. aq. NH4Cl (2 mL) and ex-
tracting with EtOAc (3 × 5 mL). The combined organic lay-
ers were then dried over Na2SO4, filtered and concentrated
under reduced pressure. The residue was purified by silica
gel flash column chromatography (gradient eluent: petro-
leum ether/EtOAc = 200:1→100:1) to afford 8 (125 mg,
82% yield) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ
7.28 – 7.24 (m, 2H), 7.22 (d, J = 7.8 Hz, 2H), 7.12 (d, J = 7.8
Hz, 2H), 4.60 (s, 2H), 3.51 – 3.35 (m, 2H), 3.05 – 2.78 (m, 2H),
2.40 (s, 3H), 1.38 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
141.0, 137.6, 135.5, 134.7, 130.7, 130.6, 130.5, 129.1, 128.5,
120.3, 71.8, 62.3, 40.1, 36.7, 23.4, 21.2. IR (neat) cm-1 2922,
1578, 1513, 1374, 1290, 1196, 1064, 906, 818. HRMS (ESI-
TOF) m/z: (M+H)+ calcd for C18H19Br2O 408.9797; found
408.9797.
(2-Cinnamyl-6-(2-methylallyl)-4-(trimethylsilyl)phe-
nyl)methanol (3ac): Using the same procedure as that used
for 3a afforded 3ac (18 mg, 51% yield) as a colorless liquid.
1H NMR (600 MHz, CDCl3) δ 7.36 – 7.31 (m, 2H), 7.31 – 7.26
(m, 3H), 7.25 – 7.22 (m, 1H), 7.20 (d, J = 7.5 Hz, 1H), 6.46 –
6.34 (m, 2H), 4.85 (d, J = 1.9 Hz, 1H), 4.70 (s, 2H), 4.49 (s,
1H), 3.72 (d, J = 5.8 Hz, 2H), 3.48 (s, 2H), 1.81 (s, 3H), 0.26
(s, 9H).13C{1H} NMR (100 MHz, CDCl3) δ 147.3, 140.7, 138.8,
138.1, 137.7, 137.4, 134.5, 133.8, 130.6, 130.1, 128.5, 127.1,
126.1, 111.7, 58.9, 41.7, 36.8, 23.0, -1.1. IR (neat) cm-1 3335,
1954, 2923, 2852, 1649, 1446, 1382, 1247, 1205, 1108, 996,
967, 833, 751; HRMS (ESI-TOF) m/z: (M+Na)+ calcd for
C23H30OSiNa 373.1958; found 373.1964.
(2-(2-Methylallyl)-6-(3-methylbut-2-en-1-yl)-4-(trime-
thylsilyl)phenyl)methanol (3ad): Using the same procedure
as that used for 3a afforded 3ad (20 mg, 66% yield) as a
colorless liquid. 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 1.4
Hz, 1H), 7.18 (d, J = 1.4 Hz, 1H), 5.31 – 5.21 (m, 1H), 4.85 –
4.80 (m, 1H), 4.63 (s, 2H), 4.49 (d, J = 1.6 Hz, 1H), 3.47 (d, J
= 5.9 Hz, 4H), 1.79 (s, 3H), 1.77 (d, J = 1.3 Hz, 3H), 1.73 (d, J
= 1.4 Hz, 3H), 0.25 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ
147.1, 140.6, 140.4, 138.0, 137.5, 134.1, 133.4, 132.2, 124.2,
111.6, 58.9, 41.7, 32.3, 25.7, 23.0, 18.0, -1.1. IR (neat) cm-1
3319, 2956, 2921, 2825, 1649, 1443, 1380, 1247, 1130,
1103, 996, 908, 890, 832, 753; HRMS (ESI-TOF) m/z:
(M+Na)+ calcd for C19H30OSiNa 325.1958; found 325.1958.
(4'-Methyl-3-(2-methylallyl)-5-(trimethylsilyl)-[1,1'-bi-
phenyl]-2-yl)methanol (3ae): Using the same procedure as
that used for 3p afforded 3ae (22 mg, 68% yield) as a color-
less viscous liquid. 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.29
3-(Bromomethyl)-6-(furan-2-yl)-3-methyl-8-(p-tolyl)iso-
chromane (9a): To a solution of 8 (20.5 mg, 0.05 mmol), fu-
ran-2-ylboronic acid (9 mg, 0.075 mmol) in toluene (0.4
mL) and MeOH (0.1 mL) was added Pd(PPh3)4 (6 mg, 10
mol%) and CsCO3 (10 mg, 0.12 mmol) under Ar atmosphere
o
at room temperature. The reaction was refluxed at 100 C
for 4 h. The mixture was concentrated in vacuo. Purification
of the crude residue via silica gel flash column chromategra-
phy
(gradient
eluent:
petroleum
ether/EtOAc
=200:1→50:1) afforded 9a (15 mg, 76% yield) as a colorless
1
viscous liquid. H NMR (400 MHz, CDCl3) δ 7.51 – 7.37 (m,
3H), 7.25 – 7.15 (m, 4H), 6.63 (d, J = 3.4 Hz, 1H), 6.47 (dd, J
= 3.4, 1.8 Hz, 1H), 4.68 (s, 2H), 3.58 – 3.35 (m, 2H), 3.11 –
2.83 (m, 2H), 2.41 (s, 3H), 1.40 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 153.6, 142.1, 139.5, 137.2, 136.7, 132.9,
130.8, 129.4, 129.1, 128.6, 123.4, 123.1, 111.6, 105.0, 71.9,
62.5, 40.3, 37.1, 23.5, 21.2. IR (neat) cm-1 2953, 2897, 1621,
1482, 1406, 1379, 1320, 1246, 1086, 942, 823, 764, 690.
