Gold-Catalyzed Stereoselective Synthesis of Bicyclic Lactams and Ketones from N-Tosylynamidomethyl-Tethered Cyclohexenes

Article abstract of DOI:10.1021/acs.joc.6b02479

Six-membered ring 3-enynamides underwent cycloisomerization in the presence of a catalytic amount of a gold(I) complex delivering mainly 4-azatricyclo[4.3.1.0^3,10]dec-2-ene derivatives and dibenz[cd,f]indole derivatives as the minor products under mild reaction conditions. Upon exposure to air, most aryl-substituted azatricycles led to bicyclic γ-lactams, while the ortho-tolyl- or alkyl-substituted azatricycles provided the corresponding bicyclic γ-lactams after oxidation with osmium tetraoxide and N-methylmorpholine-N-oxide. Under acidic conditions, the ortho-tolyl- or alkyl-substituted azatricycles were further transformed into 5-N-tosylaminomethyl-tethered bicyclo[4.2.0]octan-7-ones. The gold(I)-catalyzed tandem cycloisomerization/oxidation reaction also provided a new route for the synthesis of bridged bicyclic δ-lactams from six-membered ring 4-enynamides. The mild reaction conditions allowed the synthesis of a range of bicyclic γ- and δ-lactams and N-tosylaminomethyl-tethered bicyclo[4.2.0]octan-7-ones with high diastereoselectivities.

Full text of DOI:10.1021/acs.joc.6b02479

Subscriber access provided by Olson Library | Northern Michigan University
Article
Gold-Catalyzed Stereoselective Synthesis of Bicyclic Lactams
and Ketones from N-Tosylynamidomethyl-Tethered Cyclohexenes
Chang-Zhi Zhong, Po-Ting Tung, Tsung-Han Chao, and Ming-Chang P. Yeh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02479 • Publication Date (Web): 05 Dec 2016
Downloaded from http://pubs.acs.org on December 6, 2016
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 100
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Gold-Catalyzed Stereoselective Synthesis of Bicyclic Lactams and Ketones from
N-Tosylynamidomethyl-Tethered Cyclohexenes
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
*
Chang-Zhi Zhong, Po-Ting Tung, Tsung-Han Chao, and Ming-Chang P. Yeh
Department of Chemistry, National Taiwan Normal University, 88 Ding-Jou Road,
Section 4, Taipei 11677, Taiwan, Republic of China
*
E-mail: cheyeh@ntnu.edu.tw
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
Abstract: Six-membered ring 3-enynamides underwent cycloisomerization in the
presence of a catalytic amount of a gold(I) complex delivering mainly
3,10
4
-azatricyclo[4.3.1.0 ]dec-2-ene derivatives and dibenz[cd,f]indole derivatives as
the minor products under mild reaction conditions. Upon exposure to air, most
aryl-substituted azatricycles led to bicyclic -lactams, while the ortho-tolyl- or
alkyl-substituted azatricycles provided the corresponding bicyclic -lactams after
oxidation with osmium tetraoxide and N-methylmorpholine-N-oxide. Under acidic
conditions, the ortho-tolyl- or alkyl-substituted azatricycles were further transformed
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 100
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
into
5-N-tosylaminomethyl-tethered
bicyclo[4.2.0]octan-7-ones.
The
gold(I)-catalyzed tandem cycloisomerization/oxidation reaction also provided a new
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
route for the synthesis of bridged bicyclic -lactams from six-membered ring
4
-enynamides. The mild reaction conditions allowed the synthesis of a range of
bicyclic - and -lactams and N-tosylaminomethyl-tethered
bicyclo[4.2.0]octan-7-ones with high diastereoselectivities.
INTRODUCTION
Ynamides are versatile N-containing building blocks for the synthesis of
1
nitrogen-containing heterocycles and nitrogen-substituted carbocycles. Recently,
transition-metal-catalyzed enynamide cyclization reactions have been studied
extensively for the synthesis
a
variety of azabicycles including the
2
palladium-catalyzed synthesis of indole derivatives from halogenated enynamides,
the cobalt-catalyzed synthesis of azabicyclo[3.3.0]octenones via the intramolecular
3
Pauson-Khand reaction of 3-enynamides, the platinum-catalyzed cycloisomerization
4
of enynamides in the synthesis of azabicyclo[4.2.0]octenes, the gold-catalyzed
5
synthesis of the azabicyclo[3.1.0]heptenes from acyclic 3-enynamides, the
rhodium-catalyzed [4+2] cycloaddition of 1,3-dienes with ynamides in the synthesis
6
of tetrahydroindoles, and the gold-catalyzed oxidation of N-arylynamides in the
7
synthesis of oxindoles. In our recent study, we described that six-membered ring
2
ACS Paragon Plus Environment

Page 3 of 100
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2
-enynamides underwent a carbochlorination reaction with FeCl in dry air providing
2
chlorinated bicyclic-lactams in a high stereoselective fashion and in good yields
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
8
(
Scheme 1, eq 1). However, treatment of six-membered ring 3-enynamides with
FeCl under the same reaction conditions failed to give any bicyclic lactams. Inspired
2
by the work of Cossy on the gold-catalyzed cycloisomerization of an acyclic
3
-enynamide to the 2-azabicyclo[3.2.0]heptene intermediate, which after hydration,
5
a
affording an aminoethyl-tethered cyclobutanone, we envisage that a cyclic
3-enynamide may undergo the similar cycloisomerization with a gold(I) cationic
complex forming a strained azatricycles. Herein, we report the formation of
3
,10
4
-azatricyclo[4.3.1.0 ]dec-2-enes via Au(I)/Ag(I)-catalyzed cycloisomerization of
six-membered ring 3-enynamides (Scheme 1, eq 2). Most aryl-substituted azatricyclic
compounds oxidized spontaneously in air generating fused bicyclic -lactams, while
the o-tolyl- and alkyl-substituted azatricycles transformed into the corresponding
bicyclic -lactams upon treatment with OsO and N-methylmorpholine-N-oxide in
4
acetone/water. Moreover, bridged bicyclic -lactams were formed via a
Au(I)/Ag(I)-catalyzed cycloisomerization/oxidation sequence from six-membered
ring 4-enynamides (Scheme 1, eq 3).
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 100
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 1. FeCl - and Au(I)/Ag(I)-Promoted Cyclization Reactions of
2
Six-Membered Ring Enynamides
8
Previous work:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(1)
This work:
(2)
(3)
RESULTS AND DISCUSSION
The model substrate 1a was prepared starting from addition of n-BuLi to
cyclohexene followed by quenching the resulting cyclohexenyl anion with
paraformaldehyde to give 3-hydroxymethylcyclohexene. The hydroxyl group was
9
replaced by NHTsBoc under the Mitsunobu reaction conditions, followed by removal
1
0
of the Boc group to give 3-tosylaminomethylcyclohexene. Finally, a copper-assisted
11
amidation
of phenylbromoacetylene with 3-N-tosylaminomethylcyclohexene
furnished 1a in a 33% overall yield from cyclohexene (see Experimental Section for
details). Results of screening of various acids for the cycloisomerization of 1a are
shown in Table 1. First, performing the reaction of 1a with FeCl , following our
2
4
ACS Paragon Plus Environment

