Synthesis of 3-Azabicyclo[ m.2.0] Ring Systems via a Copper-Catalyzed Cascade Reaction of Diazo Compounds with 1, n-Allenynes

Article abstract of DOI:10.1021/acs.joc.0c00149

A copper-catalyzed cascade reaction of diazo compounds with 1,n-allenynes (n = 6,7) was reported, which provides efficient access to various functionalized 3-azabicyclo[m.2.0] frameworks (m = 5,6) in moderate to excellent yields under mild reaction conditions. The reaction proceeds through intermolecular cross-coupling to form bisallene intermediates, followed by subsequent intramolecular [2+2] cycloaddition.

Full text of DOI:10.1021/acs.joc.0c00149

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Article
Synthesis of 3-Azabicyclo[m.2.0] Ring Systems via Copper-
Catalyzed Cascade Reaction of Diazo Compounds with 1,n-Allenynes
Min He, Nuan Chen, Lala Liu, Yuqi Zhu, Qing Li, Hongguang Li, Ming Lang, Jian Wang, and Shiyong Peng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00149 • Publication Date (Web): 24 Feb 2020
Downloaded from pubs.acs.org on February 24, 2020
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Page 1 of 34
The Journal of Organic Chemistry
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Synthesis of 3-Azabicyclo[m.2.0] Ring Systems via Copper-Catalyzed
Cascade Reaction of Diazo Compounds with 1,n-Allenynes
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Min He,†,§ Nuan Chen,†,§ Lala Liu,† Yuqi Zhu,† Qing Li,† Hongguang Li,† Ming Lang,† Jian Wang,†,‡
and Shiyong Peng*,†
†School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, P. R. China
‡School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorous Chemistry &
Chemical Biology (Ministry of Education), Tsinghua University, Beijing, 100084, P. R. China
E-mail: psy880124@mail.nankai.edu.cn
ABSTRACT GRAPHIC
CO2R4
Ar
R1
R2
R1
R2
[Cu]
N2
x
x
+
R3
Ar
CO2R4
N
R
•
N
R
R3
(x = 0,1)
copper catalysis
mild reaction conditions
36 examples & up to 91% yield
general and efficient
3-azabicyclo[m.2.0] skeleton (m = 5,6)
bisallene isolated
√
√
√
√
√
√
ABSTRACT
A copper-catalyzed cascade reaction of diazo compounds with 1,n-allenynes (n = 6,7) was reported,
which provides an efficient access to various functionalized 3-azabicyclo[m.2.0] frameworks (m = 5,6)
in moderate to excellent yields under mild reaction conditions. The reaction proceeds through
intermolecular cross-coupling to form bisallene intermediates followed by subsequent intramolecular
[2+2] cycloaddition.
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INTRODUCTION
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Four-membered carbocycles are widely found in natural products and other biologically active
compounds.1 In particular, cyclobutane-fused frameworks are found in several natural products (Figure
1). For example, Cytosporolide A–C, caryophyllene-derived meroterpenoids with a cyclobutane motif,
were isolated from cultures of the fungus Cytospora sp. and showed significant antimicrobial activity
against the Gram-positive bacteria Staphylococcus aureus and Streptococcus pneumoniae.2
Tripartilactam, a structurally unprecedented cyclobutane-bearing tricyclic lactam metabolite from a
Streptomyces sp. in a dung beetle’s brood ball, was evaluated as a Na+/K+ ATPase inhibitor.3 Paesslerins
A–B, novel cyclobutane-containing tricyclic sesquiterpenoids isolated from the soft coral Alcyonium
paessleri, showed moderate cytotoxicity against human tumor cell lines.4 Psiguadial B, a novel
sesquiterpenoid-diphenylmethane meroterpenoid isolated from the leaves of Psidium guajava, exhibited
potent antiproliferative activity against human hepatoma cells.5 Flueggedine, isolated from the twigs and
leaves of Flueggeavirosa, was an interesting axisymmetric [2+2] cycloaddition indolizidine alkaloid
dimer.6 As such, the development of methodologies for the synthesis of these cyclobutane-fused
structures is of significant interest.
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O
O
OH
O
O
HO
O
OH
R1
OH
OH
HN
HO
H
H
H
Tripartilactam
O
OR3
OR2
R
Cytosporolide A-C
(A: R1 = OH, R2 = H, R3 = Me)
(B: R1 = H, R2 = H, R3 = H)
(C: R1 = OH, R2 = Ac, R3 = Me)
AcO
Paesslerins A-B
(A: R = H; B: R = OAc)
H
O
O
CHO
O
H
O
H
OH
O
H
H
H
H
H
CHO
N
N
H
OH
Ph
Psiguadial B
Flueggedine
Figure 1. Selected Natural Products.
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Recently, Vaquero and co-workers reported regiodivergent electrophilic cyclizations of
alkynylcyclobutanes bearing an appended hydroxyl group for the synthesis of cyclobutane-fused O-
heterocycles (Scheme 1a).7-8 Compared with the efficient yet limited methods through functionalization
of preexisting cyclobutanes, the intramolecular [2+2] cycloaddition of bisallenes has been found to be a
more efficient alternative for the construction of cyclobutane-fused bicyclic systems.9 For example, in
2006, Ma and co-workers realized two different [2+2] cycloaddition pathways of 1,5-bisallenes,
providing two types of cyclobutane-fused bicyclic products (Scheme 1b).9b However, such strategies are
limited presumably due to the high instability of bisallenes and difficulty of their synthesis. The
complementary method has been well established by in situ bisallene formation from diyne precursors
via intramolecular rearrangement.10 For example, in 2013, Liu and co-workers discovered a novel gold-
catalyzed cascade cyclization of diynes for the synthesis of naphtho[b]cyclobutenes, in which the
generation of bisallenes via double 3,3-rearrangement of diyne precursors was considered to be the key
step (Scheme 1c).10a Recently, our group reported a novel copper-catalyzed cascade reaction of diazo
compounds with 1,6-allenynes bearing an aromatic linker for the synthesis of 3-azabicyclo[5.2.0] ring
systems, which proceeds through intermolecular cross-coupling to form bisallene intermediates
followed by subsequent intramolecular [2+2] cycloaddition (Scheme 1d).11 Despite these advances,
general and efficient strategies for the rapid assembly of cyclobutane-fused bicyclic scaffolds still
remain scarce. Based on the former reports and our continuous interests in diazo chemistry,12 we
describe herein a novel and general copper-catalyzed cascade reaction of diazo compounds with benzo-
free 1,n-allenynes under mild reaction conditions for the rapid assembly of cyclobutane-fused
bicyclo[m.2.0] ring systems, which would be potentially useful in the total synthesis of natural products
and attractive for drug development in medicinal chemistry (Scheme 1e).
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Scheme 1. Synthesis of Cyclobutane-Fused Bicyclic Structures.