HRMS (ESI-TOF) m/z: (M+Na)+ calcd for C22H21BrO2Na
419.0617; found 419.0624.
3-(Bromomethyl)-6-(4-methoxyphenyl)-3-methyl-8-(p-
tolyl)isochromane (9b): To a solution of 8 (20.5 mg, 0.05
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 15
mmol), (4-methoxyphenyl)magnesium bromide (0.1 mL,
HRMS (ESI-TOF) m/z: (M+Na)+ calcd for C24H36O2Si2Na
435.2146; found 435.2150.
1
2
3
4
5
6
7
8
1.0 M in THF) in 1,4-dioxane (0.5 mL) was added Pd2(dba)3
(2 mg, 4 mol %) and IPrHCl (4 mg, 0.01 mmol) under Ar at-
((((2-Methylenepropane-1,3-diyl)bis(6-(2-methylallyl)-
2,1-phenylene))bis(methylene))bis(oxy))bis(trimethylsilane)
(11): To a solution of CuI (8 mg, 0.04 mmol) in DMF (0.8 mL)
was added t-BuOLi (0.1 mL, 1.0 M in THF) at 0 °C under Ar
atmosphere. The reaction was stirred at room temperature
for 10 min. L5 (9 mg, 0.04 mmol), 10 (17 mg, 0.04 mmol)
and 3-chloro-2-methylprop-1-ene (18 mg, 0.2 mmol) was
added successively. The resulted mixture was stirred at
room temperature for 2 h before quenching with sat. aq.
NaCl (2 mL), extracting with EtOAc (3 × 3 mL) and washing
with sat. aq. NaCl (3 × 2 mL). The combined organic layers
were then dried over Na2SO4, filtered and concentrated un-
der reduced pressure. The residue was purified by silica gel
flash column chromatography (gradient eluent: petroleum
ether/EtOAc = 200:1→80:1) to afford 11 (9 mg, 43% yield)
as a colorless viscous liquid. 1H NMR (400 MHz, CDCl3) δ
7.16 (t, J = 7.5 Hz, 2H), 7.07 – 7.00 (m, 4H), 4.80 (s, 2H), 4.55
(s, 2H), 4.50 (s, 4H), 4.46 (s,2H), 3.47 (s, 4H), 3.43 (s, 4H),
1.76 (d, J = 9.8 Hz, 6H), 0.12 (s, 18H).13C{1H} NMR (150 MHz,
CDCl3) δ 149.1, 145.6, 139.1, 138.8, 137.1, 129.0, 128.9,
127.9, 113.0, 111.7, 58.2, 41.3, 40.1, 23.0, -0.3; IR (neat) cm-
o
mosphere. The reaction was stirred at 80 C for 3 h before
quenching with sat. aq. NH4Cl (1 mL) and extracting with
EtOAc (3 × 3 mL). The combined organic layers were then
dried over Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by silica gel flash column
chromatography (gradient eluent: petroleum ether/EtOAc
= 200:1→80:1) to afford 9b (13 mg, 60% yield) as colorless
liquid. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.7 Hz, 2H),
7.22 (m, 6H), 6.96 (d, J = 8.7 Hz, 2H), 4.70 (s, 2H), 3.84 (s,
3H), 3.56 – 3.37 (m, 2H), 3.12 – 2.86 (m, 2H), 2.40 (s, 3H),
1.42 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.2, 139.5,
139.2, 137.1, 137.0, 133.1, 132.9, 130.1, 129.0, 128.7, 128.0,
126.3, 126.0, 114.2, 71.9, 62.5, 55.3, 40.3, 37.2, 23.6, 21.1. IR
(neat) cm-1 2924, 1607, 1516, 1374, 1275, 1259, 1177, 822,
764, 749. HRMS (ESI-TOF) m/z: (M+Na)+ calcd for
C25H25BrO2Na 459.0930; found 459.0934.