Page 5 of 100
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
o
previous reaction conditions for the cyclization of cyclic 2-enynamide (40 C, THF,
8
dry air), led to a complex mixture (Table 1, entry 1). Next, we turned our attention to
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
the Au(I)/Ag(I) catalyst. Reaction of 1a with the 10 mol % of [AuCl(PPh )]/AgPF
3
6
catalyst in DCM (0.1 M) at room temperature for 1.5 h led to bicyclic -lactam 2a in
3
1
5% yield together with dibenz[cd,f]indole derivative 3a in 15% isolated yield (Table
, entry 2). The assignment of all cis relative stereochemistry of the protons at ring
junctures was further confirmed by X-ray diffraction analysis of both 2a (Figure 1)
1
2
and 3a. It has been described previously that a Au(I)/Ag(I) complex was used for the
1
3a
synthesis of bicyclic -lactams from acyclic N-allylynamides. However, in this
transformation, pyridine N-oxide (2 molar equiv) was used as an oxygen delivery
reagent to oxidize the alkynyl carbon adjacent to the nitrogen atom of the
13b
ynamides. Our current method for the construction of the bicyclic -lactam 2a from
the cyclic 3-enynamide 1a required only a Au(I)/Ag(I) catalyst in DCM at room
temperature and the oxygen in air. With the goal to optimize the yield of 2a, the
effects of different silver salts with [AuCl(PPh )] were examined (Table 1, entrie 3–4).
3
In this series, the better yield was obtained in 15 min with 10 mol % of
[
AuCl(PPh )]/AgSbF leading to 2a and 3a in 52 and 17% isolated yield, respectively
3 6
(Table 1, entry 4). Next, several Au(I) complexes with various ligands, in combination
with AgSbF , were screened. (Table 2, entries 5–8). The use of 10 mol % of
6
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 100
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
[
AuCl(IPr)]/AgSbF6
([AuCl(IPr)]
=
chloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]gold(I)) gave the similar
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
result as that of [AuCl(PPh )]/AgSbF as 2a (50 %) and 3a (20%) were isolated in
3
6
minutes and in comparable yields (Table 1, entry 7). Increasing the concentration of
AuCl(PPh )]/AgSbF from 0.1 to 0.3 M in DCM did not significantly affect the
[
3
6
reaction time (14 min) and yields (2a, 50%, 3a, 13%) (Table 1, entry 9). Next, the
reaction was heated at reflux in DCM, while the reaction time was slightly decreased
to 10 min, the yield of 2a and 2b was diminished to 44 and 12%, respectively (Table 1,
entry 10). The solvent effect on the cycloisomerization was also investigated. The use
of toluene as solvent afforded 2a (47%) and 3a (17%) in comparable yields, albeit
requiring a longer reaction time (1 h, Table 1, entry 11). Other solvents, such as
dichloroethane (DCE), THF, and acetonitrile (ACN) were totally ineffective (Table 1,
entries 12–14). It has been reported that platinum dichloride was capable of
transforming acyclic enynamides in toluene into cyclobutenyl azabicyclic
1
4
compounds. However, the starting substrate 1a was recovered quantitatively when
o
1
a was treated with PtCl (10 mol%) in toluene at 90 C for 24 h (Table 1, entry 15).
2
Moreover, performing the reaction with In(NTf2)3 or HNTf2 afforded the
dibenz[cd,f]indole derivative 3a as the only cycloisomerization product in 17 and 15%
yield, respectively (Table 1, entries 16 and 17). Therefore, we identified 10 mol% of
6
ACS Paragon Plus Environment

Page 7 of 100
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
[
AuCl(PPh )] and 10 mol% of AgSbF in DCM (0.1 M concentration) under nitrogen
3
6
at ambient temperatures as the optimum reaction conditions for the formation of 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
bicyclic -lactam 2a and the dibenz[cd,f]indole derivative 3a (Table 1, entry 4).
Figure 1. ORTEP plot of the crystal structure of 2a (50% thermal ellipsoids).
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 100
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
Table 1. Optimization of the Cycloisomerization Reaction Conditions
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
b
yield (%)
temp
( C)
28
28
o
entry Catalyst
solvent
THF
DCM
time
3 min
1.5 h
2a
−
35
3a
−
15
1
2
FeCl2
[AuCl(PPh )]/AgPF
3
6
3
4
5
6
7
8
9
1
1
[AuCl(PPh )]/AgBF
DCM
DCM
DCM
DCM
DCM
28
28
28
28
28
28
28
2 h
38
52
34
29
50
31
50
44
47
N.R.
−
15
17
12
14
20
15
13
12
17
N.R.
−
3
4
[AuCl(PPh )]/AgSbF
15 min
8 min
5 min
18 min
10 min
14 min
3
6
[AuCl(PCy )]/AgSbF
3
6
[AuCl(P(C F ) )]/AgSbF
6
6
5 3
c
[AuCl(Ipr)] /AgSbF
6
d
[AuCl(JhonPhos)] /AgSbF6 DCM
e
[AuCl(PPh )]/AgSbF
DCM
DCM
Toluene
DCE
3
6
6
6
6
6
6
0
1
[AuCl(PPh )]/AgSbF
reflux 10 min
3
[AuCl(PPh )]/AgSbF
28
28
28
28
90
28
28
1 h
3
12
[AuCl(PPh )]/AgSbF
24 h
24 h
24 h
24 h
5 min
1.2 h
3
1
3
[AuCl(PPh )]/AgSbF
THF
3
14
[AuCl(PPh )]/AgSbF
ACN
−
−
3
1
5
PtCl2
Toluene
DCM
DCM
N.R.
−
N.R.
17
15
f
16
In(NTf2)3
1
7
HNTf2
−
a
Reaction conditions: all reactions were carried out using 1a (0.3 mmol) and the catalyst (10
b
mol %) in the indicated solvent (3 mL). Isolated yields obtained from column
c
chromatography
over
silica
gel.
[AuCl(Ipr)]
=
=
d
chloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]gold(I).
[AuCl(JhonPhos)]
e
chloro[(1,1′-biphenyl-2-yl)di-tert-butylphosphine]gold(I). The concentration of 1a was 0.03
f
M in DCM. Tf = trifluoromethanesulfonyl.
Suggested reaction paths for the formation of 2a and 3a from 1a are shown in
Scheme 2. Initially, reaction of [AuCl(PPh )] with AgSbF generated the gold(I)
3
6
cation species. Coordination of the gold(I) cation to the alkyne formed a
gold-activated alkyne complex, which was then attacked by the pendant olefin to
8
ACS Paragon Plus Environment

