Copper(I)-catalyzed regio- and stereoselective intramolecular alkylboration of propargyl ethers and amines

Article abstract of DOI:10.1021/acs.joc.7b02071

The copper(I)-catalyzed regio- and stereoselective intramolecular alkylation of propargyl ethers and amines bearing an alkyl electrophilic moiety has been developed. The reaction showed high functional group tolerance and gave highly functionalized alkenylboronates bearing heterocyclic rings, which are versatile synthetic intermediates in organic chemistry. The borylation products can be transformed into multisubstituted alkenes through stereospecific transformations. Mechanistic studies showed that the chemo- and stereoselectivity of copper(I)-catalyzed borylation depends on the type of leaving group. Density functional theory calculations suggested that the regioselectivity of the borylcupration of the alkyne is controlled by the electronic effect of the oxygen atom of the propargyl ether in combination with the steric congestion between the boryl group and the substituent at the propargylic position.

Full text of DOI:10.1021/acs.joc.7b02071

Subscriber access provided by UNIV OF CAMBRIDGE
Article
Copper(I)-Catalyzed Regio- and Stereoselective
Intramolecular Alkylboration of Propargyl Ethers and Amines
Hiroaki Iwamoto, Yu Ozawa, Koji Kubota, and Hajime Ito
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02071 • Publication Date (Web): 19 Sep 2017
Downloaded from http://pubs.acs.org on September 20, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Copper(I)ꢀCatalyzed Regioꢀ and Stereoselective
Intramolecular Alkylboration of Propargyl Ethers and
Amines
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
Hiroaki Iwamoto, Yu Ozawa, Koji Kubota, Hajime Ito*
Division of Applied Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo,
Hokkaido 060ꢀ8628, Japan
KEYWORDS: Alkenylboronates, Heterocyclic compounds, Carboboration, Copper(I) catalyst, Diboron
ABSTRACT: The copper(I)ꢀcatalyzed regioꢀ and stereoselective intramolecular alkylation of propargyl
ethers and amines bearing an alkyl electrophilic moiety has been developed. The reaction showed high
functional group tolerance and gave highly functionalized alkenylboronates bearing heterocyclic rings,
which are versatile synthetic intermediates in organic chemistry. The borylation products can be
transformed into multiꢀsubstituted alkenes through stereospecific transformations. Mechanistic studies
showed that the chemoꢀ and stereoselectivity of copper(I)ꢀcatalyzed borylation depends on the type of
leaving group. Density functional theory calculations suggested that the regioselectivity of
borylcupration of the alkyne is controlled by the electronic effect of the oxygen atom of the propargyl
ether in combination with the steric congestion between the boryl group and the substituent at the
propargylic position.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 42
1
2
3
4
Introduction
5
6
7
8
Multiꢀsubstituted alkenes are important structures in various functional and natural organic
compounds.1 Alkenylboronates are versatile intermediates for the synthesis of multiꢀsubstituted
alkenes because they can be derivatized through stereospecific transformations.2,3 Considerable
research has therefore been devoted to the development of transitionꢀmetalꢀcatalyzed
stereoselective synthesis of alkenylboron compounds.4 Copper(I)ꢀcatalyzed carboboration of
alkynes with carbon electrophiles is a useful method for the synthesis of multiꢀsubstituted
alkenylboronates.5 In most cases, the carboboration regioselectivity depends on the nature of the
alkyne substituent. Aryl and silyl groups, and propargyl ethers are strong directing groups for the
regioselective carboboration of C≡C bonds to provide multiꢀsubstituted alkenylboronates.6
However, controlling the regioselectivity of the carboboration is often difficult when asymmetric
internal alkynes or aliphatic terminal alkynes are used as the substrates (Scheme 1a).7
Scheme 1. Copper(I)-Catalyzed Carboboration of Alkynes.
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
a) Intermolecular carboboration
E
B(pin)
CuI
B(pin)
L
cat. Cu(I) / L
(pin)B–B(pin)
carbon
electrophile
R1
R2
R1
R2
R1
R2
base
+
+
"E"
regioisomer
regioisomer
b) Intramolecular carboboration
L
E
B(pin)
Intramolecular
cyclization
CuI
E
cat. Cu(I) / L
(pin)B–B(pin)
B(pin)
E
R
R
R
base
+
regioisomer (non-productive pathway)
A few examples of copper(I)ꢀcatalyzed intramolecular carboborations of alkynes have been
reported. These reactions offer concise methods for the synthesis of cyclic compounds with
borylꢀsubstituted exoꢀmethylene structures. In the design of these reactions, it is necessary to
achieve high regioselectivity in the borylcupration step and to install an appropriate functional
ACS Paragon Plus Environment
2

Page 3 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
group that reacts selectively with the alkenylcopper(I) intermediate (Scheme 1b). In 2013, Lin
and coꢀworkers reported the intramolecular carboboration of propargyl ethers bearing an enone
moiety to afford alkenylboronates bearing a hydrobenzofuran framework (Scheme 2a).8 This
reaction is useful for the construction of fusedꢀring structures, but it requires the introduction of a
highly reactive enone moiety to trap the alkenylcopper(I) intermediate. They suggested that
coordination of the oxygen atom in the propargyl ether to copper(I) contributes to the
regioselectivity of the borylcupration step, but no detailed studies of the regioselectivity were
conducted. Recently, our group reported a stereoselective copper(I)ꢀcatalyzed borylative
cyclization of alkynylsilanes bearing an unactivated and simple alkyl bromide moiety to give
alkenylboronates containing a silolane structure, based on silylꢀgroupꢀdirected regiocontrol
(Scheme 2b).9 Furthermore, during the course of our study, the transitionꢀmetal catalyzed
borylative cyclization reactions of the enyne substrate have been reported.10 Although this
intramolecular carboboration strategy is a promising approach for synthesizing cyclic
compounds with multiꢀsubstituted alkenylboron moieties, a few examples described above have
been reported.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In this work, we developed a copper(I)ꢀcatalyzed stereoꢀ and regioselective intramolecular
carboboration of alkynes bearing an alkyl halide or alkyl mesylate moiety. This reaction was
applicable to substrates with propargyl ethers or amines (Scheme 2c). The reaction using a
monophosphine ligand afforded the corresponding multiꢀsubstituted alkenylboronates containing
a tetrahydrofuran or pyrrolidine framework. Density functional theory (DFT) calculations
suggested that both the electronic and steric effects of propargyl ethers contribute to the
regioselectivity of borylcupration of the propargyl ether.11
ACS Paragon Plus Environment
3

The Journal of Organic Chemistry
Page 4 of 42
1
2
3
4
Scheme 2. Copper(I)-Catalyzed Stereoselective Intramolecular Carboboration of Alkynes.
5
6
7
8
9
a) Intramolecular carboboration of propargyl ethers (2013, Lin and co-workers)
R1
B(pin)
L*
O
cat. Cu(I) / L*
(pin)B–B(pin)
(pin)B
R1
H
CuI
O
O
R1
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
base, MeOH
O
R2
O
O
R2
L* = phosphoramidate
R2
• electrophilic moiety: enone, • directing group: oxygen atom at propargylic position
b) Intramolecular carboboration of alkynyl silanes (2015, our group)
R
L
B(pin)
cat. Cu(I) / L
(pin)B–B(pin)
(pin)B
R
CuI
Br
Br
R
base
Ph
Si
Ph Si
Si
Ph
Ph
L = NHC ligand
Ph
Ph
• electrophilic moiety: alkyl halide, • directing group: silicon atom
c) This Work: Intramolecular Carboboration of Propargyl Ethers and Amines (2017)
R1
B(pin)
B(pin)
cat. Cu(I) / L
(pin)B–B(pin)
L
R1
R1
R2
(pin)B
X
CuI
or
X
R1
base
R3
Y
R3
R2
N
O
L = monophosphine
R2
Y
R3
R4
X = Br or OMs, Y = O or N
• electrophilic moiety: alkyl electrophile
• directing group: oxygen and nitrogen atom at propargylic position
Results and discussion
First, we investigated the reaction conditions for the intramolecular alkylboration of propargyl
ether 1a (Table 1). The reaction with an Nꢀheterocyclic carbene ligand (IMes·HCl) resulted in
moderate conversion of the starting material to give the desired product (E)ꢀ3a as a single isomer
(entry 1: 43%, E/Z = >95:5). The bisphosphine ligand Xantphos showed low reactivity, but dppp
showed moderate reactivity and gave the corresponding cyclization product in good yield with
excellent stereoselectivity (entry 2: 7% and entry 3: 57%, E/Z = >95:5). The reaction using the
monophosphine ligand PCy3 afforded the product in moderate yield (entry 4: 48%), whereas
PPh3 showed high reactivity and gave the product in good yield (entry 5: 75%). The use of
triarylphosphine ligands bearing an electronꢀdonating or ꢀwithdrawing substituent on the phenyl
ring did not improve the yield (entry 6: 71% and entry 7: 75%). The yield of (E)ꢀ3a improved
ACS Paragon Plus Environment
4