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a) Functionalization of preexisting cyclobutanes
1
2
3
R
I
RO
R
RO
RO
[Au]
I+
R
O
OH
O
4
5
6
7
8
9
b) [2+2] Cycloaddition of bisallenes
R1
R1
R1
R2
•
•
[Pd]
heat
X
X
X
R2
R2
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c) [2+2] Cycloaddition of in situ formed bisallenes
BnO2CO
OCO2Bn
R
R
R
•
O
O
[Au]
R
O
R
R
•
OCO2Bn
BnO2CO
d) Our reported method
R2
R2
R3
R1
[Cu]
R3
•
N2
+
R1
R2
R3
•
N
R
N
R
N
R1
•
R
(e) This report
CO2R4
Ar
R1
R1
R2
[Cu]
N2
x
x
+
R3
Ar
CO2R4
R2
N
•
N
R3
R
R
(x = 0,1)
copper catalysis
general and efficient
3-azabicyclo[m.2.0] skeleton (m = 5,6)
bisallene isolated
√
√
√
√
mild reaction conditions
36 examples & up to 91% yield
√
√
RESULTS AND DISCUSSIONS
We first utilized benzo-free 1,6-allenyne 1a and phenyl diazoacetate 2a as model substrates to
optimize the reaction conditions (Table 1). Both the catalyst and the reaction medium were crucial for
the reaction. When the reaction was performed in methylene dichloride (CH2Cl2) at room temperature
without catalyst, the reaction did not happen (entry 1). Different copper catalysts were then tested.
Gratifyingly, CuCl gave desired product 3aa in 45% yield, while CuBr afforded product in 27% yield
and CuI did not catalyze the reaction at all (entries 2–4). The low efficiency was due to the diazo homo-
coupling reaction and the incomsumption of allenyne substrate. When Cu(PPh3)3Br was employed, the
yield was increased to 83% (entry 5). It is worth noting that the catalytic activity of CuBr is quite
different with our previous report.11 Other copper catalysts and metal catalysts13 showed no catalytic
activity for the reaction (entries 6–9). These results indicate that both the solubility and ligand type of
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copper catalysts have significant impact on the reaction. Next, various solvents were screened. CH2Cl2
was better than the alternative 1,2-dichloroethane (DCE), whereas other solvents14 such as acetonitrile
(MeCN) and tetrahydrofuran (THF) were not suitable for the reaction (entries 10–12). The reaction did
1
2
3
4
5
6
o
o
7
not happen at 0 C, and led to a lower yield at 60 C due to product decomposition (entries 13–14).
Notebly, the adding method of phenyl diazoacetate 2a was detrimental to the reaction. When the
reaction was conducted in a one-pot manner without a syringe pump, almost no product was obtained
(entry 15). Bases did not improve the reaction outcome (entries 16–17).
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Table 1. Optimization of Reaction Conditionsa
CO2Me
N2
catalyst
Ph
+
Ph
CO2Me
2a
solvent, T
N
•
N
Ts
Ts
1a
3aa
entry
1
catalyst
-
solvent
yield (%)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
-
2
CuCl
CuBr
CuI
45
27
-
3
4
5
Cu(PPh3)3Br
83
-
6
Cu(1,10-Phen)(PPh3)Br
CuOTf
7
-
8
Cu(tfacac)2
-
9
IPrCuOTf
-
10
11
12
13b
14c
15d
16e
17f
Cu(PPh3)3Br
Cu(PPh3)3Br
Cu(PPh3)3Br
Cu(PPh3)3Br
Cu(PPh3)3Br
Cu(PPh3)3Br
Cu(PPh3)3Br
Cu(PPh3)3Br
32
-
MeCN
THF
<10
-
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
46
<10
37
-
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aReaction conditions: 2a (0.4 mmol) in solvent (1.0 mL) was injected into a solution of 1a (0.2 mmol) and catalyst (10
1
2
3
mol %) in solvent (1.0 mL) via a syringe pump within 2 h, and the reaction was continued at rt for another 12 h. bAt 0
4
5
c
o
d
f
oC. At 60 C. Without a syringe pump. eEt3N (0.2 mmol) was added. Cs2CO3 (0.2 mmol) was added. ( IPr = 1,3-
6
7
bis(diisopropylphenyl)imidazol-2-ylidene. Tf = trifluoromethanesulfonyl. tfacac = trifluoroacetoacetyl.
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With the established optimal reaction conditions, we investigated the scope of diazo compounds for
the synthesis of 3-azabicyclo[5.2.0] products (Scheme 2). Diazo compounds with various ester groups,
such as methyl, ethyl, benzyl or even active allyl group, were all tolerated for the reaction and gave the
corresponding products in good yields (3aa–ad). Aryl diazoacetates bearing electron-donating or
electron-withdrawing substituents at the aryl moiety were all found to be suitable for the reaction,
providing the desired products in moderate to excellent yields (3ae–ao). Both the position and electronic
properties of substituents have significant influence on the reaction. Additionally, disubstituted aryl
diazoacetates, 2-naphthyl substituted diazoacetate, and benzofuran-derived diazoacetate were also
amenable to the reaction (3ap–as). Thiophene-derived diazoacetate was not suitable for the reaction,
presumably due to the sulfur deactivation of copper-containing catalyst. Gram-scale synthesis gave
product 3aa in 72% yield under standard reaction conditions. Unfortunately, diazo compounds of
acceptor-H type and acceptor-acceptor type were not suitable for this reaction. The structure of 3al was
confirmed by X-ray diffraction analysis.15
Scheme 2. Scope of Diazo Substratesa
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CO2R
Ar
N2
Cu(PPh3)3Br (10 mol %)
CO2R
CH2Cl2, rt
1
2
3
4
5
6
7
8
+
Ar
N
•
N
Ts
Ts
1a
2
3aa-at
MeO
RO
O
MeO
O
O
R
X
N
N
N
Ts
Ts
Ts
b
3ai
3aj
3ak
(X = F), 71%
(X = Cl), 68%
(X = Br), 66%
3aa
3ab
3ac
3ad
3ae
3af
(R = Me), 83% (72%)
(R = Et), 81%
(R = Me), 87%
t
(R = Bu), 85%
9
3ag
3ah
(R = Bn), 70%
(R = Ph), 78%
10
11
12
13
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(R = Allyl), 65%
(R = OMe), 91%
MeO
O
MeO
O
MeO
O
I
N
N
N
Cl
CF3
Ts
Ts
Ts
3al
3am
3an
, 61%
, 69%
O
, 53%
O
(CCDC 1956563)
MeO
O
MeO
MeO
Cl
F
N
N
N
N
Me
Cl
Br
S
Ts
Ts
Ts
Ts
Ts
3ao
3ap
3aq
, 23%
, 60%
O
, 63%
O
MeO
O
MeO
MeO
O
N
N
Ts
3ar
3as
3at
, 0%
, 58%
, 69%
aReaction conditions: 2 (0.4 mmol) in CH2Cl2 (1.0 mL) was injected into a solution of 1a (0.2 mmol) and Cu(PPh3)3Br
(10 mol %) in CH2Cl2 (1.0 mL) via a syringe pump within 2 h, and the reaction was continued at rt for another 12 h.
bYield of 5.0 mmol scale in parentheses.