Page 9 of 100
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
produce the cationic vinylgold species 4. Intermediate 4 led to the cyclopropylgold
carbene 5 (path a). Ring expansion of 5 gave a cationic azatricyclic skeleton. 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
3
,10
4
-azatricyclo[4.3.1.0 ]dec-2-ene intermediate 8 was formed by attack of
-
hexafluoroantimonate anion (SbF ) at the gold center of the cationic azatricycle and
6
regeneration of the gold(I) cation into the catalytic cycle. This observation was
1
5
consistent with the formation of the carbotricyclic analog 7 via platinum- and
1
6
gold- catalyzed cycloisomerization of carbocyclic enynes of type 6 (Figure 2).
Carbotricycles 7 containing a strained cyclobutene moiety were stable under air at
room temperature. Although the gold(I)-catalyzed cycloisomerization of 1a was
conducted under nitrogen, subsequent exposure of the crude mixture to air was
sufficient to promote the oxidation of the strained cyclobutene moiety of azatricycle 8
and delivered the bicyclic -lactam derivative 2a. Thus, the current approach allowed
a direct access to the bicyclic -lactam 2a from a simple cyclic 3-enynamide 1a
without an additional oxidant. However, the cationic intermediate 4 may undergo
Freidel-Crafts alkylation of the pendant phenyl group by the carbonium ion to provide
a tetracyclic carbocation 9 (path b). Rearomatization followed by protodeauration led
to the dibenz[cd,f]indole derivative 3a and regenerated the gold(I) cation.
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 100
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 2. Proposed Mechanism for the Gold-Catalyzed Cycloisomerization of 1a
to 2a and 3a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 2. Structures of 6 and 7.
The cycloisomerization of various cyclic 3-enynamides 1 was then evaluated
with the optimized reaction conditions (10 mol % [AuCl(PPh )]/AgSbF , DCM, rt).
3
6
As illustrated in Table 2, substrates 1b, 1e, and 1f, with a methyl or phenyl group at
the para-position of the phenyl ring, were found to react well with the Au(I)/Ag(I)
12
catalyst in 7–9 min producing bicyclic -lactams 2b, 2e, and 2f in yields ranging
from 42 to 54% (Table 2, entries 2 and 4–5) and the minor products
1
2
dibenz[cd,f]indoles 3b, 3e, and 3f in yields ranging from 18 to 26%. However, a
10
ACS Paragon Plus Environment

Page 11 of 100
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
methyl substituent at the meta-position of the phenyl moiety, 1c, gave the
corresponding bicyclic -lactams 2c in 45% yield and a trace amount of the
Friedel-Craft cyclization product (Table 2, entry 3). While the electron-donating
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
2
meta-methoxyphenyl-substituted enynamide, 1h, was well tolerated forming 2h
1
2
(50%) and 3h
(23%) in 10 min (Table 2, entry 7), the
para-methoxyphenyl-substituted ynamide 1g required a longer reaction time (300 min)
and gave low yields of 2g (17%) and 3g (28%) (Table 2, entry 6). Substrtaes 1i–k,
bearing a halogen atom at the para-position of the phenyl ring, were well tolerated
and produced the corresponding bicyclic -lactams 2i–k (39–51%) and the minor
1
2
products dibenz[cd,f]indoles 3i –k (10–14%) in comparable yields in 6-7 min (Table
, entries 8-10). Substrate 1l, with an electron-deficient ester group at the
para-position of the phenyl ring, also generated the desired cyclized products (2l,
1%; 3l, 7%) in 10 min (Table 2, entry 11). Only bicyclic -lactams 2m (50%) and 2n
43%) were isolated when subjecting electron-deficient nitroarene enynamides 1m
2
4
(
and 1n, to the optimized reaction conditions. No trace of Freidel-Craft cyclization
products were detected in both cases (Table 2, entries 12 and 13).
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 100
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 2. Gold-Catalyzed Cycloisomerzation of 1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Time
Substrate (min)
a
entry Ar
Product (%)
1
2
12
12
1
2
3
4
5
6
7
8
9
R = H, R = H
1a
1b
1c
1e
1f
15
7
2a (52%) 3a (17%)
1
2
R = Me, R = H
2b (42%)
2c (45%)
2e (44%)
3b (21%)
trace
1
2
R = H, R = Me
44
7
1
2
R = Me, R = Me
3e (26%)
1
2
12
12
R = Ph, R = H
9
2f (54%)
3f (18%)
1
2
R = OMe, R = H
1g
1h
1i
300
10
6
2g (17%)
3g (28%)
1
2
12
12
R = H, R = OMe
2h (50%) 3h (23%)
1
2
12
R = F, R = H
2i (51%)
2j (41%)
2k (39%)
2l (41%)
2m (50%)
2n (43%)
3i (14%)
3j (10%)
3k (12%)
3l (7%)
-
1
2
R = Cl, R = H
1j
7
1
2
1
0
1
2
R = Br, R = H
1k
1l
7
1
2
1
1
R = CO Me, R = H
10
9
2
1
2
R = NO , R = H
1m
1n
2
1
2
13
R = H, R = NO
19
-
2
a
Isolated yields obtained from column chromatography over silica gel.
The effect of a thienyl group at the alkyne terminus, 1o, was explored in this
cycloisomerization process. Compound 1o produced the Freidel-Craft cyclization
1
2
product 3o in 10 min in 22% yield when treated with the Au(I)/Ag(I) catalyst under
the optimized reaction conditions and none of the desired bicyclic -lactam was
obtained (Scheme 3).
12
ACS Paragon Plus Environment