Page 5 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
slightly when (oꢀMeOꢀC6H4)3P was used (entry 8: 77%). The reaction with (oꢀtol)3P showed
high reactivity and gave the corresponding borylative cyclization product in high yield with high
stereoselectivity (entry 9: 88%, E/Z = >95:5). We then identified the optimum leaving group
from the substrate. The reactivity of the substrate bearing iodide 1b was higher reactivity than
that of the substrate with bromide 1a, but the yield was moderate (entry 10: 58%). In contrast,
the borylative cyclization of 1c gave the product in good yield (entry 11: 61%).
Table 1. Catalyst Optimization for Copper(I)-Catalyzed Intramolecular Alkylboration of
1.a
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
B(pin)
5 mol % CuCl
O
O
O
O
X
5 mol % Ligand
B B
+
Me
K(O-t-Bu) (1.2 equiv)
THF, 30 ˚C, 24 h
O
1
O
Me
2 (1.2 equiv)
(E)-3a
Entry
Ligand
Yield of 3a
E/Z c
X
(%)b
1
2
IMes•HCl
Xantphos
dppp
Br (1a)
Br (1a)
Br (1a)
Br (1a)
Br (1a)
Br (1a)
Br (1a)
Br (1a)
Br (1a)
I (1b)
43
7
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
3
57
4
PCy3
48
5
PPh3
75
6
(pꢀMeOꢀC6H4)3P
(pꢀFꢀC6H4)3P
(oꢀMeOꢀC6H4)3P
(oꢀtol)3P
71
7
75
8
77
9
10d
11e
88 (71)
58
(oꢀtol)3P
(oꢀtol)3P
OMs (1c)
61
aConditions: 1 (0.5 mmol), CuCl (0.025 mmol), ligand (0.025 mmol), 2 (0.6 mmol), base (0.6
b
1
mmol) in THF (1.0 mL). NMR yield was determined by H NMR analysis of crude material
c
1
using an internal standard. Isolated yield is shown in parentheses. Determined by H NMR
analysis of crude material. dReaction time was 3 h. eOMs: mesylate (OSO2Me).
ACS Paragon Plus Environment
5

The Journal of Organic Chemistry
Page 6 of 42
1
2
3
4
5
6
7
8
9
With the optimized conditions in hand, we conducted substrate screening (Table 2). The
reactions of alkylꢀ substituted terminal propargyl ethers gave the corresponding cyclization
products (E)ꢀ3a and (E)ꢀ3d in good yields [(E)ꢀ3a: 71%, (E)ꢀ3d: 67%]. Products bearing silyl
ether (E)ꢀ3e or benzyl ether (E)ꢀ3f were obtained in good yields [(E)ꢀ3e: 60%, (E)ꢀ3f: 75%]. The
substrate prepared from tertiary propargyl alcohol reacted under the borylative cyclization
reaction conditions to afford a product containing a spiroꢀcyclic moiety, (E)ꢀ3g, in moderate
yield (60%). The reaction of a benzylꢀprotected propargylamine substrate gave a product
containing a pyrrolidine moiety, (E)ꢀ3h, in moderate yield (49%). We then tested internal
propargyl ether and amine substrates. The reactions of internal propargyl ethers bearing a methyl
group or alkyl chain gave the corresponding products (Z)ꢀ3i and (Z)ꢀ3j in good yields with
excellent stereoselectivities [(Z)ꢀ3i: 74%, (Z)ꢀ3j: 72%]. The catalytic system gave excellent
chemoselectivity. The reaction of the internal propargyl ether containing an alkyl chloride
moiety gave the corresponding cyclization product (Z)ꢀ3k in good yield (64%).12 The propargyl
ether bearing a prenyl ether moiety was smoothly converted to the desired product (Z)ꢀ3l in high
yield (86%). A spiroꢀcyclic product consisting of piperidine and furan rings, (Z)ꢀ3m, was
obtained in excellent yield with perfect stereoselectivity (86%). The alkylꢀsubstituted internal
propargylamine participated in this borylative cyclization to give the desired tetrasubstituted
alkenylboronate bearing a pyrrolidine moiety (Z)ꢀ3n (78%).13
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
ACS Paragon Plus Environment
6

Page 7 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
Table 2. Substrate Scope of Intramolecular Alkylboration of Propargyl Ethers and
Amines.a
7
8
9
R1
B(pin)
5 mol % CuCl
R1
O
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5 mol % (o-tol)3P
Br
B
B
+
K(O-t-Bu) (1.2 equiv)
THF, 30 ˚C, 24 h
R2
Y
R2
Y
1
2 (1.2 equiv)
(E) or (Z)-3
B(pin)
B(pin)
B(pin)
B(pin)
Me
O
O
O
O
BnO
OTBDPS
Ph
(E)-3db
(E)-3fb
(E)-3a
(E)-3eb
E/Z = >95:5, 71% E/Z = >95:5, 67%
E/Z = >95:5, 60% E/Z = >95:5, 75%
B(pin)
B(pin)
B(pin)
B(pin)
Me
Me
O
N
O
O
Ph
Ph
Bn
(E)-3gb
(E)-3hb
E/Z = >95:5, 49%
(Z)-3i
E/Z = <5:95, 74%
(Z)-3j
E/Z = <5:95, 72%
E/Z = >95:5, 60%
B(pin)
B(pin)
B(pin)
B(pin)
O
Me
Cl
Me
N
O
O
O
N
Boc
Ts
Ph
(Z)-3l
E/Z = <5:95, 86%
Ph
(Z)-3k
(Z)-3mc
(Z)-3n
E/Z = <5:95, 64%
E/Z = <5:95, 86% E/Z = <5:95, 78%
aConditions: 1 (0.5 mmol), CuCl (0.025 mmol), ligand (0.025 mmol), 2 (0.6 mmol), base (0.6
mmol) in THF (1.0 mL) at 30 °C. Reaction temperature was 50 °C. PPh3 was used as a ligand
instead of (oꢀtol)3P.
b
c
To investigate the chemoselectivity of this intramolecular alkylboration, we performed the
reaction using a propargyl allyl ether substrate (E)ꢀ1o (Scheme 3). This catalytic system showed
perfect chemoselectivity and gave the alkenylboronate (Z,E)ꢀ3o as a single isomer; this is formed
in high yield and with perfect chemoꢀ and stereoꢀselectivity by reaction with the alkyne moiety,
rather than the alkene group. The alkylboronate, which is formed by reaction with the alkene
moiety, was not detected.14
ACS Paragon Plus Environment
7

The Journal of Organic Chemistry
Page 8 of 42
1
2
3
4
Scheme 3. Chemoselective Intramolecular Alkylboration of Propargyl Allyl Ether (E)-1o.
5
6
7
8
9
Me
B(pin)
B(pin)
5 mol % CuCl
5 mol % (o-tol)3P
2 (1.2 equiv)
Me
Me
Br
+
O
K(O-t-Bu) (1.2 equiv)
THF, 30 ˚C, 24 h
O
nBu
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
O
Me
(E)-1o
E/Z = >95:5
not detected
(Z,E)-3o, single isomer
80%
We then tested the substrate bearing an enyne moiety 1p (Scheme 4). The reaction of 1p gave
successful conversion to the desired borylation product containing a diene structure, (Z)ꢀ3p, with
good stereoselectivity. The Diels–Alder reaction of (Z)ꢀ3p with a dienophile proceeded with
excellent diastereoselectivity to give the corresponding alkenylboronate 4 containing a highly
fused ring system as a single isomer in good yield. The configuration of 4 was confirmed by
singleꢀcrystal Xꢀray structural analysis and the nOe technique. The stereoselectivity of this
reaction was completely controlled by the stereocenter at the allylic position of (Z)ꢀ3p.
Scheme 4. Regio- and Stereoselective Intramolecular Alkylboration of Enyne Substrate 1p
and Stereoselective Diels–Alder Reaction of Borylation Product (Z)-3p.
B(pin)
5 mol % CuCl
5 mol % (o-Tol)3P
O
O
O
O
+
B B
Br
Ph
K(O-t-Bu) (1.2 equiv)
THF, 30 ˚C, 24 h
O
O
Ph
1p
2 (1.2 equiv)
(Z)-3p
61%, E/Z = 7:93
(pin)B
Ph
O
O
O
N
H
O
(2.0 equiv)
Ph
H
O
N
Ph
4
Toluene, 80 ˚C
X-ray
62%, d.r. = >95:5
ACS Paragon Plus Environment
8

Page 9 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Next, we applied this intramolecular alkylboration to a Ueno–Storkꢀtype haloacetal substrate,
which is often used under radical cyclization conditions (Scheme 5).15,16 Our borylative
cyclization method was successfully used with haloacetal substrate 5. The corresponding
trisubstituted alkenylboronate containing an acetal moiety, (E)ꢀ6, was obtained in high yield with
excellent stereoselectivity.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Stereoselective Intramolecular Alkylboration of Alkyne Bearing a Haloacetal
Moiety.
B(pin)
5 mol % CuCl
5 mol % (o-tol)3P
Br
O
O
O
O
B B
+
K(O-t-Bu) (1.2 equiv)
THF, 30 ˚C, 24 h
OEt
O
5
OEt
O
2 (1.2 equiv)
(E)-6
74% E/Z = >95:5
To demonstrate the utility of these alkenylboronates synthesized via our borylative cyclization
reaction, we conducted Suzuki–Miyaura crossꢀcouplings of alkenylboronates 3 and 6 (Table 3).17
The reactions of the tetraꢀsubstituted alkenylboronate (Z)ꢀ3j with aryl or heteroaromatic
bromides gave the corresponding tetraꢀsubstituted alkenes (E)ꢀ7a and (E)ꢀ7b stereospecifically
and in excellent yields [(E)ꢀ7a: 92%, (E)ꢀ7b: 93%]. The alkenylboronate (E)ꢀ6 containing an
acetal moiety was used in the crossꢀcoupling reaction. The corresponding trisubstituted alkenes
bearing methoxybenzene and pyridine substituents, (E)ꢀ7c and (E)ꢀ7d, were obtained in high
yields [(E)ꢀ7c: 58%, (E)ꢀ7d: 87%].
ACS Paragon Plus Environment
9