For the scope of 1,6-allenynes (Scheme 3), the reaction tolerated different sulfonyl substituents at the
R position, furnishing the corresponding products in good yields (3ba–ea). Unfortunately, no desired
product obtained when R is acetyl group. Then, the reaction of phenyl diazoacetate 2a with 1,6-
allenynes bearing methyl (R1) or phenyl (R2) substituent on the aliphatic linker afforded the desired
products as mixtures of two inseparable regioisomers (3fa–ga). Furthermore, cyclohexane-derived 1,6-
allenyne 1h was also tested and product 3ha was isolated in 35% yield. Gratifyingly, 1,6-allenyne 1i (R3
= Me) was well suitable for the reaction, leading to the desired product 3ia in 74% yield. The relative
stereochemistry of 3ha and 3ia as well as the structure of 3ga were determined by X-ray diffraction
analysis.15
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Scheme 3. Scope of 1,6-Allenyne Substratesa
1
2
3
4
5
R1
R1
R2
CO2Me
Ph
N2
Cu(PPh3)3Br (10 mol %)
CH2Cl2, rt
R2
+
R3
Ph
CO2Me
2a
N
R
•
N
R3
R
1
3
6
7
8
9
Me
1b
1c
1d
1e
(R = C6H5SO2)
(R = 4-BrC6H4SO2)
(R = 4-NO2C6H4SO2)
(R = MeSO2)
N
•
N
•
R
Ts
1f
10
11
12
13
14
15
16
17
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60
Ph
N
•
N
•
N
•
Me
Ts
1g
Ts
Ts
1i
b
1h
(dr ~ 4:1)
MeO
O
MeO
O
Me
3ba
3ca
3da
3ea
(R = C6H5SO2), 80%
(R = 4-BrC6H4SO2), 76%
(R = 4-NO2C6H4SO2), 71%
(R = MeSO2), 73%
N
N
R
Ts
b
3fa
, 82%, (dr ~ 1.5:1)
MeO
O
MeO
O
MeO
O
Ph
N
N
N
Me
Ts
Ts
Ts
d
b
c,d
3ia
rac- , 74%
3ga
3ha
, 73%, (dr ~ 2:1)
(CCDC 1956564)
rac-
, 35%
(CCDC 1974058)
(CCDC 1974057)
aReaction conditions: 2a (0.4 mmol) in CH2Cl2 (1.0 mL) was injected into a solution of 1 (0.2 mmol) and Cu(PPh3)3Br
(10 mol %) in CH2Cl2 (1.0 mL) via a syringe pump within 2 h, and the reaction was continued at rt for another 12 h.
bDr values were determined by H NMR analysis. Yield of flash chromotography followed by recrystallization. One
1
c
d
diastereomer was obtained.
In addition to 1,6-allenynes, 1,7-allenyne 4 was also evaluated for the reaction and the expected 3-
azabicyclo[6.2.0] product 5a was obtained in 61% yield under the optimized reaction conditions
(Scheme 4). The reactions of 1,7-allenyne 4 with various substituted aryl diazoacetates all proceeded
well and afforded the desired 3-azabicyclo[6.2.0] products in moderate to good yields (5b–h). Notably,
bulky 2-naphthyl substituted diazoacetate was also suitable for the reaction and gave product 5i in 47%
yield.
Scheme 4. Scope of Diazo Substrates with 1,7-Allenynea
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CO2Me
Ar
N2
Cu(PPh3)3Br (10 mol %)
1
2
3
4
+
•
N
Ar
CO2Me
CH2Cl2, rt
N
Ts
Ts
4
2
5
MeO
O
MeO
O
MeO
O
5
6
7
8
Me
Ph
Br
N
Ts
N
Ts
N
Ts
5a
, 61%
O
5b
, 65%
O
5c
, 68%
O
MeO
MeO
MeO
9
F
Cl
10
11
12
13
14
15
16
17
18
N
Ts
N
Ts
N
Ts
5d
5e
5f
, 60%
O
, 58%
O
, 55%
O
MeO
MeO
MeO
I
N
Ts
N
Ts
N
Ts
Cl
5g
5h
5i
, 47%
, 52%
, 38%
aReaction conditions: 2 (0.4 mmol) in CH2Cl2 (1.0 mL) was injected into a solution of 4 (0.2 mmol) and Cu(PPh3)3Br
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46
47
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49
50
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53
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55
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57
58
59
60
(10 mol %) in CH2Cl2 (1.0 mL) via a syringe pump within 2 h, and the reaction was continued at rt for another 12 h.
Control experiments were conducted to understand the cycloaddition process (Scheme 5). The
reaction went smoothly to give the desired product 3aa in good yield when a radical inhibitor BHT or
TEMPO was present, which showed that the reaction did not proceed via a radical mechanism (Scheme
5a). When 1,8-allenyne 6 with longer aliphatic chain was subjected to the reaction, only the cross-
coupling bisallene 7 was isolated in 56% yield, which indicated that the reaction may involve a bisallene
intermediate. Unfortunately, efforts for transformations of product 3aa, such as reduction of double
bond or thermal rearrangement, all failed.
Scheme 5. Control Experiments.
MeO
O
N2
Additive (1.0 equiv)
a)
+
N
•
Ph
CO2Me
2a
N
"standard conditions"
Ts
Ts
1a
Additive
Yield of 3aa
BHT
TEMPO
80 %
84 %
N2
•
Ph
"standard conditions"
b)
+
Ph
CO2Me
2a
•
N
•
CO2Me
N
Ts
Ts
6
7
, 56%
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Based on our previous report and related investigations,9c,12,16 a plausible mechanism has been
proposed in Scheme 6. The whole sequence is initiated by the formation of copper-carbene intermediate
A from the reaction of 1,6-allenyne 1a with phenyl diazoacetate 2a in the presence of copper catalyst,
which is followed by migratory insertion of the carbenic carbon to the alkynyl group to generate
intermediate B. Protonation of intermediate B afforded bisallene intermediate C. The regioselective
coordination of bisallene intermediate C to copper species followed by C-C bond formation would
produce the cupracyclopentane intermediate D, which would undergo quick reductive elimination to
give product 3aa.
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Scheme 6. Proposed Reaction Mechanism.
1a + 2a
3aa
Cu(I)
N2 + HBr
Ph
CO2Me
MeO2C
Cu(I)
Ph
Cu(III)
D
A
N
Ts
N
•
Ts
CO2Me
Ph
Cu(I)
Cu(I)
•
CO2Me
H
C
Ph
N
•
B
Ts
N
•
Cu(I)
Ts
CONCLUSION
In summary, we have developed a general and efficient strategy for the synthesis of various
functionalized 3-azabicyclo[5.2.0] and 3-azabicyclo[6.2.0] frameworks via copper-catalyzed tandem
cross-coupling/[2+2] cycloaddition reaction of diazo compounds with benzo-free 1,n-allenynes. This
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protocol features mild reaction condition, moderate to excellent yields, and broad substrate scope.
Further applications of this method are currently underway in our laboratory.