Page 13 of 100
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Scheme 3. Gold-Catalyzed Cycloisomerization of 1o
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
However, Subjection of the 2-methylphenyl-substituted enynamide 1d, or
aliphatic enynamides 1p–s to the optimum reaction conditions did not provide the
corresponding bicyclic -lactams after aqueous work-up and column chromatography
over silica gel. Instead, the reactions gave air- and moisture-stable
3
,10
4-azatricyclo[4.3.1.0 ]dec-2-enes 8a–e in 44 to 50% isolated yields (Scheme 4). The
1
2
relative stereochemistry of three protons at the ring junctures of 8a was assigned as
all-cis and was further confirmed by X-ray diffraction analysis (Figure 3). It must be
mentioned that the terminal alkyne, 1t, gave a mixture of unidentified products when
subjected to the standard reaction conditions. Moreover, azatricyclic N-tosylenamines
8
a–e could further be oxidized quantitatively to bicyclic -lactams 2d and 2p–s after
treatment with OsO and N-methylmorpholine-N-oxide (NMO) in acetone/H O
4
2
1
7
without the use of iodobenzene diacetate (PhI(OAc) ) (Scheme 4). Furthermore,
2
azatricyclic N-tosylenamines 8a–e were treated with 1.0 M HCl(aq) in EtOAc for 3 h to
afford 5-N-tosylaminomethyl-tethered bicyclo[4.2.0]octan-7-ones 10a–e in high
4
a
yields (93-99%) and with high stereoselectivity in each case. The all cis relative
chemistry of four adjoining stereogenic centers was determined by their NMR
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 100
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
spectropic measurements and was compared to those of the related bicyclic ketone 14
(vide infra), which was confirmed by X-ray analysis. In general,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
bicyclo[4.2.0]octan-7-ones were available by the [2+2] cycloaddition reaction of
dichloroketene with cyclohexene derivatives followed by reductive dechlorination
1
8
with
Zn
and
acetic
acid.
Thus,
the
present
gold(I)-catalyzed
cycloisomerization/hydration sequence provided an alternative to 5,8-disubstituted
bicyclo[4.2.0]octan-7-ones in a diastereoselective fashion from simple six-membered
ring 3-enynamides under mild reaction conditions.
Figure 3. ORTEP plot of the crystal structure of 8a (50% thermal ellipsoids).
14
ACS Paragon Plus Environment

Page 15 of 100
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Scheme 4. Gold-Catalyzed Cycloisomerization of 1d, and 1p–t Followed by
Oxidation or Hydration
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
The gold-catalyzed cycloisomerization/oxidation strategy can also be applied in
preparation
of
bridged
bicyclic
-lactams.
The
starting
substrate
C-4-N-tosylynamidomethyl-tethered cyclohexene 11a was prepared in three steps
from cyclohex-3-ene-1-carbaldehyde (see Experimental Section for details). However,
treatment of 11a with 10 mol % [AuCl(PPh )]/AgSbF failed to provide any cyclized
3
6
product. Next, various combinations of Au(I)/Ag(I) catalysts, solvents, and reaction
temperatures were screened, the best result was obtained with 10 mol % of
o
[
AuCl(PPh )]/AgBF in DCM at 40 C. Thus, treatment of 11a with 10 mol % of
3
4
o
[
AuCl(PPh )]/AgBF in DCM at 40
C
for 10 min furnished the
3
4
3,8
12
4
-azatricyclo[4.2.2.0 ]dec-2-ene derivative 12a in 78% isolated yield. The
azatricyclic compound 12a was stable at room temperature and could further be
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 100
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
oxidized with OsO and NMO in acetone/H O to afford the bridged bicyclic -lactam
4
2
12
1
3a in 60% yield over two steps. Thus, the current approach provided an alternative
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
to the synthesis of the 3-azabicyclo[3.3.1]nonan-2-one skeleton which is known to
1
9
possess pharmacological properties. The relationship of three methine protons was
assigned as all cis for 13a and was further confirmed by X-ray diffraction analysis
(Figure 4). Results of the gold(I)-catalyzed cycloisomerization/oxidation sequence of
C-4-N-tosylynamidomethyl-tethered cyclohexenes 11 to provide directly bridged
bicyclic -lactams 13 are shown in Scheme 5. Substrates with a methyl, methoxy,
carbmethoxy, or halogen substituent on the phenyl ring were well tolerated and
1
2
afforded the corresponding bridged bicyclic -lactams 13a–j in 43–70% isolated
yields over two steps. Substrates 11k and 11l, with a strong electron-withdrawing
para-CF and -NO groups, respectively, gave low yields of the desired products (13k,
3
2
3
0%, 13l, 20%). The two-step sequence also performed well with the substrate
containing a thienyl fragment. The thienyl-substituted cyclic 4-enynamide 11m
furnished 13m in 51% isolated yield. The cycloisomerization/oxidation sequence
leading to the bridged bicyclic -lactams was not restricted to aromatic enynamides,
the aliphatic enynamides, 11n–11p, were also effective generating the desired bridged
1
2
bicyclic -lactams 13n–13p in 31–55% yield. Unfortunately, enynamide 11q,
bearing a terminal alkyne, decomposed when treated with 10 mol % of
16
ACS Paragon Plus Environment

Page 17 of 100
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
[
AuCl(PPh )]/AgBF in DCM. Moreover, gold-catalyzed cycloisomerization of the
3
4
ethyl-substituted enynamide 11n followed by hydration of the resultant azatricyclic
intermediate 12n with HCl(aq) in EtOAc furnished the
-N-tosylaminomethyl-tethered bicyclo[4.2.0]octan-7-one 14 in 60% yield over two
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
M
1
2
4
steps (Scheme 6). Compound 14 was isolated as a single stereoisomer. The relative
stereochemistry of four stereocenters of bicyclic ketone 14 was determined as all cis
and was further confirmed by X-ray diffraction analysis (Figure 5).
Scheme 5. Gold-Catalyzed Cycloisomerization/Oxidation of Six-Membered Ring
a
4
-Enynamides 11 to Bridged Bicyclic -Lactams 13
a
o
Reagents and conditions: (a) 10 mol% [AuCl(PPh )]/AgBF , CH Cl , 40 C, 4-25 min; (b)
3
4
2
2
b
OsO /NMO, (CH ) CO/H O, rt, 24 h. All yields were reported over two steps.
4
3 2
2
Figure 4. ORTEP plot of the crystal structure of 13a (50% thermal ellipsoids).
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 100
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 6. Cycloisomerization/Hydration of 11n to 14
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 5. ORTEP plot of the crystal structure of 14 (50% thermal ellipsoids).
CONCLUSION
In conclusion, we have shown
cycloisomerization/oxidation of cyclic enynamides generating fused and bridged
bicyclic -lactams in stereoselective manner. In gold-catalyzed
cycloisomerization/hydration sequence, N-tosylaminomethyl-tethered
a
simple and mild gold-catalyzed
a
a
bicyclo[4.2.0]octan-7-ones were obtained in good yields over two steps and with high
stereoselectivity. The substrate scope was proved to be general for both aryl- and
alkyl-substituted cyclic enynamides, providing a series of bicyclic - and -lactams
and N-tosylaminomethyl-tethered bicyclo[4.2.0]octanones, which may be of interest
in synthetic organic chemistry.
18
ACS Paragon Plus Environment