The Journal of Organic Chemistry
Page 10 of 42
1
2
3
4
Table 3. Suzuki–Miyaura Cross-Coupling of Borylation Products.a
5
6
7
8
9
B(pin)
Ar
2 mol % Pd2(dba)3
4 mol % SPhos
R1
R2
(Z)-3j or (E)-6
R1
R2
+
Ar–Br
R3
THF/NaOH (3 M) (3:1)
60ºC, 15–18 h
R3
O
O
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
(1.5 equiv)
(E)-7
OMe
Me
CN
Ph
S
N
Me
Me
OEt
OEt
O
O
O
O
Ph
Ph
(E)-7a
E/Z = >95:5, 92%
(E)-7b
(E)-7c
(E)-7d
E/Z = >95:5, 87%
E/Z = >95:5, 93% E/Z = >95:5, 58%
aConditions: (Z)ꢀ3j or (E)ꢀ6 (0.2 mmol), Pd2dba3 (0.004 mmol), SPhos (0.006 mmol), ArBr
(0.3 mmol) in THF (1.8 mL), and NaOH aq (3 M) (0.6 mL) at 60 °C.
The reactions of bulky substrates showed different selectivities. The cyclizations of internal
alkyne substrates bearing bulky substituents such as secondary or tertiary alkyl groups were
conducted (Scheme 6). The bromide substrate 1q gave the corresponding product 3q in good
yield, but the stereoselectivity was moderate (Scheme 6a, 66%, E/Z = 16:84). The reaction of the
substrate containing a tertiaryꢀbutyl group, 1s, afforded a mixture of stereoisomers of 3s (Scheme
6b, E/Z = 1:1). The stereoselectivity improved when substrate 1r, bearing a mesylate moiety as
the leaving group, was used (Scheme 6a, 47%, E/Z = 7:93). This result shows that the
stereoselectivity depends on the leaving group for an alkyne substrate with a bulky substituent,
although the stereoselectivities of less bulky substrates do not depend on the leaving group
(Table 1, entries 10 and 11). Recently, our group reported a copper(I)ꢀcatalyzed borylative
radical cyclization of alkenes bearing alkyl halide moieties.14 As discussed later, we postulate
that this low stereoselectivity with a bulky substrate is attributable to the radical reactivity of the
copper(I) salt/diboron catalytic system with an alkyl halide.12,18 The alkenyl radical intermediate
ACS Paragon Plus Environment
10

Page 11 of 42
The Journal of Organic Chemistry
1
2
species isomerizes easily.19 However, a sulfonate leaving group such as mesylate improves the
stereoselectivity because mesylate is less reactive in the radical pathway under the conditions of
a copper(I)ꢀcatalyzed borylation reaction.12b
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
Scheme 6. Intramolecular Alkylboration of Propargyl Ethers Bearing Bulky Substituents
and Leaving Group Effect.
B(pin)
5 mol % CuCl
O
O
O
O
5 mol % (o-tol)3P
X
B B
+
(a)
Ph
K(O-t-Bu) (1.2 equiv)
THF, 30 ˚C
O
O
Ph
1
2 (1.2 equiv)
3q
X = Br: 1q,
30 ºC, 24 h, 66%, E/Z = 16:84
X = OMs: 1r, 50 ºC, 48 h, 47%, E/Z = 7:93
B(pin)
5 mol % CuCl
5 mol % (o-tol)3P
O
O
O
O
Br
B B
+
(b)
Ph
K(O-t-Bu) (1.2 equiv)
THF, 30 ˚C, 24 h
O
O
1s
Ph
2 (1.2 equiv)
3s
E/Z = 1:1, complex mixture
To investigate the reaction mechanism, we conducted a competitive experiment using a
mixture of 1a and alkyl halide 8 (Scheme 7a). The reaction gave only the borylative cyclization
product (E)ꢀ3a in high yield, and alkyl halide 8 recovery was satisfactory (91%). This result
suggests that our catalytic system first reacts selectively with the alkyne moiety of 1a rather than
the alkyl halide. This initial step in the reaction pathway first gives the alkenyl copper(I)
intermediate and then intramolecular substitution of the bromide moiety occurs rapidly to
produce the cyclization product 3a (Scheme 2). We then conducted the borylation reaction of 6ꢀ
bromoꢀ1ꢀhexyne (10) (Scheme 7b). The reaction showed low reactivity and the corresponding
intramolecular alkylboration product 11 was obtained in low yield (8%). This indicates that the
propargyl ether or amine moiety is important for this borylative cyclization and generation of the
regioisomer of alkenylcopper(I) intermediate would lead to deactivation of the catalyst.
ACS Paragon Plus Environment
11

The Journal of Organic Chemistry
Page 12 of 42
1
2
3
4
Scheme 7. Mechanistic Study.
5
6
7
(a) Control experiment with alkyl halide 8
8
9
Br
Me
B(pin)
B(pin)
5 mol % CuCl
5 mol % (o-tol)3P
2 (1.2 equiv)
Ph
not detected
Br
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
O
9
1a
Me
+
O
+
K(O-t-Bu) (1.2 equiv)
THF, 30 ºC, 24 h
Br
Ph
1.0 equiv
(b) Reaction of 6-bromo-1-hexyne (10)
Ph
3a
E/Z = >95:5
86% yield (NMR)
8
8
91% recovery
B(pin)
5 mol % CuCl
5 mol % (o-Tol)3P
O
O
O
O
Br
B
B
+
K(O-t-Bu) (1.2 equiv)
THF, 30 ˚C, 24 h
10
2 (1.2 equiv)
11
8% (NMR)
L
Cu
no reaction
and
L–Cu–B(pin)
B(pin)
10
catalyst deactivation
Br
Regioisomer of alkenylcopper(I)
intermediate
Next, DFT calculations were performed, using the borylcupration of propargyl ether as a model
compound, to investigate the regioselectivity of this borylation reaction. Partly conflicting
discussions appear in the literature on the regioselectivity of the borylcupration of propargylic
substrates. Carretero and coꢀworkers previously reported DFT calculation results for the
regioselective protoboration of a “primary” propargyl ether. They concluded that “the electronic
effect” of the oxygen atom of propargyl ether predominantly controls the regioselectivity of the
borylcupration step.11a In contrast, Lin and coꢀworkers suggested that “the coordination of the
oxygen atom” at the propargylic position to the copper(I) center controls the regioselectivity,
based on their experimental results.8 To clarify the main factors in the regioselectivity of our
system, we performed DFT calculations on borylcupration using terminal “secondary” propargyl
ethers and 3ꢀmethylꢀ1ꢀpentyne lacking an oxygen atom at the propargylic position (Scheme
ACS Paragon Plus Environment
12

Page 13 of 42
The Journal of Organic Chemistry
1
2
8a).20 Both of the transition states (TSꢀβ) in borylcupration that introduce the boryl group at the
βꢀposition of the alkyne were observed. The difference between the activation energies of
borylcupration of the propargyl ether via TSꢀβ and TSꢀα (+2.5 kcal/mol) was larger than that for
3ꢀmethylꢀ1ꢀpentyne (+1.7 kcal/mol). These calculation results suggest that the electronic effect
of the oxygen atom of the propargyl ether contributes to the high regioselectivity.11a In addition,
the results for 3ꢀmethylꢀ1ꢀpentyne, which lacks an oxygen atom, also suggest that the steric
interaction between the B(pin) group and the substituent on the propargylic position would also
enhance the regioselectivity (Scheme 8b).21 The transition state in which the oxygen atom
coordinates to the copper was not observed in our calculations. We suggest that a combination of
electronic and steric effects decides the regioselectivity of the borylcupration step in our system.
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
ACS Paragon Plus Environment
13

The Journal of Organic Chemistry
Page 14 of 42
1
2
3
4
Scheme 8. DFT Calculation for Borylcupration Step [ωB97XD/6-311G(d,p), SDD for Cu in
5
6
7
THF (IEF-PCM)].a
8
9
(a)
L
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
B(pin)
H
L
Cu
B(pin)
H
LCu
α
R
B(pin)
β
Cu
R
R
H
Me
Me
H
H
Me
II-β
TS-β
R = OCH3: +8.3
R = CH2CH3, +11.5
III-β
R = OCH3: +3.1
R = CH2CH3: +5.1
R = OCH3: –44.9
R = CH2CH3, –40.5
β-Borylation pathway
L Cu
B(pin)
R = OMe
R = CH2CH3
ꢀGTS- ꢀGTS-
α
+
R
ꢀGTS-
ꢀGTS-
α
<
<
β
β
H
α
β
ꢀꢀG = +2.5 kcal/mol
ꢀꢀG = +1.7 kcal/mol
Me
I
R = OCH3 or CH2CH3
L = PPh3
α-Borylation pathway
L
L
(pin)B
CuL
β
(pin)B
R
Cu
(pin)B
Cu
α
H
H
H
Me
R
H
H
Me
R
Me
II-α
TS-α
R = OCH3: +10.8
R = CH2CH3: +13.7
III-α
R = OCH3: +1.0
R = CH2CH3: +5.4
R = OCH3: –40.2
R = CH2CH3: –32.6
aRelative G value (kcal/mol) at 298 K in THF.
A plausible catalytic cycle for the intramolecular alkylboration of propargyl ethers and
propargylamines, based on the above experimental and theoretical results, is shown in Scheme 9.
The copper(I) alkoxide A is formed from copper(I) chloride and potassium alkoxide. The
ACS Paragon Plus Environment
14