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EXPERIMENTAL SECTION
9
General Information. All reactions were carried out in oven-dried glassware. All solvents for
reactions were analytical grade and purified/dried according to standard procedures. Solvents for flash
chromatography were technical grade and distilled before use. All commercially available compounds
were used without further purification. 10-Channels syringe pump (model: LSP10-1B) of Longer
Precision Pump Co., Ltd. was used for slow injection. Thin layer chromatography (TLC) was carried
out using precoated silica gel plates (0.25 mm, F254) and visualization was accomplished under UV
light (254 nm). Flash chromatography was performed using silica gel (200–300 mesh). Melting points
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1
13
were obtained uncorrected from an SGW X-4B melting point apparatus. H NMR and C{1H} NMR
spectra were recorded in CDCl3 on a Bruker Ascend™ 500 spectrometer (500 MHz), chemical shifts are
reported in ppm with the solvent signals as reference, and coupling constants (J) are given in Hertz. The
peak information is described as: s (singlet), d (doublet), dd (doublet of doublet), t (triplet), q (quartet),
and m (multiplet). All high-resolution mass spectra (HRMS) were obtained on a Thermo Scientific™ Q
Exactive™ UHMR (Ultra-High Mass Range) Hybrid Quadrupole-Orbitrap™ mass spectrometer.
Safety Note. Handling of diazo compounds should only be done in a well-ventilated fume cupboard
using an additional blast shield.
Synthesis of Cu(PPh3)3Br Catalyst. Copper catalyst Cu(PPh3)3Br used in this reaction was
synthesized according to reported method.17
Synthesis of Diazo Substrates. The aryldiazoacetates 2a–t were prepared according to well-
documented literature procedures.18
General Procedure for the Synthesis of 1,n-Allenyne Substrates 1, 4 and 6 (GP-A). The
corresponding aminoalkynes (1.0 equiv) and K2CO3 (5.0 equiv) were added into acetone (0.5 M). Then,
propargyl bromide (2.5 equiv) was added in one portion. The reaction mixture was stirred at 60 oC in an
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oil bath under an N2 balloon. After the reaction was completed (monitored by TLC), the resulting
mixture was cooled down to rt, filtered via a short pad of celite and washed once with acetone. The
combined organic phase was concentrated under reduced pressure to obtain the propargylated crude
product, which was dissolved in THF (0.33 M). The mixture was cooled down to 0 ºC in an ice-bath and
tBuOK (30 mol %) was added in portions. Then, the reaction was warmed to rt and stirred until
completed (monitored by TLC). The resulting mixture was filtered via a short pad of celite and washed
with CH2Cl2. The combined organic phase was concentrated and the residue was purified by flash
column chromatography on silica gel (eluent: hexanes/EtOAc) to afford the pure 1,n-allenyne
substrates.
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N-(but-3-yn-1-yl)-4-methyl-N-(propa-1,2-dien-1-yl)benzenesulfonamide (1a): The title compound
was synthesized from the corresponding 3-bromopropyne and aminoalkyne19 following GP-A, and
obtained as white solid in 60% yield (1568.0 mg, 10 mmol scale); mp: 59–60 oC; 1H NMR (500 MHz,
CDCl3): δ 7.70 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 6.84 (t, J = 6.2 Hz, 1H), 5.36 (d, J = 6.2
13
Hz, 2H), 3.42–3.15 (m, 2H), 2.47–2.42 (m, 5H), 1.98 (t, J = 2.7 Hz, 1H); C{1H} NMR (125 MHz,
CDCl3): δ 200.8, 144.1, 135.3, 130.0, 127.2, 100.0, 88.4, 80.5, 70.2, 45.1, 21.7, 18.4; HRMS (ESI) m/z:
[M + Na]+ Calcd. for C14H15NO2SNa 284.0716; Found 284.0716.
N-(but-3-yn-1-yl)-N-(propa-1,2-dien-1-yl)benzenesulfonamide (1b): The title compound was
synthesized from the corresponding 3-bromopropyne and aminoalkyne19 following GP-A, and obtained
as colorless oil in 71% yield (878.0 mg, 5 mmol scale); 1H NMR (500 MHz, CDCl3): δ 7.84–7.80 (m,
2H), 7.64–7.59 (m, 1H), 7.57–7.52 (m, 2H), 6.84 (t, J = 6.3 Hz, 1H), 5.36 (d, J = 6.3 Hz, 2H), 3.35–3.30
(m, 2H), 2.48–2.43 (m, 2H), 1.99 (t, J = 2.7 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 200.8, 138.2,
133.2, 129.3, 127.1, 99.8, 88.5, 80.4, 70.2, 45.1, 18.4; HRMS (ESI) m/z: [M + Na]+ Calcd. For
C13H13NO2SNa 270.0559; Found 270.0556.
4-Bromo-N-(but-3-yn-1-yl)-N-(propa-1,2-dien-1-yl)benzenesulfonamide (1c): The title compound
was synthesized from the corresponding 3-bromopropyne and aminoalkyne19 following GP-A, and
o
1
obtained as white solid in 74% yield (1207.0 mg, 5 mmol scale); mp: 66–68 C; H NMR (500 MHz,
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CDCl3): δ 7.68 (s, 4H), 6.80 (t, J = 6.2 Hz, 1H), 5.38 (d, J = 6.2 Hz, 2H), 3.33–3.28 (m, 2H), 2.49–2.44
1
2
3
13
(m, 2H), 2.00 (t, J = 2.7 Hz, 1H); C{1H} NMR (125 MHz, CDCl3): δ 200.9, 137.2, 132.7, 128.7,
4
5
6
7
128.3, 99.6, 88.7, 80.3, 70.4, 45.2, 18.5; HRMS (ESI) m/z: [M + H]+ Calcd. for C13H13BrNO2S
325.9845; Found 325.9841.
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N-(but-3-yn-1-yl)-4-nitro-N-(propa-1,2-dien-1-yl)benzenesulfonamide (1d): The title compound was
synthesized from the corresponding 3-bromopropyne and aminoalkyne19 following GP-A, and obtained
as white solid in 38% yield (555.0 mg, 5 mmol scale); mp: 79–81 oC; 1H NMR (500 MHz, CDCl3): δ
8.42–8.37 (m, 2H), 8.04–7.99 (m, 2H), 6.81 (t, J = 6.2 Hz, 1H), 5.41 (d, J = 6.2 Hz, 2H), 3.37–3.33 (m,
2H), 2.52–2.47 (m, 2H), 2.01 (t, J = 2.7 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 201.0, 150.4, 143.8,
128.5, 124.7, 99.3, 89.1, 79.9, 70.6, 45.4, 18.6; HRMS (ESI) m/z: [M + Na]+ Calcd. for C13H12N2O4SNa
315.0410; Found 315.0408.
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N-(but-3-yn-1-yl)-N-(propa-1,2-dien-1-yl)methanesulfonamide (1e): The title compound was
synthesized from the corresponding 3-bromopropyne and aminoalkyne19 following GP-A, and obtained
as white solid in 66% yield (611.2 mg, 5 mmol scale); mp: 73–75 oC; 1H NMR (500 MHz, CDCl3): δ
6.69 (t, J = 6.3 Hz, 1H), 5.46 (d, J = 6.3 Hz, 2H), 3.51 (t, J = 7.4 Hz, 2H), 2.95 (s, 3H), 2.51 (td, J = 7.6,
2.7 Hz, 2H), 2.03 (t, J = 2.7 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 200.5, 99.5, 88.6, 80.5, 70.5,
45.3, 38.5, 18.6; HRMS (ESI) m/z: [M + Na]+ Calcd. for C8H11NO2SNa 208.0403; Found 208.0402.