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
3-(Bromomethyl)-3-methyl-6-(phenylethynyl)-8-(p-
tolyl)isochromane (9c): To a solution of 8 (20.5 mg, 0.05
mmol), ethynylbenzene (11 μL, 0.1 mmol) in piperidine (0.5
mL) was added Pd(PPh3)4 (3 mg, 5 mol%) and CuI (1 mg,
10 mol%) under Ar atmosphere at room temperature. The
reaction was stirred at 80 oC for 5 h before quenching with
sat. aq. NH4Cl (1 mL) and extracting with EtOAc (3 × 3 mL).
The combined organic layers were then dried over Na2SO4,
filtered and concentrated under reduced pressure. The res-
idue was purified by silica gel flash column chromatography
(gradient eluent: petroleum ether/EtOAc = 200:1→100:1)
to afford 9c (20 mg, 93% yield) as colorless liquid. 1H NMR
(400 MHz, CDCl3) δ 7.56 – 7.48 (m, 2H), 7.33 (dd, J = 5.2, 2.0
Hz, 3H), 7.29 (s, 2H), 7.22 (d, J = 7.8 Hz, 2H), 7.15 (d, J = 8.1
Hz, 2H), 4.67 (s, 2H), 3.51 – 3.36 (m, 2H), 3.06 – 2.76 (m, 2H),
2.39 (s, 3H), 1.39 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
139.3, 137.3, 136.1, 132.8, 132.1, 131.6, 130.9, 130.8, 129.1,
128.6, 128.3, 128.3, 123.2, 121.6, 89.4, 89.0, 71.9, 62.5, 40.2,
36.8, 23.5, 21.2. IR (neat) cm-1 2921, 2850, 1602, 1571,
1275, 1111, 909, 820, 754. HRMS (ESI-TOF) m/z: (M+Na)+
calcd for C26H23BrONa 453.0824; found 453.0830.
1
2925, 1441, 1250, 1057, 875, 840, 751; HRMS (ESI-TOF)
m/z: (M+Na)+ calcd for C32H48O2Si2Na 543.3085; found
543.3088.
((1,3-Phenylenebis(prop-2-ene-2,1-diyl))bis(6-(trime-
thylsilyl)-2,1-phenylene))dimethanol (12): Using the same
procedure as that used for 10 afforded 12 (60 mg, 58%
1
yield) as a colorless viscous liquid. H NMR (400 MHz,
CDCl3) δ 7.57 (t, J = 1.8 Hz, 1H), 7.43 – 7.36 (m, 4H), 7.32 –
7.26 (m, 1H), 7.26 – 7.18 (m, 4H), 5.47 – 5.40 (m, 2H), 4.81
– 4.76 (m, 2H), 4.72 (d, J = 3.1 Hz, 4H), 3.98 (s, 4H), 0.34 (s,
18H). 13C{1H} NMR (100 MHz, CDCl3) δ 148.2, 143.7, 141.3,
140.5, 139.14, 133.3, 132.0, 128.5, 127.8, 125.6, 124.0,
114.7, 62.7, 38.3, 1.0. IR (neat) cm-1 3262, 3057, 2952, 1594,
1414, 1250, 1141, 1080, 1008, 838, 802, 762; HRMS (ESI-
TOF) m/z: (M+Na)+ calcd for C32H42O2Si2Na 537.2616; found
537.2619.
((1,3-Phenylenebis(prop-2-ene-2,1-diyl))bis(6-(2-methyl-
allyl)-2,1-phenylene))dimethanol (13): Using the same pro-
cedure as that used for 11 afforded 13 (7 mg, 30% yield) as
a colorless viscous liquid. 1H NMR (400 MHz, CDCl3) δ 7.56
(d, J = 1.9 Hz, 1H), 7.40 (dd, J = 7.5, 1.8 Hz, 2H), 7.29 (dd, J =
8.4, 7.0 Hz, 1H), 7.19 (t, J = 7.5 Hz, 2H), 7.09 (dd, J = 7.6, 1.5
Hz, 4H), 5.44 (d, J = 1.4 Hz, 2H), 4.82 (t, J = 1.7 Hz, 2H), 4.71
(d, J = 1.5 Hz, 2H), 4.61 (s, 4H), 4.46 (d, J = 2.2 Hz, 2H), 3.95
(s, 4H), 3.47 (s, 4H), 1.77 (s, 6H). 13C{1H} NMR (150 MHz,
CDCl3) δ 148.2, 147.0, 141.1, 139.0, 138.9, 137.2, 129.3,
129.2, 128.3, 128.1, 125.3, 123.8, 114.3, 111.6, 58.9, 41.6,
38.4, 22.9. IR (neat) cm-1 3348, 2922, 2853, 1662, 1593,
1450, 1376, 1175, 1088, 999, 892, 892, 765; HRMS (ESI-TOF)
m/z: (M+Na)+ calcd for C34H38O2Na 501.2764; found
501.2763.