Page 15 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
reaction between A and diboron reagent 2 produces the borylcopper(I) intermediate B. The
alkyne substrate 1 strongly coordinates to intermediate B to give the πꢀcomplex C. The
alkenylcopper(I) intermediate D is formed through borylcupration of the alkene, with syn
selectivity. The regioselectivity of this borylcupration is controlled by the electronic effect of the
ether or amine moiety, and the steric congestion between the B(pin) moiety and the substituents
at the propargylic position. This process is faster than the reaction with the C–Br moiety, based
on the experiments shown in Scheme 7a. Strong coordination of the alkyne moiety leads to
chemoselectivity over the alkene and alkyl halide moieties. Coordination of the alkoxide base to
the copper(I) center D gives cuprate E. The intramolecular cyclization of E provides the
intramolecular alkylboration product 3 and regenerates the copper(I) alkoxide A.9,22 The
bulkiness of the substrate results in slow borylcupration and dissociation of borylcopper moiety
B from C, followed by a radical reaction between borylcopper moiety B and the free substrate 1.
The resulting alkenyl radical intermediate G gives the stereoisomer of 3.12 However, the
sulfonate leaving group suppresses this radical reaction pathway, which improves the
stereoselectivity for (Z)ꢀ3q (Scheme 6).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
15

The Journal of Organic Chemistry
Page 16 of 42
1
2
3
4
Scheme 9. Plausible Reaction Mechanism.
5
6
7
8
9
B
CuICl + ROK
L
R1
R2
L = (o-tol)3P
O
+ KBr
KCl
B
B
=
2
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
Y
3
O
LCuI OR
A
intramolecular
R1
LCuI
B
cyclization
K
L
CuI
OR
RO B
Br
B
B
Br
R1
R2
Y
coordination
R2
Y
E
1
R1
B
L
CuI
Br
B
regioselective
borylcupration
CuI
Br
L
R1
R2
Y
ROK
dissociation
of alkyne
(side reaction)
R2
Y
D
C
R1 = small, borylcupration: fast
R1 = large, borylcupration: slow
L
B
CuI
B
L
B
R1
ROK
CuII
R1
R2
R1
R2
Br
Br
LCuI–OR (A)
R2
Y
Y
3
Y
G
F
radical reaction pathway
mixture of stereoisomers
(5-exo-dig-cyclization)
Conclusions
In summary, we developed a chemoꢀ, regioꢀ, and stereoselective copper(I)ꢀcatalyzed
intramolecular alkylboration of propargyl ethers and amines to provide alkenylboronates
containing heterocyclic moieties. Derivatization of the products gave highly functionalized
multiꢀsubstituted alkenes. Mechanistic studies showed that the borylcopper(I) intermediate
selectively reacts with an alkyne moiety of the substrate rather than an alkyl halide moiety. DFT
calculations suggested that the electronic effect of the oxygen atom of the propargyl ether and
steric congestion between the B(pin) group and the substituents on the propargylic position
contributed to the controlling regioselectivity of the borylcupration step.
ACS Paragon Plus Environment
16

Page 17 of 42
The Journal of Organic Chemistry
1
2
3
4
Experimental Section
5
6
7
8
General. Materials were obtained from commercial suppliers and purified by standard
procedures unless otherwise noted. Solvents were also purchased from commercial suppliers,
degassed via three freezeꢀpumpꢀthaw cycles, and further dried over molecular sieves (MS 4A).
NMR spectra were recorded on JEOL JNMꢀECX400P and JNMꢀECS400 spectrometers (1H: 400
MHz and 13C: 100 MHz)．Tetramethylsilane (1H) and CDCl3 (13C) were employed as the
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
external standards, respectively. CuCl (ReagentPlus® grade, 224332ꢀ25G, ≥99%) and K(Oꢀtꢀ
Bu)/THF (1.0 M, 328650ꢀ50ML) were purchased from SigmaꢀAldrich Co. and used as received.
GC analyses were conducted with a Shimadzu GCꢀ2014 or GCꢀ2025 equipped with a ULBON
HRꢀ1 glass capillary column (Shinwa Chemical Industries) and a FID detector. Highꢀresolution
mass spectra were recorded by Thermo Fisher Scientific Q Exactive Hybrid Quadrupoleꢀ
Orbitrap Mass Spectrometer for ESIꢀOrbitrap analysis and JEOL JMSꢀT100GCV High
Performance Gas Chromatograph – TimeꢀofꢀFlight Mass Spectrometer for EIꢀTOF analysis at
the Global Facility Center, Hokkaido University.
Preparation of Starting Materials.
Preparation of 3-(2-Bromoethoxy)oct-1-yne (1a) (Method A). In a vacuum dried 200 mL twoꢀ
neck roundꢀbottomed flask, 2ꢀbromoethanꢀ1ꢀol (7.50 g, 60.0 mmol) and pyridinium pꢀ
toluenesulfonate (PPTS, 1.51 g, 6.00 mmol) were dissolved in dry CH2Cl2 (60 mL), and the
mixture was cooled to 0 ºC under a nitrogen atmosphere. 3,4ꢀdihydroꢀ2Hꢀpyran (DHP, 7.57 g,
90.0 mmol) was added to the mixture, and the mixture was warmed to room temperature. After
the mixture was stirred for 18 h, the reaction mixture was quenched by H2O and extracted with
CH2Cl2 three times. The combined organic layer was then dried over MgSO4. After filtration, the
solvents were removed by evaporation. The crude product was purified by flash column
ACS Paragon Plus Environment
17

The Journal of Organic Chemistry
Page 18 of 42
1
2
3
4
5
6
chromatography to obtain the corresponding THPꢀprotected product (11.4 g, 54.5 mmol, 90%) as
a colorless oil.
7
8
9
In a vacuum dried 200 mL twoꢀneck roundꢀbottomed flask, octꢀ1ꢀynꢀ3ꢀol (3.79 g, 30.0 mmol)
was added dropwise to a suspension of NaH (60% in mineral oil, washed with hexane three
times under a nitrogen atmosphere, 1.58 g, 39.0 mmol) in DMF (60 mL) at 0 ºC under a nitrogen
atmosphere. Then, it was warmed to room temperature and stirred for 1 h. After the mixture was
cooled to 0 ºC, THPꢀprotected bromoethanol (9.41 g, 45.0 mmol) was added dropwise. Then, the
mixture was warmed to room temperature and stirred for 6 h. The reaction mixture was quenched
by H2O and extracted with EtOAc/Hexane (1:4) three times. The combined organic layer was
washed with brine and dried over MgSO4. After filtration, the solvents were removed by
evaporation. The crude product was purified by flash column chromatography to obtain the
corresponding ether (6.40 g, 25.2 mmol, 84%) as a colorless oil.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In an open 100 mL roundꢀbottomed flask, the ether (6.40 g, 25.2 mmol) and pꢀtoluenesulfonic
acid monohydrate (0.24 g, 1.30 mmol) were dissolved in dry MeOH (50 mL) at room
temperature under air. After the mixture was stirred for 2 h, the reaction mixture was quenched
by saturated NaHCO3 aq. and extracted with Et2O three times. The combined organic layer was
then dried over MgSO4. After filtration, the solvents were removed by evaporation. The crude
product was purified by flash column chromatography to obtain the corresponding alcohol (2.00
g, 11.8 mmol, 47%) as a colorless oil.
In a vacuum dried 100 mL twoꢀneck roundꢀbottomed flask, 2ꢀ(octꢀ1ꢀynꢀ3ꢀyloxy)ethanꢀ1ꢀol
(2.00 g, 11.8 mmol) and carbon tetrabromide (4.30 g, 13.0 mmol) were dissolved in dry THF (24
mL), and the mixture was cooled to 0 ºC under a nitrogen atmosphere. Triphenylphosphine (3.41
g, 13.0 mmol) was added to the mixture, and the mixture was warmed to room temperature.
ACS Paragon Plus Environment
18