4-Methyl-N-(2-methylbut-3-yn-1-yl)-N-(propa-1,2-dien-1-yl)benzenesulfonamide (1f): The title
compound was synthesized from the corresponding 3-bromopropyne and aminoalkyne20 following GP-
A, and obtained as colorless oil in 69% yield (950.0 mg, 5 mmol scale); 1H NMR (500 MHz, CDCl3): δ
7.74 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 6.54 (t, J = 6.4 Hz, 1H), 5.24 (d, J = 6.4 Hz, 2H),
4.37–4.28 (m, 1H), 2.55–2.47 (m, 1H), 2.45–2.37 (m, 4H), 1.94 (d, J = 5.3 Hz, 1H), 1.21 (d, J = 6.9 Hz,
13
3H); C{1H} NMR (125 MHz, CDCl3): δ 203.9, 143.8, 137.2, 129.8, 127.3, 94.7, 85.6, 80.9, 70.6,
53.9, 24.2, 21.7, 17.1; HRMS (ESI) m/z: [M + H]+ Calcd. for C15H18NO2S 276.1053; Found 276.1048.
4-Methyl-N-(1-phenylbut-3-yn-1-yl)-N-(propa-1,2-dien-1-yl) benzenesulfonamide (1g): The title
compound was synthesized from the corresponding 3-bromopropyne and aminoalkyne20 following GP-
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A, and obtained as colorless oil in 57% yield (961.6 mg, 5 mmol scale); 1H NMR (500 MHz, CDCl3): δ
7.65–7.61 (m, 2H), 7.32–7.21 (m, 7H), 6.35 (t, J = 6.3 Hz, 1H), 5.44 (dd, J = 8.6, 6.6 Hz, 1H), 5.09 (dd,
J = 10.5, 6.3 Hz, 1H), 5.02 (dd, J = 10.5, 6.3 Hz, 1H), 3.05 (ddd, J = 17.0, 8.7, 2.7 Hz, 1H), 2.74 (ddd, J
1
2
3
4
5
6
13
= 17.0, 6.6, 2.7 Hz, 1H), 2.41 (s, 3H), 1.92 (t, J = 2.7 Hz, 1H); C{1H} NMR (125 MHz, CDCl3): δ
7
8
9
204.6, 143.7, 137.2, 136.9, 129.6, 128.3, 128.1, 127.9, 127.4, 95.6, 85.7, 80.7, 71.3, 60.1, 22.2, 21.7;
HRMS (ESI) m/z: [M + Na]+ Calcd. for C20H19NO2SNa 360.1029; Found: 360.1024.
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N-(2-ethynylcyclohexyl)-4-methyl-N-(propa-1,2-dien-1-yl) benzenesulfonamide (1h): The title
compound was synthesized from the corresponding 3-bromopropyne and aminoalkyne20 following GP-
A, and obtained as white solid in 86% yield (1356.0 mg; 5 mmol scale; mixture of two inseparable
o
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diasteroisomers; dr ~ 4:1); mp: 63–66 C; H NMR (500 MHz, CDCl3): δ 7.85–7.75 (m, 2H), 7.31–
7.25 (m, 2H), 6.45 (t, J = 6.3 Hz, 1H), 5.24–5.17 (m, 2H), 3.98–3.72 (m, 1H), 2.83–2.44 (m, 1H), 2.43–
13
2.40 (m, 3H), 1.85–1.78 (m, 1H), 1.75–1.60 (m, 4H), 1.54–1.01 (m, 4H); C{1H} NMR (125 MHz,
CDCl3): δ 205.1, 144.0, 143.4, 137.8, 136.4, 129.5, 129.4, 127.9, 127.6, 85.0, 84.93, 84.88, 69.9, 69.8,
62.6, 62.5, 33.6, 33.3, 33.0, 32.7, 31.0, 30.2, 25.5, 25.0, 24.9, 24.6, 21.7, 21.6; HRMS (ESI) m/z: [M +
Na]+ Calcd. for C18H21NO2SNa 338.1185; Found 338.1178.
N-(but-3-yn-1-yl)-N-(buta-1,2-dien-1-yl)-4-methylbenzenesulfonamide (1i): The title compound was
synthesized from the corresponding 1-bromo-2-butyne and aminoalkyne19 following GP-A, and
obtained as colorless oil in 47% yield (647.2 mg, 5 mmol scale); 1H NMR (500 MHz, CDCl3): δ 7.73–
7.66 (m, 2H), 7.35–7.29 (m, 2H), 6.71 (dq, J = 5.6, 2.7 Hz, 1H), 5.71 (qd, J = 7.0, 5.9 Hz, 1H), 3.34–
3.22 (m, 2H), 2.45–2.40 (m, 5H), 1.97 (t, J = 2.7 Hz, 1H), 1.71 (dd, J = 7.0, 2.8 Hz, 3H); 13C{1H} NMR
(125 MHz, CDCl3): δ 195.6, 143.9, 135.4, 129.8, 127.2, 99.5, 99.0, 80.7, 70.1, 45.1, 21.6, 18.1, 16.0;
HRMS (ESI) m/z: [M + H]+ Calcd. for C15H18NO2S 276.1053; Found 276.1054.
4-Methyl-N-(pent-4-yn-1-yl)-N-(propa-1,2-dien-1-yl)benzenesulfonamide (4): The title compound
was synthesized from the corresponding 3-bromopropyne and aminoalkyne21 following GP-A, and
obtained as white solid in 44% yield (1212.0 mg, 10 mmol scale); mp: 97–99 oC; 1H NMR (500 MHz,
CDCl3): δ 7.69 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.82 (t, J = 6.2 Hz, 1H), 5.31 (d, J = 6.2
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Hz, 2H), 3.20 (t, J = 7.0 Hz, 2H), 2.43 (s, 3H), 2.23 (td, J = 7.2, 2.6 Hz, 2H), 1.94 (t, J = 2.7 Hz, 1H),
1.82–1.74 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ 201.4, 143.9, 135.4, 129.9, 127.3, 100.3, 88.0,
83.5, 68.9, 45.7, 27.0, 21.7, 15.9; HRMS (ESI) m/z: [M + Na]+ Calcd. for C15H17NO2SNa 298.0872;
Found: 298.0868.