Synthesis of 10-13. ((2-Methylenepropane-1,3-diyl)bis(6-
(trimethylsilyl)-2,1-phenylene))dimethanol (10): To a solu-
tion of CuI (40 mg, 0.2 mmol) in DMF (3.0 mL) was added t-
BuOLi (0.48 mL, 1.0 M in THF) at 0 °C under Ar atmosphere.
The reaction was stirred at room temperature for 10 min.
L5 (42 mg, 0.2 mmol), 1a (100.8 mg, 0.4 mmol) and 3-
chloro-2-methylprop-1-ene (25 mg, 0.2 mmol) was added
successively. The resulted mixture was stirred at room tem-
perature for 2 h before quenching with sat. aq. NaCl (3 mL),
extracting with EtOAc (3 × 10 mL) and washing with 1N HCl
(3 × 3 mL). The combined organic layers were then dried
over Na2SO4, filtered and concentrated under reduced pres-
sure. The residue was purified by silica gel flash column
chromatography (gradient eluent: petroleum ether/EtOAc
= 200:1→20:1) to afford 10 (41 mg, 50% yield) as a color-
less viscous liquid. 1H NMR (400 MHz, CDCl3) δ 7.43 (dd, J =
6.9, 1.7 Hz, 2H), 7.29 – 7.19 (m, 4H), 4.66 (s, 4H), 3.57 (s,
4H), 0.35 (s, 18H). 13C{1H} NMR (100 MHz, CDCl3) δ 150.9,
143.9, 140.8, 138.6, 133.4, 132.1, 127.7, 113.4, 62.5, 39.8,
0.9. IR (neat) cm-1 3339, 2953, 1411, 1250, 1005, 838, 761;
ASSOCIATED CONTENT
Reaction schemes for the syntheses of compounds S1-S8
and preparations of compounds 1a and 1b; 1 H and 13C NMR
spectra for all new compounds (PDF). This material is
available free of charge via the Internet at
http://pubs.acs.org.
ACS Paragon Plus Environment

Page 13 of 15
The Journal of Organic Chemistry
Iridium-Catalyzed Sequential Silylation and Borylation of Het-
eroarenes Based on Regioselective C-H Bond Activation. An-
gew. Chem. Int. Ed. 2018, 57, 5843-5847.
(4) Ros, A.; López-Rodríguez, R.; Estepa, B.; Álvarez, E.; Fer-
nández, R.; Lassaletta, J. M. Hydrazone as the Directing Group
for Ir-Catalyzed Arene Diborylations and Sequential Function-
alizations. J. Am. Chem. Soc. 2012, 134, 4573-4576.
(5) Bellan, A. B.; Knochel, P. Highly Regioselective Remote
Lithiation of Functionalized 1,3-bis-Silylated Arenes. Angew.
Chem. Int. Ed. 2019, 58, 1838-1841.
(6) For latest progress, see: (a) Liu, Z. J.; Lin, X. L.; Yang, N.; Su,
Z. S.; Hu, C. W.; Xiao, P. H.; He, Y. Y.; Song, Z. L. Unique Steric
Effect of Geminal Bis(silane) To Control the High Exo-selectiv-
ity in Intermolecular Diels-Alder Reaction. J. Am. Chem. Soc.
2016, 138, 1877-1883. (b) Chu, Z. W.; Wang, K.; Gao, L.; Song, Z.
L. Chiral crotyl geminal bis(silane): a useful reagent for asym-
metric Sakurai allylation by selective desilylation-enabled chi-
rality transfer. Chem. Commun. 2017, 53, 3078-3081. (c) Zhang,
Y. B.; Guo, Q. Y.; Sun, X. W.; Lu, J.; Cao, Y. J.; Pu, Q.; Chu, Z. W.; Gao,
L.; Song, Z. L. Total Synthesis of Bryostatin 8 Using an Orga-
nosilane-Based Strategy. Angew. Chem. Int. Ed. 2018, 57, 942-
946.
(7) For selected progresses, see: (a) Smith, III, A. B.; Adams, C.
M. Evolution of Dithiane-Based Strategies for the Construction
of Architecturally Complex Natural Products. Acc. Chem. Res.
2004, 37, 365-377. (b) Smith, III, A. B.; Wuest, W. M. Evolution
of multi-component anion relay chemistry (ARC): construction
of architecturally complex natural and unnatural products.
Chem. Commun. 2008, 45, 5883-5895. (c) Smith, III, A. B.; Kim,
W. -S.; Wuest, W. M. Ortho-TMS Benzaldehyde: An Effective
Linchpin for Type II Anion Relay Chemistry (ARC). Angew.