Page 19 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
After the mixture was stirred for 4 h, the solvents were removed by evaporation. The crude
product was purified by flash column chromatography and bulbꢀtoꢀbulb distillation to obtain the
7
8
9
1
corresponding bromide 1a (1.34 g, 5.74 mmol, 49%) as a colorless oil. H NMR (392 MHz,
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
CDCl3, δ): 0.90 (t, J = 6.9 Hz, 3H), 1.26–1.38 (m, 4H), 1.43–1.50 (m, 2H), 1.66–1.81 (m, 2H),
2.45 (d, J = 2.0 Hz, 1H), 3.44–3.53 (m, 2H), 3.73 (dt, J = 6.4, 10.8 Hz, 1H), 4.04 (dt, J = 6.1,
10.6 Hz, 1H), 4.10 (td, J = 2.0, 6.7 Hz, 1H). 13C NMR (99 MHz, CDCl3, δ): 13.9 (CH3), 22.4
(CH2), 24.7 (CH2), 30.1 (CH2), 31.3 (CH2), 35.4 (CH2), 68.5 (CH2), 69.6 (CH), 73.9 (C), 82.4
(CH). HRMS (ESIꢀOrbitrap) (m/z): [M+Na]+ calcd for C10H17BrONa, 255.0355; found,
255.0361.
Preparation of [3-(2-Bromoethoxy)pent-4-yn-1-yl]benzene (1d) (Method B). In a vacuum
dried 200 mL twoꢀneck roundꢀbottomed flask, 3ꢀphenylpropionaldehyde (2.68 g, 20.0 mmol)
was dissolved in dry Et2O (56 mL), and the mixture was cooled to 0 ºC under a nitrogen
atmosphere. Ethynylmagnesium bromide solution in THF (0.5 M, 48.0 mL, 24.0 mmol) was
added dropwise to the mixture, and the mixture was warmed to room temperature. After the
mixture was stirred for 12 h, the reaction mixture was quenched by saturated NH4Cl aq. and
extracted with Et2O three times. The combined organic layer was then dried over MgSO4. After
filtration, the solvents were removed by evaporation. The crude product was purified by flash
column chromatography to obtain the corresponding propargyl alcohol (1.95 g, 12.2 mmol, 61%)
as a colorless oil.
In a vacuum dried 50 mL twoꢀneck roundꢀbottomed flask, the propargyl alcohol (1.95 g, 12.2
mmol) was added dropwise to a suspension of NaH (60% in mineral oil, washed with hexane
three times under a nitrogen atmosphere, 0.54 g, 13.4 mmol) in THF (7.4 mL) at 0 ºC under a
nitrogen atmosphere. Then, the mixture was warmed to room temperature and stirred for 1 h.
ACS Paragon Plus Environment
19

The Journal of Organic Chemistry
Page 20 of 42
1
2
3
4
5
6
7
8
9
After the mixture was cooled to 0 ºC, ethyl bromoacetate (2.45 g, 14.6 mmol) was added
dropwise to the mixture. Then, the mixture was warmed to room temperature and stirred for 16
h. The reaction mixture was quenched by saturated NH4Cl aq. and extracted with Et2O three
times. The combined organic layer was then dried over MgSO4. After filtration, the solvents
were removed by evaporation. The corresponding crude ether was used to the next reaction
without further purification.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In a vacuum dried 300 mL twoꢀneck roundꢀbottomed flask, the solution of the crude product in
THF (30 mL) was added dropwise to a suspension of LiAlH4 (0.51 g, 13.4 mmol) in THF (60
mL) at –30 ºC under a nitrogen atmosphere. After the mixture was stirred for 16 h, the reaction
mixture was quenched by MeOH (1.4 mL), then NaOH aq. (1 M, 0.5 mL) and H2O (1.5 mL).
After filtration, the solvents were removed by evaporation. The crude product was purified by
flash column chromatography to obtain the corresponding reduction product (2.22 g, 10.9 mmol,
89%) as a colorless oil.
In a vacuum dried 100 mL twoꢀneck roundꢀbottomed flask, the reduction product (2.22 g, 10.9
mmol) and carbon tetrabromide (3.62 g, 10.9 mmol) were dissolved in dry THF (22 mL), and the
mixture was cooled to 0 ºC under a nitrogen atmosphere. Triphenylphosphine (2.85 g, 10.9
mmol) was added to the mixture, and the mixture was warmed to room temperature. After the
mixture was stirred for 10 h, the solvents were removed by evaporation. The crude product was
purified by flash column chromatography and bulbꢀtoꢀbulb distillation to obtain the
1
corresponding bromide 1d (2.33 g, 8.73 mmol, 80%) as a colorless oil. H NMR (392 MHz,
CDCl3, δ): 1.98–2.16 (m, 2H), 2.48 (d, J = 2.4 Hz, 1H), 2.81 (t, J = 7.6 Hz, 2H), 3.45–3.54 (m,
2H), 3.71 (dt, J = 6.5, 10.8 Hz, 1H), 4.02–4.08 (m, 2H), 7.18–7.22 (m, 3H), 7.27–7.31 (m, 2H).
13C NMR (99 MHz, CDCl3, δ): 30.2 (CH2), 31.1 (CH2), 36.9 (CH2), 68.45 (CH2), 68.51 (CH),
ACS Paragon Plus Environment
20

Page 21 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
74.4 (C), 82.1 (CH), 125.9 (CH), 128.3 (CH), 128.4 (CH), 140.9 (C). HRMS (ESIꢀOrbitrap)
(m/z): [M+Na]+ calcd for C13H15BrONa, 289.0199; found, 289.0199.
7
8
9
{[5ꢀ(2ꢀBromoethoxy)heptꢀ6ꢀynꢀ1ꢀyl]oxy}(tertꢀbutyl)diphenylsilane (1e). 1e was prepared as a
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
colorless oil from the corresponding propargyl alcohol according to Method B. H NMR (392
MHz, CDCl3, δ): 1.05 (s, 9H), 1.52–1.63 (m, 4H), 1.66–1.81 (m, 2H), 2.44 (d, J = 2.2 Hz, 1H),
3.43–3.52 (m, 2H), 3.65–3.74 (m, 3H), 4.00–4.10 (m, 2H), 7.36–7.45 (m, 6H), 7.65–7.68 (m,
13
4H). C NMR (99 MHz, CDCl3, δ): 19.1(C), 21.4 (CH2), 26.8 (CH3), 30.1 (CH2), 32.0 (CH2),
35.2 (CH2), 63.5 (CH2), 68.5 (CH2), 69.6 (CH), 74.1 (C), 82.4 (C), 127.5 (CH), 129.5 (CH),
133.9 (C), 135.5 (CH). HRMS (ESIꢀOrbitrap) (m/z): [M+Na]+ calcd for C25H33BrO2SiNa,
495.1325; found, 495.1330.
({[2ꢀ(2ꢀBromoethoxy)butꢀ3ꢀynꢀ1ꢀyl]oxy}methyl)benzene (1f). 1f was prepared as a colorless oil
1
from the corresponding propargyl alcohol according to Method B. H NMR (392 MHz, CDCl3,
δ): 2.50 (d, J = 2.0 Hz, 1H), 3.50 (t, J = 6.5 Hz, 2H), 3.67 (s, 1H), 3.69 (d, J = 0.8 Hz, 1H),
3.81 (dt, J = 6.6, 10.7 Hz, 1H), 4.06 (dt, J = 6.4, 10.8 Hz, 1H), 4.36 (ddd, J = 2.2, 5.1, 5.9 Hz,
1H), 4.64 (dd, J = 12.2, 22.3 Hz, 2H), 7.27–7.38 (m, 5H). 13C NMR (99 MHz, CDCl3, δ): 29.8
(CH2), 68.7 (CH2), 69.3 (CH), 71.8 (CH2), 73.2 (CH2), 75.2 (C), 79.5 (CH), 127.5 (CH), 128.1
(CH), 137.6 (C). HRMS (EIꢀTOF) (m/z): [M]+ calcd for C13H15BrO2, 282.0255; found,
282.0252.
1ꢀ(2ꢀBromoethoxy)ꢀ1ꢀethynylcyclohexane (1g). 1g was prepared as a colorless oil from the
corresponding propargyl alcohol according to Method B. 1H NMR (392 MHz, CDCl3, δ): 1.26–
1.35 (m, 1H), 1.48–1.72 (m, 7H), 1.86–1.90 (m, 2H), 2.48 (s, 1H), 3.48 (t, J = 6.5 Hz, 2H), 3.88
(t, J = 6.5 Hz, 2H). 13C NMR (99 MHz, CDCl3, δ): 22.3 (CH2), 25.1 (CH2), 30.8 (CH2), 36.8
ACS Paragon Plus Environment
21