Page 19 of 100
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
EXPERIMENTAL SECTION
General Considerations. All reactions were conducted under nitrogen atmosphere in
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
dried glassware with dry solvents. The addition of anhydrous solvents or liquid
(
reagents) was performed with an oven-dried syringe or cannula through a septum.
Solids were added under gentle stream of nitrogen. Solvents were pre-dried by
molecular sieves and then by passing through activate Al O columns. All
2
3
commercially available reagents were used as received without further purification.
Melting points were measured in open glass capillaries with an electronic apparatus
and were uncorrected. Flash column chromatography was carried out using silica gel
P60, 40−63 m (230−400 mesh). Infra-red spectra were recorded as a solid or a thin
1
film on an infra-red spectroscopy. H nuclear magnetic resonance (NMR) spectra
were recorded with a 400 or 500 MHz spectrometer. Chemical shifts () are quoted in
parts per million (ppm) relative to Me Si (0.00 ppm) using Me Si or the residual
4
4
solvent signal (CHCl : 7.26 ppm) as internal standard. Abbreviations used in the
3
description of coupling patterns are: s (singlet), d (doublet), t (triplet), q (quartet), m
1
3
(multiplet). Coupling constants (J) are given in Herz (Hz). Proton-decoupled
C
NMR spectra were recorded with a 100 or 125 MHz spectrometer. Chemical shifts ()
are quoted in parts per million (ppm) downfield from tetramethylsilane, using the
residual solvent signal (CDCl :77.0 ppm) as internal standard. Mass spectra were
3
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 100
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
determined by using a spectrometer at a 70-eV ionization potential. Peaks are listed
according to their mass/charge (m/e) value with percent relative abundance.
High-resolution mass spectra were obtained with a double-focusing mass
spectrometer.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Representative Experimental Procedure for the Synthesis of Aryl-Substituted
3-N-Tosylynamidomethyl-Tethered Cyclohexene 1a. Tetramethylethylenediamine
(TMEDA, 15.0 mL) was slowly added to a stirred solution of 1.6 M n-butyllithium
o
(67.0 mL) in hexanes at 0 C under nitrogen. Cyclohexene (82.0 mL, 800 mmol) was
then added, and the resulting reaction mixture was stirred for 16 h at room
temperature. Paraformaldehyde (3.9901 g, 166.25 mmol) was added over a period of
o
2
h while the reaction temperature was kept under 30 C. The reaction mixture was
stirred for 3 h at room temperature followed by addition of water (100.0 mL) and
HCl(aq) (10.0 mL ). The water layer was extracted with ether (200.0 mL × 3) and
NaCl(aq) (200.0 mL × 3) and dried over anhydrous MgSO , evaporated under reduced
4
pressure to give the crude product. The crude mixtures (7.1142 g), was further
o
purified by vacuum distillation [51–54
C
(1.3 mmHg)] to give
2
-cyclohexenemethanol as an oil (4.6001 g, 41.010 mmol, 41%). To a flame-dried
flask were added triphenylphosphine (5.3242 g, 20.299 mmol), diisopropyl
azodicarboxylate (DIAD, 4.0 mL, 20.3 mmol), TsNH(Boc) (4.6004 g, 16.955 mmol),
20
ACS Paragon Plus Environment

Page 21 of 100
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
o
and THF (85.0 mL) at 0 C. After 0.5 h, a solution of 2-cyclohexenemethanol (2.0522
o
g, 18.295 mmol) in THF (10.0 mL) was added to the reaction mixture at 0 C. 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
reaction was allowed to warm to room temperature and stirred for an additional 0.5 h.
The crude mixture was purified via flash column chromatography over silica gel
(EtOAc/hexanes
=
1:20)
to
give
tert-butyl
(cyclohex-2-en-1-ylmethyl)-(tosyl)carbamate as a white solid (5.5771 g, 15.259 mmol,
90%). To a solution of tert-butyl (cyclohex-2-en-1-ylmethyl)(tosyl)carbamate (5.5771
g, 15.259 mmol) in CH Cl (153.0 mL) was added trifluoroacetic acid (TFA, 5.8 mL).
2
2
The reaction mixture was stirred for 4 h at room temperature, then added saturated
NaHCO3(aq) (keep the pH value of the aqueous layer above 10). The water layer was
extracted with CH Cl (100.0 mL × 3) and NaCl (100.0 mL × 3) and dried over
2
2
(aq)
anhydrous MgSO , evaporated under reduced pressure to give the crude product. The
4
crude mixture was purified via flash column chromatography over silica gel
(EtOAc/hexanes
=
1:10)
to
give
N-(cyclohex-2-en-1-ylmethyl)-4-methylbenzenesulfonamide as a white solid (4.0040
g, 15.087 mmol, 99%). To a dry and nitrogen-flushed 2-neck-flask, equipped with a
magnetic stirring bar and a septum, were charged with (bromoethynyl)benzene
(0.5975
g,
3.301
mmol),
toluene
(3.0
ml),
tert-butyl
(cyclohex-2-en-1-ylmethyl)(tosyl)carbamate (0.7961 g, 3.000 mmol), and K CO
2
3
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 100
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
0.8292 g, 6.000 mmol). The reaction mixture was stirred at room temperature for 5
min and then were added CuSO ·5H O (0.0754 g, 0.302 mmol), and
4
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
,10-phenanthroline (0.1081 g, 0.5999 mmol). The reaction was stirred at 70 C until
no trace of starting material can be detected on TLC. Upon cooling to room
temperature, the reaction mixture was filtered and concentrated. The crude mixture
was purified via flash column chromatography over silica gel (EtOAc/hexanes = 1:20)
to give N-(cyclohex-2-en-1-ylmethyl)-4-methyl-N-(phenylethynyl)benzenesulfon-
o
1
amide (1a) as a white solid (0.9871 g, 2.701 mmol, 90% ): mp 105‒106 C; H NMR
(400 MHz, CDCl ) δ 7.86‒7.81 (m, 2H), 7.38‒7.32 (m, 4H), 7.31‒7.25 (m, 3H), 5.83‒
3
5
2
1
1
2
.76 (m, 1H), 5.59‒5.53 (m, 1H), 3.35‒3.22 (m, 2H), 2.67‒2.56 (m, 1H), 2.45 (s, 3H),
.04‒1.97 (m, 2H), 1.87‒1.78 (m, 1H), 1.77‒1.67 (m, 1H), 1.58‒1.49 (m, 1H), 1.46‒
13
.36 (m, 1H); C NMR (100 MHz, CDCl ) δ 144.5, 134.5, 131.3, 129.7, 129.7, 128.2,
3
27.7, 127.7, 127.0, 122.9, 82.6, 70.6, 56.1, 34.1, 26.0, 25.2, 21.6. 20.3; IR (CH Cl )
2
2
-1
932, 2236, 1598, 1443, 1367, 1168, 754, 586 cm ; MS (ESI) m/e (%) 366.2
+
([M+H] , 100), 282.3 (70), 122.0 (30); HRMS (ESI) m/e calcd for C H NO S
2
2
24
2
+
[
M+H] 366.1528, found 366.1533.
N-(Cyclohex-2-en-1-ylmethyl)-4-methyl-N-(p-tolylethynyl)benzenesulfonamide (1b).
The crude mixture was purified by flash column chromatography over silica gel
(EtOAc/hexanes = 1:20) to give 1b as a white solid (0.8312 g, 2.190 mmol, 73%): mp
22
ACS Paragon Plus Environment