Chem. Int. Ed. 2008, 47, 7082-7086. (d) Smith, III, A. B.; Kim, W.
-S.; Tong, R. B. Uniting Anion Relay Chemistry with Pd-Medi-
ated Cross Coupling: Design, Synthesis and Evaluation of Bi-
functional Aryl and Vinyl Silane Linchpins. Org. Lett. 2010, 12,
588-591. (e) Smith, III, A. B.; Kim, W. S. Diversity-oriented syn-
thesis leads to an effective class of bifunctional linchpins unit-
ing anion relay chemistry (ARC) with benzyne reactivity. PNAS,
2011, 108, 6787-6792. (f) Sanchez, L.; Smith, III, A. B. Long-
Range Anion Relay Chemistry (LR-ARC): A Validated ARC Tac-
tic; Org. Lett. 2012, 14, 6314-6317. (g) Martinez-Solorio, D.;
Hoye, A. T.; Nguyen, M. H.; Smith, III, A. B. The Design, Synthesis
and Validation of Recoverable and Readily Reusable Siloxane
Transfer Agents for Pd-Catalyzed Cross-Coupling Reactions.
Org. Lett. 2013, 15, 2454-2457. (h) Nguyen, M. H.; Smith, III, A.
B. Copper-Catalyzed Electrophilic Amination of Organolithi-
ums Mediated by Recoverable Siloxane Transfer Agents. Org.
Lett. 2013, 15, 4872-4875. (i) Nguyen, M. H.; Imanishi, M.; Ku-
rogi, T.; Smith, III, A. B. Total Synthesis of (−)-Mandelalide A Ex-
ploiting Anion Relay Chemistry (ARC): Identification of a Type
II ARC/CuCN Cross-Coupling Protocol. J. Am. Chem. Soc. 2016,
138, 3675-3678. (j) Liu, Q.; Chen, Y.; Zhang, X.; Houk, K. N.; Liang,
Y.; Smith, III, A. B. Type II Anion Relay Chemistry: Conforma-
tional Constraints To Achieve Effective [1,5]-Vinyl Brook Rear-
rangements. J. Am. Chem. Soc. 2017, 139, 8710-8717.
AUTHOR INFORMATION
1
2
3
4
5
6
7
8
Corresponding Author
lugao@scu.edu.cn; zhenleisong@scu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful for financial support from the the National Nat-
ural Science Foundation of China (21622202).
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
REFERENCES
(1) For selected reviews, see: (a) Saito, S.; Yamamoto,Y. Re-
cent Advances in the Transition-Metal-Catalyzed Regioselec-
tive Approaches to Polysubstituted Benzene Derivatives. Chem.
Rev. 2000, 100, 2901-2915. (b) Astruc, D. Modern Arene Chem-
istry, Wiley-VCH, Weinheim, 2002. (c) van Otterlo, W. A. L.; de
Koning, C. B. Metathesis in the Synthesis of Aromatic Com-
pounds. Chem. Rev. 2009, 109, 3743-3782.
(2) (a) Dong, C. -G.; Hu, Q. -S. Preferential Oxidative Addition
in Palladium(0)-Catalyzed Suzuki Cross-Coupling Reactions of
Dihaloarenes with Arylboronic Acids. J. Am. Chem. Soc. 2005,
127, 10006-10007. (b) Engle, K. M.; Wang, D. -H.; Yu, J. -Q. Con-
structing Multiply Substituted Arenes Using Sequential Palla-
dium(II)-Catalyzed C-H Olefination. Angew. Chem. Int. Ed. 2010,
49, 6169-6173. (c) Zhao, X. D.; Yeung, C. S.; Dong, V. M. Palla-
dium-Catalyzed Ortho-Arylation of O-Phenylcarbamates with
Simple Arenes and Sodium Persulfate. J. Am. Chem. Soc. 2010,
132, 5837-5844. (d) Daniels, M. H.; Armand, J. R.; Tan, K. L. Se-
quential Regioselective C-H Functionalization of Thiophenes.
Org. Lett. 2016, 18, 3310-3313.
(3) (a) Gulevich, A. V.; Melkonyan, F. S.; Sarkar, D.; Gevorgyan,
V. Double-Fold C-H Oxygenation of Arenes Using PyrDipSi: a
General and Efficient Traceless/Modifiable Silicon-Tethered
Directing Group. J. Am. Chem. Soc. 2012, 134, 5528−5531. (b)
Sarkar, D.; Gulevich, A. V.; Melkonyan, F. S.; Gevorgyan, V. Syn-
thesis of Multisubstituted Arenes via PyrDipSi-Directed Un-
symmetrical Iterative C-H Functionalizations. ACS Catal. 2015,
5, 6792-6801. For two-fold unsymmetrical C-H bond 2,6-bi-
functionalization via separated two steps, see: (c) Yu, M.; Liang,
Z. J.; Wang, Y. Y.; Zhang, Y. H. Palladium(II)-Catalyzed Direct
Alkenylation and Arylation of Arenes: Removable 2-Pyridyl-
sulfinyl Group Assisted C-H Bond Activation. J. Org. Chem.