The Journal of Organic Chemistry
Page 22 of 42
1
2
3
4
5
6
(CH2), 63.4 (CH2), 73.5 (C), 73.9 (C), 84.6 (CH). HRMS (EIꢀTOF) (m/z): [M]+ calcd for
C10H15BrO, 230.0306; found, 230.0311.
7
8
9
[3ꢀ(2ꢀBromoethoxy)hexꢀ4ꢀynꢀ1ꢀyl]benzene (1i). 1i was prepared as a colorless oil from the
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
corresponding propargyl alcohol according to Method B. H NMR (392 MHz, CDCl3, δ): 1.87
(d, J = 2.4 Hz, 3H), 1.93–2.10 (m, 2H), 2.79 (t, J = 7.4 Hz, 2H), 3.45–3.53 (m, 2H), 3.68 (dt, J =
6.5, 11.1 Hz, 1H), 3.98–4.05 (m, 2H), 7.16–7.22 (m, 3H), 7.26–7.30 (m, 2H). 13C NMR (99
MHz, CDCl3, δ): 3.5 (CH3), 30.4 (CH2), 31.3 (CH2), 37.3 (CH2), 68.3 (CH2), 69.1 (CH), 77.6
(C), 82.4 (C), 125.8 (CH), 128.3 (CH), 128.4 (CH), 141.3 (C). HRMS (ESIꢀOrbitrap) (m/z):
[M+Na]+ calcd for C14H17BrONa, 303.0355; found, 303.0357.
[3ꢀ(2ꢀBromoethoxy)nonꢀ4ꢀynꢀ1ꢀyl]benzene (1j). 1j was prepared as a colorless oil from the
1
corresponding propargyl alcohol according to Method B. H NMR (392 MHz, CDCl3, δ): 0.92
(t, J = 7.1 Hz, 3H), 1.37–1.54 (m, 4H), 1.93–2.11 (m, 2H), 2.23 (td, J = 2.0, 7.0 Hz, 2H), 2.79 (t,
J = 7.6 Hz, 2H), 3.45–3.54 (m, 2H), 3.70 (dt, J = 6.6, 10.7 Hz, 1H), 3.98–4.08 (m, 2H), 7.17–
7.22 (m, 3H), 7.27–7.30 (m, 2H). 13C NMR (99 MHz, CDCl3, δ): 13.5 (CH3), 18.2 (CH2), 21.8
(CH2), 30.3 (CH2), 30.6 (CH2), 31.3 (CH2), 37.4 (CH2), 68.2 (CH2), 69.0 (CH), 78.4 (C), 86.9
(C), 125.7 (CH), 128.2 (CH), 128.4 (CH), 141.3 (C). HRMS (ESIꢀOrbitrap) (m/z): [M+Na]+
calcd for C17H23BrONa, 345.0825; found, 345.0828.
[3ꢀ(2ꢀBromoethoxy)ꢀ8ꢀchlorooctꢀ4ꢀynꢀ1ꢀyl]benzene (1k). 1k was prepared as a colorless oil
1
from the corresponding propargyl alcohol according to Method B. H NMR (392 MHz, CDCl3,
δ): 1.93–2.12 (m, 4H), 2.44 (td, J = 1.8, 6.7 Hz, 2H), 2.79 (t, J = 7.9 Hz, 2H), 3.45–3.54 (m,
13
2H), 3.64–3.72 (m, 3H), 3.98–4.07 (m, 2H), 7.17–7.22 (m, 3H), 7.27–7.31 (m, 2H). C NMR
(99 MHz, CDCl3, δ): 16.0 (CH2), 30.4 (CH2), 31.2 (CH2), 31.3 (CH2), 37.3 (CH2), 43.5 (CH2),
ACS Paragon Plus Environment
22

Page 23 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
68.3 (CH2), 69.0 (CH), 79.5 (C), 84.8 (C), 125.8 (CH), 128.3 (CH), 128.4 (CH), 141.2 (C).
HRMS (ESIꢀOrbitrap) (m/z): [M+Na]+ calcd for C16H20BrClONa, 365.0278; found, 369.0280.
{3ꢀ[2ꢀBromoethoxy]ꢀ7ꢀ[(3ꢀmethylbutꢀ2ꢀenꢀ1ꢀyl)oxy]heptꢀ4ꢀynꢀ1ꢀyl}benzene (1l). 1l was prepared
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
as a colorless oil from the corresponding propargyl alcohol according to Method B. H NMR
(392 MHz, CDCl3, δ): 1.68 (s, 3H), 1.74 (s, 3H), 1.93–2.11 (m, 2H), 2.52 (td, J = 1.8, 7.2 Hz,
2H), 2.79 (t, J = 7.4 Hz, 2H), 3.47–3.56 (m, 4H), 3.69 (dt, J = 6.6, 10.8 Hz, 1H), 3.98–4.07 (m,
4H), 5.33–5.37 (m, 1H), 7.17–7.21 (m, 3H), 7.27–7.30 (m, 2H). 13C NMR (99 MHz, CDCl3, δ):
17.8 (CH3), 20.0 (CH2), 25.6 (CH3), 30.3 (CH2), 31.2 (CH2), 37.2 (CH2), 67.1 (CH2), 68.0 (CH2),
68.2 (CH2), 68.9 (CH), 79.3 (C), 83.7 (C), 120.7 (CH), 125.7 (CH), 128.2 (CH), 128.3 (CH),
136.9 (C), 141.2 (C). HRMS (ESIꢀOrbitrap) (m/z): [M+Na]+ calcd for C20H27BrO2Na, 401.1087;
found, 401.1089.
tertꢀButyl 4ꢀ(2ꢀbromoethoxy)ꢀ4ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)piperidineꢀ1ꢀcarboxylate (1m). 1m was prepared
1
as a colorless oil from the corresponding propargyl alcohol according to Method B. H NMR
(392 MHz, CDCl3, δ): 0.92 (t, J = 7.2 Hz, 3H), 1.36–1.54 (m, 4H), 1.46 (s, 9H), 1.66–1.72 (m,
2H), 1.81–1.84 (br, 2H), 2.23 (t, J = 7.0 Hz, 2H), 3.27 (ddd, J = 3.8, 9.2, 13.3 Hz, 2H), 3.47 (t, J
= 6.3 Hz, 2H), 3.70–3.73 (br, 2H), 3.87 (t, J = 6.5 Hz, 2H). 13C NMR (99 MHz, CDCl3, δ): 13.6
(CH3), 18.3 (CH2), 21.9 (CH2), 28.4 (CH3), 30.7 (CH2), 31.0 (CH2), 36.7 (CH2), 40.0 (CH2), 40.9
(CH2), 63.6 (CH2), 72.4 (C), 79.3 (C), 79.5 (C), 88.0 (C), 154.6 (C). HRMS (ESIꢀOrbitrap) (m/z):
[M+Na]+ calcd for C18H30O3NBrNa, 410.1301; found, 410.1299.
(E)ꢀ4ꢀ(2ꢀBromoethoxy)decꢀ2ꢀenꢀ5ꢀyne [(E)ꢀ1o]. 1o was prepared as a colorless oil from the
1
corresponding propargyl alcohol according to Method B. H NMR (392 MHz, CDCl3, δ): 0.92
(t, J = 7.2 Hz, 3H), 1.37–1.56 (m, 4H), 1.75 (d, J = 6.7 Hz, 3H), 2.26 (dt, J = 1.9, 7.1 Hz, 2H),
3.48 (dt, J = 1.1, 6.7 Hz, 2H), 3.75 (dt, J = 6.6, 10.7 Hz, 1H), 3.90 (dt, J = 6.5, 10.4 Hz, 1H),
ACS Paragon Plus Environment
23

The Journal of Organic Chemistry
Page 24 of 42
1
2
3
4
13
4.62 (d, J = 8.1 Hz, 1H), 5.52–5.59 (m, 1H), 5.87–5.96 (m, 1H). C NMR (99 MHz, CDCl3, δ
5
6
7
8
9
): 13.5 (CH3), 17.4 (CH3), 18.3 (CH2), 21.9 (CH2), 30.2 (CH2), 30.6 (CH2), 67.2 (CH2), 70.3
(CH), 76.8 (C), 88.1 (C), 128.3 (CH), 129.9 (CH). HRMS (EIꢀTOF) (m/z): [M]+ calcd for
C12H19OBr, 258.0619; found, 258.0619.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[3ꢀ(2ꢀBromoethoxy)ꢀ5ꢀ(cyclohexꢀ1ꢀenꢀ1ꢀyl)pentꢀ4ꢀynꢀ1ꢀyl]benzene (1p). 1p was prepared as a
1
colorless oil from the corresponding propargyl alcohol according to Method B. H NMR (392
MHz, CDCl3, δ): 1.57–1.70 (m, 4H), 1.97–2.14 (m, 6H), 2.81 (t, J = 7.7 Hz, 2H), 3.45–3.57 (m,
2H), 3.68–3.74 (m, 1H), 4.03 (dt, J = 6.1, 10.8 Hz, 1H), 4.18 (t, J = 6.6 Hz, 1H), 6.12 (quint, J =
2.0 Hz, 1H), 7.17–7.23 (m, 3H), 7.27–7.31 (m, 2H). 13C NMR (99 MHz, CDCl3, δ): 21.3 (CH2),
22.1 (CH2), 25.5 (CH2), 29.1 (CH2), 30.4 (CH2), 31.3 (CH2), 37.3 (CH2), 68.3 (CH2), 69.2 (CH),
84.6 (C), 88.1 (C), 119.9 (C), 125.8 (CH), 128.2 (CH), 128.4 (CH), 135.2 (CH), 141.2 (C).
HRMS (ESIꢀOrbitrap) (m/z): [M+Na]+ calcd for C19H23BrONa, 369.0825; found, 369.0822.
Preparation of N-Benzyl-N-(2-bromoethyl)prop-2-yn-1-amine (1h). 2ꢀ[Benzyl(propꢀ2ꢀynꢀ1ꢀ
yl)amino]ethanꢀ1ꢀol was synthesized through the reaction of the corresponding ethanolamine
derivative according to the literature procedure.23 In a vacuum dried 100 mL twoꢀneck roundꢀ
bottomed flask, 2ꢀ[benzyl(propꢀ2ꢀynꢀ1ꢀyl)amino]ethanꢀ1ꢀol (2.89 g, 15.3 mmol) and carbon
tetrabromide (5.06 g, 15.3 mmol) were dissolved in dry THF (22 mL), and the mixture was
cooled to 0 ºC under a nitrogen atmosphere. Triphenylphosphine (4.00 g, 15.9 mmol) was added
to the mixture, and the mixture was warmed to room temperature. After the mixture was stirred
for 10 h, the solvents were removed by evaporation. The crude product was purified by flash
column chromatography to obtain NꢀbenzylꢀNꢀ(2ꢀbromoethyl)propꢀ2ꢀynꢀ1ꢀamine (1h) (2.94 g,
1
11.7 mmol, 76%) as a colorless oil. H NMR (392 MHz, CDCl3, δ): 2.26 (t, J = 2.2 Hz, 1H),
3.00 (t, J = 7.0 Hz, 2H), 3.36 (d, J = 2.2 Hz, 2H), 3.44 (t, J = 7.2 Hz, 2H), 3.70 (s, 2H), 7.25–
ACS Paragon Plus Environment
24