Page 23 of 100
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
o
1
1
03‒104 C; H NMR (400 MHz, CDCl ) δ 7.86‒7.81 (m, 2H), 7.37‒7.32 (m, 2H),
3
7
.27‒7.23 (m, 2H), 7.11‒7.04 (m, 2H), 5.82‒5.76 (m, 1H), 5.59‒5.53 (m, 1H), 3.29
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
(
dd, J = 12.5, 8.6 Hz, 1H), 3.24 (dd, J = 12.5, 6.6 Hz, 1H), 2.66‒2.56 (m, 1H), 2.45 (s,
3
1
1
H), 2.34 (s, 3H), 2.03‒1.97 (m, 2H), 1.86‒1.78 (m, 1H), 1.76‒1.67 (m, 1H), 1.60‒
1
3
.49 (m, 1H), 1.46‒1.36 (m, 1H); C NMR (100 MHz, CDCl ) δ 144.5, 137.9, 134.6,
3
31.4, 129.7, 129.0, 128.4, 127.7, 127.1, 119.7, 81.9, 70.6, 56.1, 34.1, 26.1, 25.2, 21.6,
-1
21.2, 20.4; IR (CH Cl ) 2922, 2236, 1362, 1170, 816, 583 cm ; MS (ESI) m/e (%)
2
2
+
+
388.2 (35), 380.2 ([M+H] , 100); HRMS (ESI) m/e calcd for C H NO S [M+H]
2
3
26
2
380.1684, found 380.1678.
N-(Cyclohex-2-en-1-ylmethyl)-4-methyl-N-(m-tolylethynyl)benzenesulfonamide (1c).
The crude mixture was purified by flash column chromatography over silica gel
(EtOAc/hexanes = 1:20) to give 1c as a white solid (0.8881 g, 2.340 mmol, 78%): mp
o
1
6
7
4‒65 C; H NMR (400 MHz, CDCl ) δ 7.86‒7.81 (m, 2H), 7.38‒7.32 (m, 2H),
3
.21‒7.14 (m, 3H), 7.12‒7.06 (m, 1H), 5.83‒5.76 (m, 1H), 5.59‒5.53 (m, 1H), 3.30
(dd, J = 12.6, 8.6 Hz, 1H), 3.24 (dd, J = 12.4, 6.6 Hz, 1H), 2.67‒2.57 (m, 1H), 2.45 (s,
3
H), 2.31 (s, 3H), 2.04‒1.97 (m, 2H), 1.87‒1.78 (m, 1H), 1.77‒1.67 (m, 1H), 1.61‒
1
3
1
.49 (m, 1H), 1.46‒1.36 (m, 1H); C NMR (100 MHz, CDCl ) δ 144.5, 137.9, 134.6,
3
131.9, 129.7, 128.6, 128.4, 128.1, 127.7, 122.7, 82.3, 70.8, 56.1, 34.1, 26.1, 25.2, 21.6,
-1
21.2, 20.4; IR (CH Cl ) 2925, 2234, 1598, 1365, 1167, 1090, 879, 753, 586 cm ; MS
2
2
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 100
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
(
ESI) m/e (%) 402.3 ([M+Na] , 100), 380.2 ([M+H] , 79); HRMS (ESI) m/e calcd for
+
C H NO S [M+H] 380.1684, found 380.1686.
23
26
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N-(Cyclohex-2-en-1-ylmethyl)-4-methyl-N-(o-tolylethynyl)benzenesulfonamide (1d).
The crude mixture was purified by flash column chromatography over silica gel
(
EtOAc/hexanes = 1:20) to give 1d as a colorless oil (0.7742 g, 2.040 mmol, 68%):
1
H NMR (400 MHz, CDCl ) δ 7.87‒7.81 (m, 2H), 7.36‒7.29 (m, 3H), 7.19‒7.15 (m,
3
2H), 7.15‒7.08 (m, 1H), 5.82‒5.77 (m, 1H), 5.59‒5.54 (m, 1H), 3.33 (dd, J =12.5, 8.7
Hz, 1H), 3.25 (dd, J = 12.5, 6.6 Hz, 1H), 2.69‒2.59 (m, 1H), 2.44 (s, 3H), 2.37 (s, 3H),
2.04‒1.97 (m, 2H), 1.88‒1.79 (m, 1H), 1.77‒1.67 (m, 1H), 1.60‒1.49 (m, 1H), 1.47‒
1
3
1
1
.37 (m, 1H); C NMR (100 MHz, CDCl ) δ 144.5, 139.6, 134.6, 131.3, 129.7 (2C),
3
29.3, 127.7 (2C), 125.4, 122.7, 86.3, 69.6, 56.1, 34.1, 26.0, 25.2, 21.6, 20.7, 20.3; IR
-1
(
CH Cl ) 2935, 2236, 1598, 1452, 1367, 1168, 1091, 944, 815 cm ; MS (ESI) m/e (%)
2
2
+
+
3
80.1 ([M+H] , 100); HRMS (ESI) m/e calcd for C H NO S [M+H] 380.1684,
23 26 2
found 380.1689.
N-(Cyclohex-2-en-1-ylmethyl)-N-((3,4-dimethylphenyl)ethynyl)-4-methylbenzenesul
fonamide (1e). The crude mixture was purified by flash column chromatography over
silica gel (EtOAc/hexanes = 1:20) to give 1e as a white solid (0.9563 g, 2.430 mmol,
o
1
81%): mp 103‒104 C; H NMR (400 MHz, CDCl ) δ 7.85‒7.80 (m, 2H), 7.35‒7.29
3
(m, 2H), 7.17‒7.07 (m, 2H), 7.05‒6.99 (m, 1H), 5.82‒5.73 (m, 1H), 5.61‒5.52 (m,
24
ACS Paragon Plus Environment