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N-(hex-5-yn-1-yl)-4-methyl-N-(propa-1,2-dien-1-yl)benzenesulfonamide (6): The title compound
was synthesized from the corresponding 3-bromopropyne and aminoalkyne21 following GP-A, and
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obtained as colorless oil in 23% yield (665.6 mg, 10 mmol scale); H NMR (500 MHz, CDCl3): δ
7.70–7.66 (m, 2H), 7.33–7.29 (m, 2H), 6.82 (t, J = 6.2 Hz, 1H), 5.30 (d, J = 6.2 Hz, 2H), 3.12 (t, J = 7.0
Hz, 2H), 2.43 (s, 3H), 2.20 (td, J = 7.0, 2.7 Hz, 2H), 1.94 (t, J = 2.7 Hz, 1H), 1.70–1.63 (m, 2H), 1.58–
1.52 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ 201.5, 143.8, 135.4, 129.8, 127.2, 100.1, 87.7, 84.1,
68.7, 46.0, 26.8, 25.3, 21.6, 18.1; HRMS (ESI) m/z: [M + H]+ Calcd. for C16H20NO2S 290.1209; Found
290.1203.
General Procedure for the Synthesis of Compounds 3, 5 and 7 (GP-B).
A solution of aryl diazoacetate (0.4 mmol, 2.0 equiv) in CH2Cl2 (1.0 mL) was injected into a solution
of 1,n-allenyne (0.2 mmol, 1.0 equiv) and Cu(PPh3)3Br (18.6 mg, 0.02 mmol, 10 mol %) in CH2Cl2 (1.0
mL) via a syringe pump over 2 h at rt. Then the resulting solution was continued at rt for 12 h. The
mixture was concentrated under reduced pressure and purified by flash column chromatography (eluent:
hexanes/EtOAc) on silica gel to afford the corresponding 3-azabicyclo[m.2.0] products 3 and 5 or the
bisallene product 7.
Methyl 8-phenyl-3-tosyl-3-azabicyclo[5.2.0]nona-1,6 diene-8-carboxylate (3aa): The title compound
was prepared following GP-B, purified by flash column chromatography (hexanes/EtOAc = 7:1) on
1
silica gel and obtained as colorless oil in 83% yield (68.0 mg); H NMR (500 MHz, CDCl3): δ 7.66 (d,
J = 8.3 Hz, 2H), 7.34–7.23 (m, 7H), 6.58 (s, 1H), 5.96 (t, J = 4.9 Hz, 1H), 3.86–3.34 (m, 6H), 2.87 (dd,
13
J = 14.8, 2.1 Hz, 1H), 2.51–2.29 (m, 5H); C{1H} NMR (125 MHz, CDCl3): δ 173.5, 144.0, 141.3,
140.9, 136.2, 130.0, 128.6, 127.3, 127.1, 126.3, 125.7, 122.7, 121.0, 57.2, 52.8, 46.9, 38.5, 32.7, 21.7;
HRMS (ESI) m/z: [M + Na]+ Calcd. for C23H23NO4SNa 432.1240; Found 432.1238.
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Ethyl 8-phenyl-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3ab): The title compound
was prepared following GP-B, purified by flash column chromatography (hexanes/EtOAc = 7:1) on
silica gel and obtained as colorless oil in 81% yield (68.6 mg); 1H NMR (500 MHz, CDCl3): δ 7.66 (d,
J = 8.2 Hz, 2H), 7.33–7.22 (m, 7H), 6.58 (s, 1H), 5.96 (t, J = 4.9 Hz, 1H), 4.18–4.04 (m, 2H), 3.81–3.30
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7
8
9
13
(m, 3H), 2.87 (dd, J = 14.8, 1.9 Hz, 1H), 2.52–2.27 (m, 5H), 1.15 (t, J = 7.1 Hz, 3H); C{1H} NMR
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(125 MHz, CDCl3): δ 172.9, 143.9, 141.4, 141.0, 136.2, 130.0, 128.5, 127.2, 127.1, 126.3, 125.6,
122.5, 121.2, 61.4, 57.2, 46.9, 38.4, 32.6, 21.7, 14.1; HRMS (ESI) m/z: [M + Na]+ Calcd. for
C24H25NO4SNa 446.1397; Found 446.1388.
Benzyl 8-phenyl-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3ac): The title compound
was prepared following GP-B, purified by flash column chromatography (hexanes/EtOAc = 7:1) on
1
silica gel and obtained as colorless oil in 70% yield (68.0 mg); H NMR (500 MHz, CDCl3): δ 7.68–
7.63 (m, 2H), 7.32–7.21 (m, 10H), 7.17–7.10 (m, 2H), 6.58 (s, 1H), 5.93 (t, J = 4.9 Hz, 1H), 5.14–5.05
13
(m, 2H), 4.00–3.20 (m, 3H), 2.90 (dd, J = 14.8, 1.9 Hz, 1H), 2.47–2.25 (m, 5H); C{1H} NMR (125
MHz, CDCl3): δ 172.6, 143.9, 141.1, 140.7, 136.2, 135.9, 130.0, 128.52, 128.47, 128.1, 127.7, 127.3,
127.1, 126.4, 125.8, 122.6, 121.0, 66.9, 57.3, 46.9, 38.4, 32.6, 21.7; HRMS (ESI) m/z: [M + Na]+ Calcd.
for C29H27NO4SNa 508.1553; Found 508.1549.
Allyl 8-phenyl-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3ad): The title compound
was prepared following GP-B, purified by flash column chromatography (hexanes/EtOAc = 7:1) on
1
silica gel and obtained as colorless oil in 65% yield (56.6 mg); H NMR (500 MHz, CDCl3): δ 7.68–
7.64 (m, 2H), 7.35–7.22 (m, 7H), 6.59 (s, 1H), 5.99 (t, J = 4.9 Hz, 1H), 5.84–5.75 (m, 1H), 5.15–5.09
(m, 2H), 4.60–4.51 (m, 2H), 4.10–3.15 (m, 3H), 2.90 (dd, J = 14.9, 1.9 Hz, 1H), 2.49–2.30 (m, 5H);
13C{1H} NMR (125 MHz, CDCl3): δ 172.6, 143.9, 141.2, 140.9, 136.2, 132.0, 130.0, 128.5, 127.3,
127.1, 126.3, 125.8, 122.6, 121.0, 117.8, 65.7, 57.2, 46.9, 38.5, 32.7, 21.7; HRMS (ESI) m/z: [M + Na]+
Calcd. for C25H25NO4SNa 458.1397; Found 458.1388.
Methyl 8-(p-tolyl)-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3ae): The title
compound was prepared following GP-B, purified by flash column chromatography (hexanes/EtOAc =
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7:1) on silica gel and obtained as colorless oil in 87% yield (73.7 mg); 1H NMR (500 MHz, CDCl3): δ
7.65 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H),
6.57 (s, 1H), 5.94 (t, J = 4.9 Hz, 1H), 3.82–3.22 (m, 6H), 2.85 (dd, J = 14.8, 1.9 Hz, 1H), 2.50–2.26 (m,
8H); 13C{1H} NMR (125 MHz, CDCl3): δ 173.6, 143.9, 141.1, 138.3, 137.0, 136.2, 130.0, 129.3,
127.1, 126.2, 125.6, 122.6, 121.0, 56.9, 52.7, 46.9, 38.5, 32.6, 21.7, 21.2; HRMS (ESI) m/z: [M + Na]+
Calcd. for C24H25NO4SNa 446.1397; Found 446.1388.