Page 25 of 42
The Journal of Organic Chemistry
1
2
7.38 (m, 5H). 13C NMR (99 MHz, CDCl3, δ): 30.0 (CH2), 41.6 (CH2), 54.9 (CH2), 57.6 (CH2),
73.5 (C), 78.1 (CH), 127.3 (CH), 128.3 (CH), 128.9 (CH), 138.0 (C). HRMS (ESIꢀOrbitrap)
(m/z): [M+H]+ calcd for C12H15BrN, 252.0382; found, 252.0384.
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
Preparation of N-(2-Bromoethyl)-4-methyl-N-(oct-2-yn-1-yl)benzenesulfonamide (1n). In a
vacuum dried 100 mL twoꢀneck roundꢀbottomed flask, 1ꢀchlorooctꢀ2ꢀyne (2.17 g, 15.0 mmol),
4ꢀmethylbenzenesulfonamide (10.3 g, 60.0 mmol) and potassium carbonate (2.08 g, 15.0 mmol)
were dissolved in dry acetonitrile (40 mL), and then the mixture was warmed to 80 ºC. After the
mixture was stirred for 16 h, the solid was filtered off and the filtrate was concentrated in vacuo.
The crude product was purified by flash column chromatography to obtain 4ꢀmethylꢀNꢀ(octꢀ2ꢀ
ynꢀ1ꢀyl)benzenesulfonamide (2.00 g, 7.14 mmol, 48%) as a white solid (m.p. = 36–37 ℃).
In
a
vacuum dried 50 mL roundꢀbottomed flask, 4ꢀmethylꢀNꢀ(octꢀ2ꢀynꢀ1ꢀ
yl)benzenesulfonamide (0.83 g, 3.00 mmol), 1,2ꢀdibromoethane (5.63 g, 30.0 mmol) and cesium
carbonate (1.47 g, 4.50 mmol) were dissolved in dry acetonitrile (12 mL), and then warmed to 80
ºC. After the mixture was stirred for 15 h, the solid was filtered off and the filtrate was
concentrated in vacuo. The crude product was purified by flash column chromatography to
obtain Nꢀ(2ꢀbromoethyl)ꢀ4ꢀmethylꢀNꢀ(octꢀ2ꢀynꢀ1ꢀyl)benzenesulfonamide (1n) (0.93 g, 2.40
1
mmol, 80%) as a colorless oil. H NMR (392 MHz, CDCl3, δ): 0.87 (t, J = 7.0 Hz, 3H), 1.16–
1.33 (m, 6H), 1.96 (tt, J = 2.2, 7.0 Hz, 2H), 2.43 (s, 3H), 3.52 (s, 4H), 4.13 (t, J = 2.2 Hz, 2H),
7.30 (d, J = 7.6 Hz, 2H), 7.72–7.75 (m, 2H). 13C NMR (99 MHz, CDCl3, δ): 13.8 (CH3), 18.3
(CH2), 21.4 (CH3), 22.0 (CH2), 27.8 (CH2), 29.0 (CH2), 30.8 (CH2), 38.3 (CH2), 48.1 (CH2), 72.3
(C), 86.7 (C), 127.5 (CH), 129.4 (C), 135.6 (C), 143.5 (C). HRMS (ESIꢀOrbitrap) (m/z):
[M+Na]+ calcd for C17H24BrO2NSNa, 408.0603; found, 408.0605.
ACS Paragon Plus Environment
25

The Journal of Organic Chemistry
Page 26 of 42
1
2
3
4
5
6
7
8
9
Preparation of 1-(2-Bromo-1-ethoxyethoxy)-1-ethynylcyclohexane (5). In a vacuum dried
100 mL twoꢀneck roundꢀbottomed flask, 1ꢀethynylcyclohexanꢀ1ꢀol (1.26 g, 10.0 mmol) and
ethoxyethene (2.28 mL, 24.0 mmol) were dissolved in dry CH2Cl2 (34 mL), and the mixture was
cooled to 0 ºC under a nitrogen atmosphere. NꢀBromosuccinimide (1.78 g, 10.0 mmol) was
added portionwise to the mixture, and the mixture was warmed to room temperature. After the
mixture was stirred for 3 h, the solvents were removed by evaporation. The crude product was
purified by flash column chromatography to obtain 1ꢀ(2ꢀbromoꢀ1ꢀethoxyethoxy)ꢀ1ꢀ
ethynylcyclohexane (5) (1.27 g, 4.60 mmol, 46%) as a colorless oil. 1H NMR (392 MHz, CDCl3,
δ): 1.19–1.29 (m, 4H), 1.51–1.64 (m, 5H), 1.67–1.74 (m, 2H), 1.87–1.92 (m, 1H), 2.00–2.14 (m,
1H), 2.59 (s, 1H), 3.37–3.44 (m, 2H), 3.61 (dq, J = 7.1, 9.1 Hz, 1H), 3.75 (dq, J = 7.2, 9.2 Hz,
1H), 5.17 (dd, J = 4.5, 6.3 Hz, 1H). 13C NMR (99 MHz, CDCl3, δ): 15.0 (CH3), 22.8 (CH2), 25.0
(CH2), 33.3 (CH2), 38.2 (CH2), 38.5 (CH2), 61.7 (CH2), 74.5 (C), 75.4 (C), 84.3 (C), 97.5 (CH).
HRMS (ESIꢀOrbitrap) (m/z): [M+Na]+ calcd for C12H19BrO2Na, 297.0461; found, 297.0460.
Preparation of 3-(2-Iodoethoxy)oct-1-yne (1b). In a vacuum dried 200 mL twoꢀneck roundꢀ
bottomed flask, triphenylphosphine (3.94 g, 15.0 mmol), imidazole (1.27 g, 18.6 mmol) and
iodine (4.15 g, 16.4 mmol) were dissolved in dry CH2Cl2 (100 mL) under a nitrogen atmosphere.
2ꢀ(octꢀ1ꢀynꢀ3ꢀyloxy)ethanꢀ1ꢀol (1.66 g, 10.0 mmol) synthesized through Method A was added
dropwise to the mixture. After the mixture was stirred for 1 h, 100 mL of EtOAc was added to
the reaction mixture. The organic layer was washed with 50 mL of saturated aqueous Na2S2O3
solution, 150 mL of saturated aqueous NaHCO3 solution and then 150 mL of brine. The organic
layer was then dried over MgSO4. After filtration, the solvents were removed by evaporation.
The crude product was purified by flash column chromatography to obtain 3ꢀ(2ꢀiodoethoxy)octꢀ
1ꢀyne (1b) (2.56 g, 9.14 mmol, 94%) as a colorless oil. 1H NMR (392 MHz, CDCl3, δ): 0.90 (t, J
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
ACS Paragon Plus Environment
26