Page 25 of 100
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
2
1
1
1
H), 3.33‒3.19 (m, 2H), 2.68‒2.55 (m, 1H), 2.41 (s, 3H), 2.21 (s, 3H), 2.19 (s, 3H),
.02‒1.94 (m, 2H), 1.86‒1.76 (m, 1H), 1.75‒1.65 (m, 1H), 1.59‒1.47 (m, 1H), 1.59‒
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
3
.47 (m, 1H); C NMR (100 MHz, CDCl ) δ 144.3, 136.5, 136.3, 134.3, 132.4, 129.5,
3
29.4, 129.4, 128.8, 127.5, 126.9, 119.8, 81.5, 70.5, 55.9, 33.9, 25.9, 25.1, 21.4, 20.2,
9.5, 19.3; IR (CH Cl ) 2923, 2235, 1598, 1494, 1450, 1365, 1169, 816, 666, 587
2
2
-1
+
cm ; MS (ESI) m/e (%) 394.3 ([M+H] , 100), 238.2 (24); HRMS (ESI) m/e calcd for
+
C H NO S [M+H] 394.1838, found 394.1841.
24
28
2
N-([1,1'-Biphenyl]-4-ylethynyl)-N-(cyclohex-2-en-1-ylmethyl)-4-methylbenzenesulf
onamide (1f). The crude mixture was purified by flash column chromatography over
silica gel (EtOAc/hexanes = 1:20) to give 1f as a white solid (0.9538 g, 2.160 mmol,
o
1
7
2%): mp 107‒108 C; H NMR (400 MHz, CDCl ) δ 7.88‒7.83 (m, 2H), 7.60‒7.56
3
(m, 2H), 7.55‒7.50 (m, 2H), 7.47‒7.40 (m, 4H), 7.39‒7.34 (m, 3H), 5.84‒5.77 (m,
1
H), 5.60‒5.54 (m, 1H), 3.36‒3.24 (m, 2H), 2.69‒2.58 (m, 1H), 2.46 (s, 3H), 2.05‒
1
.98 (m, 2H), 1.88‒1.80 (m, 1H), 1.78‒1.68 (m, 1H), 1.62‒1.50 (m, 1H), 1.47‒1.38
1
3
(m, 1H); C NMR (100 MHz, CDCl ) δ 144.6, 140.5, 140.4, 134.6, 131.7, 129.7,
3
1
28.8, 127.7, 127.1, 127.0, 126.9, 121.9, 83.3, 70.6, 56.2, 34.1, 26.1, 25.2, 21.6, 20.4;
-1
IR (CH Cl ) 2929, 2233, 1366, 1168, 764, 586 cm ; MS (ESI) m/e (%) 442.2
2
2
+
+
([M+H] , 100); HRMS (ESI) m/e calcd for C H NO S [M+H] 442.1841, found
2
8
28
2
442.1839.
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 100
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
N-(Cyclohex-2-en-1-ylmethyl)-N-((4-methoxyphenyl)ethynyl)-4-methylbenzenesulfo
namide (1g). The crude mixture was purified by flash column chromatography over
silica gel (EtOAc/hexanes = 1:20) to give 1g as a white solid (0.9136 g, 2.310 mmol,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
7
7%): mp 102‒103 C; H NMR (400 MHz, CDCl ) δ 7.85‒7.81 (m, 2H), 7.38‒7.28
3
(
m, 4H), 6.84‒6.79 (m, 2H), 5.82‒5.75 (m, 1H), 5.59‒5.53 (m, 1H), 3.80 (s, 3H), 3.29
dd, J =12.5, 8.6 Hz, 1H), 3.23 (dd, J = 12.5, 6.6 Hz, 1H), 2.66‒2.55 (m, 1H), 2.45 (s,
(
3H), 2.04‒1.96 (m, 2H), 1.86‒1.78 (m, 1H), 1.76‒1.67 (m, 1H), 1.60‒1.49 (m, 1H),
1
3
1.46‒1.36 (m, 1H); C NMR (100 MHz, CDCl ) δ 159.4, 144.4, 134.5, 133.3, 129.6,
3
129.6, 127.6, 127.1, 114.7, 113.8, 81.1, 70.2, 56.1, 55.2, 34.0, 26.0, 25.2, 21.6, 20.3;
-1
IR (CH Cl ) 2931, 2237, 1606, 1513, 1366, 1249, 1170, 1030, 833, 584 cm ; MS
2
2
+
(
ESI) m/e (%) 459.2 (90), 418.1 ([M+Na] , 28); HRMS (ESI) m/e calcd for
+
C H NO NaS [M+Na] 418.1453, found 418.1445.
23
25
3
N-(Cyclohex-2-en-1-ylmethyl)-N-((3-methoxyphenyl)ethynyl)-4-methylbenzenesulfo
namide (1h). The crude mixture was purified by flash column chromatography over
silica gel (EtOAc/hexanes = 1:20) to give 1h as a white solid (0.9729 g, 2.460 mmol,
o
1
8
2
2%): mp 59‒60 C; H NMR (400 MHz, CDCl ) δ 7.86‒7.82 (m, 2H), 7.38‒7.33 (m,
3
H), 7.19 (t, J = 8.0 Hz, 1H), 6.97‒6.93 (m, 1H), 6.90‒6.87 (m, 1H), 6.85‒6.81 (m,
1H), 5.83‒5.76 (m, 1H), 5.59‒5.52 (m, 1H), 3.90 (s, 3H), 3.34‒3.22 (m, 2H), 2.67‒
2.55 (m, 1H), 2.45 (s, 3H), 2.05‒1.97 (m, 2H), 1.87‒1.78 (m, 1H), 1.77‒1.67 (m, 1H),
26
ACS Paragon Plus Environment