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Methyl 8-(4-(tert-butyl)phenyl)-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3af): The
title compound was prepared following GP-B, purified by flash column chromatography
(hexanes/EtOAc = 7:1) on silica gel and obtained as colorless oil in 85% yield (79.2 mg); 1H NMR (500
MHz, CDCl3): δ 7.68–7.63 (m, 2H), 7.34–7.27 (m, 4H), 7.22 (d, J = 8.4 Hz, 2H), 6.57 (s, 1H), 5.95 (t, J
= 4.9 Hz, 1H), 3.95–3.35 (s, 6H), 2.88 (dd, J = 14.9, 2.0 Hz, 1H), 2.48–2.31 (m, 5H), 1.30 (s, 9H);
13C{1H} NMR (125 MHz, CDCl3): δ 173.7, 150.1, 143.9, 141.2, 138.2, 136.3, 130.0, 127.1, 126.0,
125.54, 125.51, 122.5, 121.1, 56.9, 52.7, 47.0, 38.5, 34.6, 32.7, 31.4, 21.7; HRMS (ESI) m/z: [M + Na]+
Calcd. for C27H32NO4S 488.1866; Found 488.1861.
Methyl 8-([1,1'-biphenyl]-4-yl)-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3ag): The
title compound was prepared following GP-B, purified by flash column chromatography
(hexanes/EtOAc = 7:1) on silica gel and obtained as colorless oil in 78% yield (75.8 mg); 1H NMR (500
MHz, CDCl3): δ 7.67 (d, J = 8.1 Hz, 2H), 7.59–7.51 (m, 4H), 7.46–7.28 (m, 7H), 6.60 (s, 1H), 6.00 (t, J
13
= 4.9 Hz, 1H), 3.98–3.39 (m, 6H), 2.92 (dd, J = 14.8, 1.9 Hz, 1H), 2.52–2.34 (m, 5H); C{1H} NMR
(125 MHz, CDCl3): δ 173.5, 144.0, 141.0, 140.7, 140.30, 140.28, 136.3, 130.0, 128.9, 127.5, 127.4,
127.19, 127.15, 126.8, 125.7, 122.8, 120.9, 57.0, 52.8, 47.0, 38.6, 32.7, 21.7; HRMS (ESI) m/z: [M +
Na]+ Calcd. for C29H27NO4SNa 508.1553; Found 508.1550.
Methyl 8-(4-methoxyphenyl)-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3ah): The
title compound was prepared following GP-B, purified by flash column chromatography
(hexanes/EtOAc = 7:1) on silica gel and obtained as colorless oil in 91% yield (80.0 mg); 1H NMR (500
MHz, CDCl3): δ 7.66 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 6.84 (d, J =
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8.8 Hz, 2H), 6.57 (s, 1H), 5.95 (t, J = 4.9 Hz, 1H), 3.84–3.62 (m, 9H), 2.85 (dd, J = 14.8, 2.0 Hz, 1H),
2.48–2.30 (m, 5H); 13C{1H} NMR (125 MHz, CDCl3): δ 173.7, 158.8, 143.9, 141.2, 136.2, 133.4,
130.0, 127.5, 127.1, 125.5, 122.6, 121.0, 113.9, 56.5, 55.4, 52.7, 46.9, 38.5, 32.7, 21.7; HRMS (ESI)
m/z: [M + Na]+ Calcd. for C24H25NO5SNa 462.1346; Found 462.1339.
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Methyl 8-(4-fluorophenyl)-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3ai): The title
compound was prepared following GP-B, purified by flash column chromatography (hexanes/EtOAc =
7:1) on silica gel and obtained as colorless oil in 71% yield (60.7 mg); 1H NMR (500 MHz, CDCl3): δ
7.66 (d, J = 8.2 Hz, 2H), 7.32–7.24 (m, 4H), 7.02–6.96 (m, 2H), 6.59 (s, 1H), 5.95 (t, J = 4.9 Hz, 1H),
3.77–3.28 (m, 6H), 2.84 (dd, J = 14.8, 1.9 Hz, 1H), 2.52–2.27 (m, 5H); 13C{1H} NMR (125 MHz,
CDCl3): δ 173.3, 162.0 (d, J = 246.3 Hz), 144.0, 140.9, 137.0 (d, J = 3.6 Hz), 136.2, 130.0, 128.1 (d, J
= 8.1 Hz), 127.1, 125.7, 122.9, 120.6, 115.4 (d, J = 21.3 Hz), 56.6, 52.8, 46.9, 38.6, 32.7, 21.7; HRMS
(ESI) m/z: [M + Na]+ Calcd. for C23H22FNO4SNa 450.1146; Found 450.1136.
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Methyl 8-(4-chlorophenyl)-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3aj): The title
compound was prepared following GP-B, purified by flash column chromatography (hexanes/EtOAc =
7:1) on silica gel and obtained as white solid in 68% yield (60.4 mg); mp: 144 –147 oC; 1H NMR (500
MHz, CDCl3): δ 7.69–7.63 (m, 2H), 7.32–7.21 (m, 6H), 6.59 (s, 1H), 5.94 (t, J = 4.8 Hz, 1H), 3.87–
3.34 (m, 6H), 2.83 (dd, J = 14.9, 2.0 Hz, 1H), 2.53–2.28 (m, 5H); 13C{1H} NMR (125 MHz, CDCl3): δ
173.1, 144.0, 140.7, 139.8, 136.2, 133.2, 130.1, 128.7, 127.9, 127.1, 125.8, 123.0, 120.5, 56.7, 52.9,
46.9, 38.5, 32.7, 21.7; HRMS (ESI) m/z: [M + Na]+ Calcd. for C23H22ClNO4SNa 466.0850; Found
466.0848.
Methyl 8-(4-bromophenyl)-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3ak): The title
compound was prepared via following GP-B, purified by flash column chromatography
(hexanes/EtOAc = 7:1) on silica gel and obtained as white solid in 66% yield (64.5 mg); mp: 153–155
1
oC; H NMR (500 MHz, CDCl3): δ 7.69–7.62 (m, 2H), 7.46–7.39 (m, 2H), 7.33–7.27 (m, 2H), 7.21–
7.14 (m, 2H), 6.59 (s, 1H), 5.93 (t, J = 4.8 Hz, 1H), 3.85–3.30 (m, 6H), 2.83 (dd, J = 14.8, 1.9 Hz, 1H),
2.54–2.28 (m, 5H); 13C{1H} NMR (125 MHz, CDCl3): δ 173.0, 144.0, 140.6, 140.3, 136.2, 131.7,
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130.1, 128.2, 127.1, 125.8, 123.0, 121.3, 120.4, 56.8, 52.9, 46.9, 38.5, 32.7, 21.8; HRMS (ESI) m/z: [M
+ Na]+ Calcd. for C23H22BrNO4SNa 510.0345; Found 510.0337.