2011, 76, 4987-4994. (d) Sarkar, D.; Melkonyan, F. S.; Gulevich,
A. V.; Gevorgyan, V. Twofold Unsymmetrical C-H Functionaliza-
tion of PyrDipSi-Substituted Arenes: A General Method for the
Synthesis of Substituted meta-Halophenols. Angew. Chem. Int.
Ed. 2013, 52, 10800-10804. (e) Mboyi, C. D.; Testa, C.; Reeb, S.;
Genc, S.; Cattey, H.; Fleurat-Lessard, P.; Roger, J.; Hierso, J. -C.
Building Diversity in ortho-Substituted s-Aryltetrazines By
Tuning N-Directed Palladium C-H Halogenation: Unsymmet-
rical Polyhalogenated and Biphenyl s-Aryltetrazines. ACS Catal.
2017, 7, 8493-8501. For one-pot two-fold C-H bond non-2,6-
bifunctionalization, see: (f) Ghosh, K.; Rit, R. K.; Ramesh, E.; Sa-
hoo, A. K. Ruthenium-Catalyzed Hydroarylation and One-Pot
Twofold Unsymmetrical C-H Functionalization of Arenes. An-
gew. Chem. Int. Ed. 2016, 55, 7821-7825. (g) Li, G.; Zhu, B.; Ma,
X. X.; Jia, C. Q.; Lv, X. L.; Wang, J. J.; Zhao, F.; Lv, Y. H.; Yang, S. L.
Ruthenium-Catalyzed ortho/meta-Selective Dual C-H Bonds
Functionalizations of Arenes. Org. Lett. 2017, 19, 5166-5169.
(h) Korvorapun, K.; Kaplaneris, N.; Rogge, T.; Warratz, S.;
Stückl, A. C.; Ackermann, L. Sequential meta-/ortho-C-H Func-
tionalizations by One-Pot Ruthenium(II/III) Catalysis. ACS
Catal. 2018, 8, 886-892. (i) Murai, M.; Nishinaka, N.; Takai, K.
(8) For selected progresses, see: (a) Taguchi, H.; Ghoroku, K.;
Tadaki, M.; Tsubouchi, A.; Takeda, T. Copper(I) tert-Butoxide-
Promoted 1,4 Csp2-to-O Silyl Migration: Stereospecific Allyla-
tion of (Z)-γ-Trimethylsilyl Allylic Alcohols. Org. Lett. 2001, 3,
3811-3814. (b) Taguchi, H.; Ghoroku, K.; Tadaki, M.; Tsubouchi,
A.; Takeda, T. Copper(I) tert-Butoxide-Promoted 1,4 Csp2-to-O
Silyl Migration:ꢀ Generation of Vinyl Copper Equivalents and
Their Stereospecific Cross-Coupling with Allylic, Aryl, and Vi-
nylic Halides. J. Org. Chem. 2002, 67, 8450-8456. (c) Tsubouchi,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 15
A.; Enatsu, S.; Kanno, R.; Takeda, T. Complete Regio- and Stere-
Mochida, K.; Shimizu, M.; Hiyama, T. Palladium-Catalyzed Intra-
1
2
3
4
5
6
7
8
oselective Construction of Highly Substituted Silyl Enol Ethers
by Three-Component Coupling. Angew. Chem. Int. Ed. 2010, 49,
7089-7091. (d) Tsubouchi, A.; Muramatsu, D.; Takeda, T. Cop-
per(I)-Catalyzed Alkylation of Aryl- and Alkenylsilanes Acti-
vated by Intramolecular Coordination of an Alkoxide. Angew.
Chem. Int. Ed. 2013, 52, 12719-12722. (e) Takeda, T.; Amarume,
S.; Sekioka, I.; Tsubouchi, A. Diversity-Oriented Stereoselective
Synthesis of β,γ-Disubstituted tert-Homoallylic Alcohols. Org.
Lett. 2015, 17, 1150-1153.