Page 27 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
= 6.7 Hz, 3H), 1.26–1.38 (m, 4H), 1.41–1.53 (m, 2H), 1.65–1.81 (m, 2H), 2.44 (d, J = 1.8 Hz,
1H), 3.23–3.32 (m, 2H), 3.68 (dt, J = 7.1, 10.6 Hz, 1H), 3.98 (ddd, J = 6.2, 7.3, 10.7 Hz 1H),
4.09 (dt, J = 2.1 6.6 Hz, 1H). 13C NMR (99 MHz, CDCl3, δ): 2.8 (CH2), 14.0 (CH3), 22.5 (CH2),
24.8 (CH2), 31.3 (CH2), 35.5 (CH2), 69.3 (CH2), 69.4 (CH), 73.9 (C), 82.6 (CH). HRMS (EIꢀ
TOF) (m/z): [M–pentyl]+ calcd for C5H6IO, 208.9463; found, 208.9463.
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 2-(Oct-1-yn-3-yloxy)ethyl methanesulfonate (1c). In a vacuum dried 50 mL
twoꢀneck roundꢀbottomed flask, 2ꢀ(octꢀ1ꢀynꢀ3ꢀyloxy)ethanꢀ1ꢀol (1.69 g, 10.0 mmol) synthesized
through Method A and triethylamine (1.53 mL, 11.0 mmol) were dissolved in dry CH2Cl2 (15
mL), and the mixture was cooled to 0 ºC under a nitrogen atmosphere. Methanesulfonyl chloride
(1.26 g, 11.0 mmol) was added dropwise to the mixture. After the mixture was stirred for 5 h, the
reaction mixture was quenched by H2O and extracted with Et2O three times. The combined
organic layer was then dried over MgSO4. After filtration, the solvents were removed by
evaporation. The crude product was purified by flash column chromatography to obtain 2ꢀ(octꢀ1ꢀ
1
ynꢀ3ꢀyloxy)ethyl methanesulfonate (1c) (2.23 g, 8.97 mmol, 90%) as a colorless oil. H NMR
(392 MHz, CDCl3, δ): 0.90 (t, J = 6.7 Hz, 3H), 1.25–1.38 (m, 4H), 1.45 (quint, J = 7.5 Hz, 2H),
1.65–1.80 (m, 2H), 2.46 (d, J = 1.8 Hz, 1H), 3.06 (s, 3H), 3.68 (ddd, J = 3.5, 5.9, 11.3 Hz, 1H),
4.00 (ddd, J = 3.4, 5.4, 11.5 Hz, 1H), 4.09 (td, J = 1.8, 6.7 Hz, 1H), 4.36–4.45 (m, 2H). 13C NMR
(99 MHz, CDCl3, δ): 13.8 (CH3), 22.3 (CH2), 24.6 (CH2), 31.2 (CH2), 35.2 (CH2), 37.5 (CH3),
66.2 (CH2), 69.2 (CH2), 69.8 (CH), 74.3 (C), 82.0 (CH). HRMS (ESIꢀOrbitrap) (m/z): [M+H]+
calcd for C11H21O4SNa, 249.1155; found, 249.1154.
2ꢀ[(6ꢀMethylꢀ1ꢀphenylheptꢀ4ꢀynꢀ3ꢀyl)oxy]ethyl methanesulfonate (1r). 1r was prepared as a
colorless oil from the corresponding primary alcohol according to the procedure described
1
above. H NMR (392 MHz, CDCl3, δ): 1.18 (d, J = 7.2 Hz, 6H), 1.90–2.08 (m, 2H), 2.55–2.66
ACS Paragon Plus Environment
27

The Journal of Organic Chemistry
Page 28 of 42
1
2
3
4
5
6
7
8
9
(m, 1H), 2.77 (t, J = 7.9 Hz, 2H), 3.06 (s, 3H), 3.60–3.67 (m, 1H), 3.97 (ddd, J = 3.6, 5.2, 11.5
Hz, 1H), 4.05 (dt, J = 1.8, 6.5 Hz, 1H), 4.36–4.45 (m, 2H), 7.18–7.21 (m, 3H), 7.26–7.31 (m,
2H). 13C NMR (99 MHz, CDCl3, δ): 20.3 (CH), 22.8 (CH3), 31.2 (CH2), 37.2 (CH2), 37.4 (CH3),
65.9 (CH2), 69.20 (CH), 69.24 (CH2), 77.0 (C), 92.8 (C), 125.7 (CH), 128.2 (CH), 128.3 (CH),
141.1 (C). HRMS (ESIꢀOrbitrap) (m/z): [M+Na]+ calcd for C17H24O4SNa, 347.1288; found,
347.1287.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure for the Copper(I)-Catalyzed Intramolecular Alkylboration of 1a.
Copper chloride (2.5 mg, 0.025 mmol) and bis(pinacolato)diboron (2) (152.4 mg, 0.60 mmol),
tri(oꢀtolyl)phosphine (7.6 mg, 0.025 mmol) were placed in an ovenꢀdried reaction vial. After the
vial was sealed with a screw cap containing a teflonꢀcoated rubber septum, the vial was
connected to a vacuum/nitrogen manifold through a needle. It was evacuated and then backfilled
with nitrogen. This cycle was repeated three times. Dry THF (0.4 mL) and K(OꢀtꢀBu)/THF (1.0
M, 0.6 mL, 0.6 mmol) were added in the vial through the rubber septum using a syringe. After
stirring for 30 min, 1a (117.0 mg, 0.50 mmol) was added to the mixture at 30°C. After the
reaction was complete, the reaction mixture was passed through a short silica gel (Φ: 10 mm,
height of the silicaꢀgel column: ca. 30 mm) eluting with Et2O. The crude material was purified
by flash column chromatography (SiO2, Et2O /hexane, typically 0:100–14:86) to give the
corresponding borylation product (E)ꢀ3a as a colorless oil.
(E)ꢀ4,4,5,5ꢀTetramethylꢀ2ꢀ{[2ꢀpentyldihydrofuranꢀ3(2H)ꢀylidene]methyl}ꢀ1,3,2ꢀdioxaborolane
[(E)ꢀ3a]. The reaction was conducted with 117.0 mg (0.50 mmol) of 1a. The product (E)ꢀ3a was
1
obtained as a colorless oil in 71% yield (100.3 mg) with E/Z = >95:5. H NMR (392 MHz,
CDCl3, δ): 0.88 (t, J = 6.9 Hz, 3H), 1.22–1.34 (m, 16H), 1.37–1.55 (m, 3H), 1.60–1.69 (m, 1H),
2.67–2.77 (m, 1H), 2.87–2.94 (m, 1H), 3.75 (td, J = 6.8, 8.4 Hz, 1H), 4.03 (td, J = 3.9, 8.3 Hz,
ACS Paragon Plus Environment
28

Page 29 of 42
The Journal of Organic Chemistry
1
2
13
3
4
1H), 4.20–4.22 (m, 1H), 5.19 (q, J = 2.1 Hz, 1H). C NMR (99 MHz, CDCl3, δ): 14.0 (CH3),
5
6
7
8
22.5 (CH2), 24.78 (CH3), 24.80 (CH3), 25.2 (CH2), 31.8 (CH2), 33.6 (CH2), 34.6 (CH2), 66.8
(CH2), 82.3 (CH), 82.8 (C), 106.6 (br, B–CH), 168.2 (C). HRMS (EIꢀTOF) (m/z): [M]+ calcd for
C16H2911BO3, 280.2210; found, 280.2223.
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
(E)ꢀ4,4,5,5ꢀTetramethylꢀ2ꢀ{[2ꢀphenethyldihydrofuranꢀ3(2H)ꢀylidene]methyl}ꢀ1,3,2ꢀ
dioxaborolane [(E)ꢀ3d]. The reaction was conducted with 132.7 mg (0.50 mmol) of 1d. The
product (E)ꢀ3d was obtained as a white solid (m.p. = 49–51 ℃) in 67% yield (105.1 mg) with
1
E/Z = >95:5. H NMR (392 MHz, CDCl3, δ): 1.27 (s, 12H), 1.79–1.88 (m, 1H), 1.93–2.02 (m,
1H), 2.67–2.83 (m, 3H), 2.88–2.96 (m, 1H), 3.79 (td, J = 7.1, 8.6 Hz, 1H), 4.07 (td, J = 4.3, 8.3
Hz, 1H), 4.24–4.26 (m, 1H), 5.21 (q, J = 2.2 Hz, 1H), 7.15–7.21 (m, 3H), 7.25–7.29 (m, 2H). 13C
NMR (99 MHz, CDCl3, δ): 24.79 (CH3), 24.82 (CH3), 31.6 (CH2), 33.7 (CH2), 36.2 (CH2), 66.9
(CH2), 81.4 (CH), 82.8 (C), 106.9 (br, B–CH), 125.6 (CH), 128.2 (CH), 128.4 (CH), 142.0 (C),
167.8 (C). HRMS (EIꢀTOF) (m/z): [M]+ calcd for C19H2711BO3, 314.2053; found, 314.2057.
(E)ꢀtertꢀButyldiphenyl{4ꢀ{3ꢀ[(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)methylene]ꢀ
tetrahydrofuranꢀ2ꢀyl}butoxy}silane [(E)ꢀ3e]. The reaction was conducted with 229.6 mg (0.50
mmol) of 1e. The product (E)ꢀ3e was obtained as a colorless oil in 60% yield (151.8 mg) with
1
E/Z = >95:5. H NMR (392 MHz, CDCl3, δ): 1.04 (s, 9H), 1.27 (s, 12H), 1.43–1.66 (m, 6H),
2.65–2.75 (m, 1H), 2.86–2.94 (m, 1H), 3.65 (t, J = 6.3 Hz, 2H), 3.74 (td, J = 6.7, 8.8 Hz, 1H),
4.01 (td, J = 4.0, 8.3 Hz, 1H), 4.19–4.20 (m, 1H), 5.17 (q, J = 2.1 Hz, 1H), 7.35–7.44 (m, 6H),
7.65–7.67 (m, 4H). 13C NMR (99 MHz, CDCl3, δ): 19.1 (CH2), 21.7 (C), 24.82 (CH3), 24.85
(CH3), 26.8 (CH3), 32.5 (CH2), 33.7 (CH2), 34.3 (CH2), 63.8 (CH2) 66.9 (CH2), 82.2 (CH), 82.8
(C), 106.8 (br, B–CH), 127.5 (CH), 129.4 (CH), 134.0 (C), 135.5 (CH), 168.1 (C). HRMS (ESIꢀ
Orbitrap) (m/z): [M+Na]+ calcd for C31H4511BO4SiNa, 543.3072; found, 543.3078.
ACS Paragon Plus Environment
29