Page 27 of 100
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
13
1
1
2
.61‒1.49 (m, 1H), 1.47‒1.36 (m, 1H); C NMR (100 MHz, CDCl ) δ 159.3, 144.6,
3
34.6, 129.7, 127.7, 127.0, 124.0, 123.8, 116.3, 114.1, 82.6, 70.7, 56.1, 55.3, 34.1,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-1
6.1, 22.7, 21.6, 20.4; IR (CH Cl ) 2930, 2237, 1599, 1366, 1169, 586, 547 cm ; MS
2
2
+
(
ESI) m/e (%) 459.2 (60), 418.1 ([M+Na] , 100); HRMS (ESI) m/e calcd for
+
C H NO SNa [M+Na] 418.1453, found 418.1444.
23 25
3
N-(Cyclohex-2-en-1-ylmethyl)-N-((4-fluorophenyl)ethynyl)-4-methylbenzenesulfona
mide (1i). The crude mixture was purified by flash column chromatography over
silica gel (EtOAc/hexanes = 1:20) to give 1i as a white solid (0.8283 g, 2.160 mmol,
o
1
72%): mp 93‒94 C; H NMR (400 MHz, CDCl ) δ 7.84‒7.81 (m, 2H), 7.38‒7.30 (m,
3
4
8
1
H), 7.02‒6.95 (m, 2H), 5.82‒5.76 (m, 1H), 5.58‒5.52 (m, 1H), 3.30 (dd, J = 12.5,
.6 Hz, 1H), 3.24 (dd, J = 12.6, 6.7 Hz, 1H), 2.65‒2.55 (m, 1H), 2.45 (s, 3H), 2.04‒
.97 (m, 2H), 1.86‒1.77 (m, 1H), 1.77‒1.65 (m, 1H), 1.61‒1.49 (m, 1H), 1.46‒1.36
13
(
m, 1H); C NMR (100 MHz, CDCl ) δ 162.2 (d, J = 247.6 Hz), 144.6, 134.5, 133.4
3
(
d, J = 8.3 Hz), 129.7, 129.7, 127.7, 127.0, 118.9, 115.5 (d, J = 21.9 Hz), 82.2, 69.5,
19
5
2
6.1, 34.1, 26.0, 25.2, 21.6, 20.3; F NMR (376 MHz, CDCl ) δ -111.58; IR (CH Cl )
3 2 2
-1
929, 2239, 1600, 1510, 1367, 1170, 837, 584 cm ; MS (ESI) m/e (%) 406.1
+
+
(
[M+Na] , 100); HRMS (ESI) m/e calcd for C H NO FSNa [M+Na] 406.1253,
22 22 2
found 406.1247.
N-((4-Chlorophenyl)ethynyl)-N-(cyclohex-2-en-1-ylmethyl)-4-methylbenzenesulfon
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 100
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
amide (1j). The crude mixture was purified by flash column chromatography over
silica gel (EtOAc/hexanes = 1:20) to give 1j as a white solid (0.9358 g, 2.340 mmol,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
7
8%): mp 108‒109 C; H NMR (400 MHz, CDCl ) δ 7.84‒7.80 (m, 2H), 7.38‒7.33
3
(m, 2H), 7.30‒7.23 (m, 4H), 5.83‒5.76 (m, 1H), 5.58‒5.52 (m, 1H), 3.34‒3.21 (m,
2
1
H), 2.65‒2.54 (m, 1H), 2.45 (s, 3H), 2.05‒1.96 (m, 2H), 1.86‒1.77 (m, 1H), 1.76‒
1
3
.67 (m, 1H), 1.61‒1.49 (m, 1H), 1.45‒1.35 (m, 1H); C NMR (100 MHz, CDCl ) δ
3
145.0, 134.8, 134.0, 132.8, 130.1, 128.9, 128.0, 127.2, 121.7, 83.9, 56.4, 34.4, 26.3,
-1
25.5, 21.9, 20.6; IR (CH Cl ) 2930, 2361, 2234, 1367, 1169, 1091, 828 cm ; MS (ESI)
2
2
+
m/e (%) 400.1 ([M+H] , 100), 334.8 (2), 244.2 (10), 218.9 (3); HRMS (ESI) m/e
+
calcd for C H NO SCl [M+H] 400.1138, found 400.1138.
2
2
23
2
N-((4-Bromophenyl)ethynyl)-N-(cyclohex-2-en-1-ylmethyl)-4-methylbenzenesulfona
mide (1k). The crude mixture was purified by flash column chromatography over
silica gel (EtOAc/hexanes = 1:20) to give 1k as a yellow solid (0.9865 g, 2.220 mmol,
o
1
7
4%): mp 114‒115 C; H NMR (400 MHz, CDCl ) δ 7.84‒7.79 (m, 2H), 7.44‒7.39
3
(m, 2H), 7.37‒7.34 (m, 2H), 7.23‒7.18 (m, 2H), 5.83‒5.76 (m, 1H), 5.58‒5.51 (m,
1
1
H), 3.34‒3.21 (m, 2H), 2.65‒2.54 (m, 1H), 2.45 (s, 3H), 2.05‒1.96 (m, 2H), 1.86‒
1
3
.77 (m, 1H), 1.77‒1.66 (m, 1H), 1.60‒1.49 (m, 1H); C NMR (100 MHz, CDCl ) δ
3
144.7, 134.5, 132.6, 131.5, 129.8, 129.8, 127.6, 126.9, 121.9, 121.7, 83.8, 69.8, 56.0,
-1
34.1, 26.0, 25.2, 21.6, 20.3; IR (CH Cl ) 2360, 1366, 1170, 680 cm ; MS (ESI) m/e
2
2
28
ACS Paragon Plus Environment

Page 29 of 100
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
+
+
(
%) 446.1 ([M+2+H] , 100), 444.1 ([M+H] , 98); HRMS (ESI) m/e calcd for
+
C H NO SBr [M+H] 444.0633, found 444.0632.
22
23
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
Methyl
-((N-(cyclohex-2-en-1-ylmethyl)-4-methylphenylsulfonamido)ethynyl)benzoate (1l).
4
The crude mixture was purified by flash column chromatography over silica gel
(EtOAc/hexanes = 1:20) to give 1l as a white solid (0.9656 g, 2.280 mmol, 76%): mp
o
1
136‒137 C; H NMR (400 MHz, CDCl ) δ 7.97‒7.94 (m, 2H), 7.85‒7.82 (m, 2H),
3
7.40‒7.34 (m, 4H), 5.84‒5.78 (m, 1H), 5.58‒5.52 (m, 1H), 3.91 (s, 3H), 3.37‒3.25 (m,
2H), 2.67‒2.57 (m, 1H), 2.45 (s, 3H), 2.05‒1.98 (m, 2H), 1.87‒1.78 (m, 1H), 1.77‒
1
3
1
1
5
1
3
.67 (m, 1H), 1.61‒1.50 (m, 1H), 1.46‒1.36 (m, 1H); C NMR (100 MHz, CDCl ) δ
3
66.6, 144.8, 134.5, 130.5, 129.9, 129.8, 129.5, 128.7, 127.9, 127.7, 126.8, 86.0, 70.8,
6.1, 52.2, 34.2, 26.0, 25.2, 21.6, 20.3; IR (CH Cl ) 2928, 2230, 1723, 1602, 1365,
2
2
-1
+
+
275, 1170, 1105, 765 cm ; MS (FAB ) m/e (%) 442.2 (32), 424.1 ([M+H] , 53),
+
07.1 (30), 154.1 (100), 136.1 (65); HRMS (FAB ) m/e calcd for C H NO S
2
4
26
4
+
[
M+H] 424.1583, found 424.1575.
N-(Cyclohex-2-en-1-ylmethyl)-4-methyl-N-((4-nitrophenyl)ethynyl)benzenesulfona
mide (1m). The crude mixture was purified by flash column chromatography over
silica gel (EtOAc/hexanes = 1:15) to give 1m as a yellow solid (0.7759 g, 1.890 mmol,
o
1
63%): mp 107‒108 C; H NMR (400 MHz, CDCl ) δ 8.18‒8.13 (m, 2H), 7.86‒7.81
3
29
ACS Paragon Plus Environment