(9) (a) Yan, L. J.; Sun, X. W.; Li, H. Z.; Song, Z. L.; Liu, Z. J. Gemi-
nal Bis(silyl) Enal: A Versatile Scaffold for Stereoselective Syn-
thesizing C3,O1-Disilylated Allylic Alcohols Based upon Anion
Relay Chemistry. Org. Lett. 2013, 15, 1104-1107. (b) Lin, X. L.;
Ye, X. C.; Sun, X. W.; Zhang, Y. B.; Gao, L.; Song, Z. L. [1,5]-Anion
Relay via Intramolecular Proton Transfer To Generate 3,3-
Bis(silyl) Allyloxy Lithium: A Useful Scaffold for Syn-Addition
to Aldehydes and Ketones. Org. Lett. 2014, 16, 1084-1087. (c)
Pu, Q.; Tang, X. X.; Gao, L.; Song, Z. L. Three-component reaction
to synthesize E-vinyl silyl anti-1,2-diols via sequential [1,4]-O-
to-O/[1,4]-C-to-O silyl migrations. Org. Chem. Front. 2018, 5,
2035-2039.
(10) (a) Moser, W. H.; Endsley, K. E.; Colyer, J. T. Stereoselec-
tive Bis-functionalizations of Arene Chromium Tricarbonyl
Complexes via Brook Rearrangements. Org. Lett. 2000, 2, 717-
719. (b) Devarie-Baez, N. O.; Shuhler, B. J.; Wang, H.; Xian, M.
Solvent-Controlled Csp2→O Silyl Migration:ꢀThe “One-Pot” Syn-
thesis of 2,3-Disubsituted Thiophenes. Org. Lett. 2007, 9, 4655-
4658. (c) Akai, S.; Ikawa, T.; Takayanagi, S.; Morikawa, Y.;
Mohri, S.; Tsubakiyama, M.; Egi, M.; Wada, Y.; Kita, Y. Synthesis
of Biaryl Compounds through Three-Component Assembly:
Ambidentate Effect of the tert-Butyldimethylsilyl Group for Re-
gioselective Diels-Alder and Hiyama Coupling Reactions. An-
gew. Chem. Int. Ed. 2008, 47, 7673-7676. (d) Huang, K.; Huang,
C.; Isobe, M. Multicomponent Strategy for the Synthesis of Pros-
taglandin E2 Methyl Ester under Anion Relay Chelation Control.
J. Org. Chem. 2016, 81, 1571-1584. (e) Huwyler, N.; Radkowski,
K.; Rummelt, S. M.; Fürstner, A. Two Enabling Strategies for the
Stereoselective Conversion of Internal Alkynes into Trisubsti-
tuted Alkenes. Chem. Eur. J. 2017, 23, 12412-12419. (f) Kwon,
Y.; Jeon, Y.; Sim, H.; Oh, I.; Shin, I.; Kim, W. 3-Hydroxy-2-(trial-
kylsilyl)phenyl Triflate: A Benzyne Precursor Triggered via 1,3-
C-sp2-to-O Silyl Migration. Org. Lett. 2017, 19, 6224-6227.
(11) For selected reviews on Brook rearrangement, see: (a)
Brook, A. G. Molecular rearrangements of organosilicon com-
pounds. Acc. Chem. Res. 1974, 7, 77-84. (b) Moser, W. H. The
Brook rearrangement in tandem bond formation strategies.
Tetrahedron 2001, 57, 2065-2084. (c) Schaumann, E.;
Kirschning, A. Domino Synthesis of Carbo- and Heterocycles In-
volving a 1,3 or 1,4 C→O Silyl Migration. Synlett 2007, 2, 177-
190.
molecular Coupling of 2-[(2-Pyrrolyl)silyl]aryl Triflates
through 1,2-Silicon Migration. J. Am. Chem. Soc. 2009, 131,
8350-8351. (c) Nakao, Y.; Takeda, M.; Matsumoto, T.; Hiyama,
T. Cross-Coupling Reactions through the Intramolecular Acti-
vation of Alkyl(triorgano)silanes. Angew. Chem. Int. Ed. 2010,
49, 4447-4450. (d) Komiyama, T.; Minami, Y.; Hiyama, T.
Aryl(triethyl)silanes for Biaryl and Teraryl Synthesis by Cop-
per(II)-Catalyzed Cross-Coupling Reaction. Angew. Chem. Int.
Ed. 2016, 55, 15787-15791. (e) Komiyama, T.; Minami, Y.; Fu-
ruya, Y.; Hiyama, T. Palladium/Copper Dual Catalysis for the
Cross-Coupling of Aryl(trialkyl)silanes with Aryl Bromides. An-
gew. Chem. Int. Ed. 2018, 57, 1987-1990.
(15) For selected examples, see: (a) Liu, T.; Myers, M. C.; Yu, J.
-Q. Copper-Catalyzed Bromination of C(sp3)-H Bonds Distal to
Functional Groups. Angew. Chem. Int. Ed. 2017, 56, 306-309. (b)
Zhang, W.; Wu, L. Q.; Chen, P. H.; Liu, G. S. Enantioselective Ary-
lation of Benzylic C−H Bonds by Copper-Catalyzed Radical Re-
lay. Angew. Chem. Int. Ed. 2019, 58, 6425-6429.
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
(16) Using DMF as solvent provided a slightly lower yield
than that using DMF/HMPA as co-solvent.
(17) We were unable to install the allyl group into the 6-po-
sition of 2b.
(18) For reviews, see: a) Larghi, E. L.; Kaufman, T. S. Synthesis
of Oxacycles Employing the Oxa-Pictet-Spengler Reaction: Re-
cent Developments and New Prospects. Eur. J. Org. Chem. 2011,
27, 5195-5231.
(19) For selected examples, see: (a) Giarrusso, M. A.; Higham,
L. T.; Kreher, U. P.; Mohan, R. S.; Rosamilia, A. E.; Scott, J. L.;
Strauss, C. R. Platform technology for dienone and phenol-for-
maldehyde architectures. Green Chem. 2008, 10, 842-852. (b)
Salmón, M.; Miranda, R.; Nicolás-Vázquez, I.; Vargas-Rodriguez,
Y. M.; Cruz-Borbolla, J.; Medrano, M. I.; Morales-Serna, J. A. Ef-
fects of Bentonite on p-Methoxybenzyl Acetate: A Theoretical
Model for Oligomerization via an Electrophilic-Substitution
Mechanism. Molecules 2011, 16, 1761-1775. (c) Sunitha, K.;
Bhuvaneswari, S.; Mathew, D.; Unnikrishnan, G.; Nair, C. P. R.
Comb Polymer Network of Polydimethylsiloxane with a Novo-
lac Stem: Synthesis via Click Coupling and Surface Morphology
Architecturing by Solvents. Macromolecules 2017, 50, 9656-
9665.
(20) Xu, B.; Tambar, U. K. Remote Allylation of Unactivated
C(sp3)–H Bonds Triggered by Photogenerated Amidyl Radicals.
ACS Catal. 2019, 9, 4627-4631.
(21) Aho, J. E.; Salomäki, E.; Rissanen, K.; Pihko, P. M. Syn-
thetic Studies Toward Pectenotoxin 2. Part I. Stereocontrolled
Access to the C10-C22 Fragment. Org. Lett. 2008, 10, 4179-4182.
(22) Grim, J. C.; Brown, T. E.; Aguado, B. A.; Chapnick, D. A.;
Viert, A. L.; Liu, X.; Anseth, K. S. A Reversible and Repeatable
Thiol−Ene Bioconjugation for Dynamic Patterning of Signaling
Proteins in Hydrogels. ACS Cent. Sci. 2018, 4, 909−916.
(23) Orcel, U.; Waser, J. Palladium-Catalyzed Vicinal Amino
Alcohols Synthesis from Allyl Amines by In Situ Tether For-
mation and Carboetherification. Angew. Chem. Int. Ed. 2015, 54,
5250 –5254.
(24) Mills, R. J.; Taylor, N. J.; Snieckus, Victor. Directed Ortho
Metalation of N, N-Diethylbenzamides. Silicon Protection of Or-
tho Sites and the o-Methyl Group. J. Org. Chem. 1989, 54, 4372-
4385.
(12) Xiao, P. H.; Tang, Z. X.; Wang, K.; Chen, H.; Guo, Q. Y.; Chu,
Y.; Gao, L.; Song, Z. L. Chemoselective Reduction of Sterically
Demanding N,N-Diisopropylamides to Aldehydes. J. Org. Chem.
2018, 83, 1687-1700.
(13) Mills,R. J.; Horvath, R. F.; Sibi,M. P.; Snieckus, V. Dilithi-
ated synthons of tertiary benzamides, phthalamides, and O,O′-
aryl dicarbamates. Tetrahedron Lett. 1985, 26, 1145–1148.
(14) (a) Nakao, Y.; Chen, J.; Tanaka, M.; Hiyama, T. A Silicon-
Based Approach to Oligoarenes by Iterative Cross-Coupling Re-
actions of Halogenated Organo[(2-hydroxymethyl)phenyl]di-
methylsilanes. J. Am. Chem. Soc. 2007, 129, 11694-11695. (b)
ACS Paragon Plus Environment

Page 15 of 15
1
2
3
4
5
6
7
The Journal of Organic Chemistry
One-Pot Two-fold Unsymmetrical C-Si bond 2,6-Bifunctionalization of
Arenes via Sequential [1,4]-Csp2 to O-Silyl Migration
switch
OH
OH
O
2 steps
ON/OFF/ON
E1
E2
Si
Si
8
9
one-pot sequential
to O-silyl
3 C-Si bonds
trifunctionalization
[1,4]-Csp2
migration
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
Si
Si
five-component: 4 C-Si bonds to 4 C-C bonds
OH
OH
OH OH
Me
Me
Me
Me
15
ACS Paragon Plus Environment