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Methyl 8-(4-iodophenyl)-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3al): The title
compound was prepared following GP-B, purified by flash column chromatography (hexanes/EtOAc =
7:1) on silica gel and obtained as white solid in 61% yield (65.3 mg); mp: 145–148 oC; 1H NMR (500
MHz, CDCl3): δ 7.68–7.60 (m, 4H), 7.30 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.3 Hz, 2H), 6.59 (s, 1H),
5.93 (t, J = 4.9 Hz, 1H), 3.85–3.34 (m, 6H), 2.82 (dd, J = 14.8, 1.9 Hz, 1H), 2.51–2.29 (m, 5H); 13C{1H}
NMR (125 MHz, CDCl3): δ 173.0, 144.0, 141.0, 140.6, 137.7, 136.2, 130.0, 128.5, 127.1, 125.8, 123.0,
120.4, 92.9, 56.8, 52.9, 46.9, 38.4, 32.7, 21.8; HRMS (ESI) m/z: [M + Na]+ Calcd. for C23H22INO4SNa
558.0206; Found 558.0195.
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Methyl 8-(3-chlorophenyl)-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3am): The
title compound was prepared following GP-B, purified by flash column chromatography
(hexanes/EtOAc = 7:1) on silica gel and obtained as colorless oil in 69% yield (61.3 mg); 1H NMR (500
MHz, CDCl3): δ 7.68–7.64 (m, 2H), 7.33–7.22 (m, 5H), 7.21–7.13 (m, 1H), 6.60 (s, 1H), 5.95 (t, J =
13
4.9 Hz, 1H), 3.90–3.35 (m, 6H), 2.84 (dd, J = 14.8, 1.9 Hz, 1H), 2.48–2.32 (m, 5H); C{1H} NMR
(125 MHz, CDCl3): δ 172.9, 144.1, 143.2, 140.3, 136.2, 134.5, 130.1, 129.9, 127.5, 127.1, 126.6,
126.0, 124.7, 123.1, 120.5, 56.9, 52.9, 46.9, 38.5, 32.6, 21.7; HRMS (ESI) m/z: [M + Na]+ Calcd. for
C23H22ClNO4SNa 466.0850; Found 466.0842.
Methyl
3-tosyl-8-(3-(trifluoromethyl)phenyl)-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate
(3an): The title compound was prepared following GP-B, purified by flash column chromatography
(hexanes/EtOAc = 7:1) on silica gel and obtained as colorless oil in 53% yield (50.6 mg); 1H NMR (500
MHz, CDCl3): δ 7.68–7.64 (m, 2H), 7.56–7.47 (m, 3H), 7.47–7.41 (m, 1H), 7.30 (d, J = 8.0 Hz, 2H),
6.62 (s, 1H), 5.97 (t, J = 4.8 Hz, 1H), 3.85–3.25 (m, 6H), 2.87 (dd, J = 14.8, 2.0 Hz, 1H), 2.47–2.33 (m,
13
5H); C{1H} NMR (125 MHz, CDCl3): δ 172.8, 144.1, 142.2, 140.3, 136.1, 130.9 (q, J = 32.3 Hz),
130.1, 130.0, 129.2, 127.1, 126.0, 124.3 (q, J = 3.6 Hz), 124.1 (q, J = 272.5 Hz), 123.2, 123.1 (q, J = 4.5
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Hz), 120.2, 57.0, 53.0, 46.9, 38.5, 32.7, 21.7; HRMS (ESI) m/z: [M + Na]+ Calcd. for C24H22F3NO4SNa
500.1114; Found 500.1108.
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Methyl 8-(o-tolyl)-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3ao): The title
compound was prepared following GP-B, purified by flash column chromatography (hexanes/EtOAc =
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10:1 to 7:1) on silica gel and obtained as colorless oil in 23% yield (19.4 mg); H NMR (500 MHz,
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CDCl3): δ 7.69–7.64 (m, 2H), 7.39 (d, J = 7.4 Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.22–7.11 (m, 3H),
6.61 (s, 1H), 5.86 (t, J = 4.8 Hz, 1H), 4.00–3.45 (m, 6H), 2.63 (dd, J = 14.5, 2.0 Hz, 1H), 2.54–2.32 (m,
5H), 2.12 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 173.4, 144.0, 140.4, 138.8, 136.3, 136.1, 131.3,
130.0, 127.5, 127.2, 126.5, 126.0, 125.7, 123.3, 120.8, 57.4, 52.9, 46.9, 37.3, 32.6, 21.7, 19.6; HRMS
(ESI) m/z: [M + Na]+ Calcd. for C24H25NO4SNa 446.1397; Found 446.1388.
Methyl 8-(3,4-dichlorophenyl)-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3ap): The
title compound was prepared following GP-B, purified by flash column chromatography
1
(hexanes/EtOAc = 7:1) on silica gel and obtained as colorless oil in 60% yield (57.4 mg); H NMR
(500 MHz, CDCl3): δ 7.66 (d, J = 8.4 Hz, 2H), 7.40–7.35 (m, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.13 (dd, J
= 8.4, 2.2 Hz, 1H), 6.61 (s, 1H), 5.93 (t, J = 4.9 Hz, 1H), 3.84–3.53 (m, 6H), 2.82 (dd, J = 15.0, 1.9 Hz,
1H), 2.49–2.33 (m, 5H); 13C{1H} NMR (125 MHz, CDCl3): δ 172.6, 144.1, 141.4, 140.2, 136.1, 132.7,
131.5, 130.6, 130.1, 128.5, 127.1, 126.0, 123.3, 120.0, 56.5, 53.0, 46.9, 38.5, 32.7, 21.7; HRMS (ESI)
m/z: [M + H]+ Calcd. for C23H22Cl2NO4S 478.0641; Found 478.0641.
Methyl 8-(3-bromo-4-fluorophenyl)-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3aq):
The title compound was prepared following GP-B, purified by flash column chromatography
(hexanes/EtOAc = 7:1) on silica gel and obtained as colorless oil in 63% yield (63.8 mg); 1H NMR (500
MHz, CDCl3): δ 7.66 (d, J = 8.3 Hz, 2H), 7.50–7.44 (m, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.24–7.18 (m,
1H), 7.08–7.03 (m, 1H), 6.61 (s, 1H), 5.94 (t, J = 4.9 Hz, 1H), 3.80–3.32 (m, 6H), 2.82 (dd, J = 14.9, 1.8
Hz, 1H), 2.51–2.31 (m, 5H); 13C{1H} NMR (125 MHz, CDCl3): δ 172.8, 158.3 (d, J = 247.3 Hz),
144.1, 140.4, 138.6 (d, J = 3.7 Hz), 136.1, 131.5, 130.1, 127.2 (d, J = 7.3 Hz), 127.1, 126.0, 123.3,
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120.1, 116.5 (d, J = 22.7 Hz), 109.2 (d, J = 21.2 Hz), 56.3, 53.0, 46.9, 38.6, 32.7, 21.8; HRMS (ESI)
m/z: [M + Na]+ Calcd. for C23H21FBrNO4SNa 528.0251; Found 528.0247.
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Methyl 8-(naphthalen-2-yl)-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3ar): The title
compound was prepared following GP-B, purified by flash column chromatography (hexanes/EtOAc =
7:1) on silica gel and obtained as colorless oil in 58% yield (53.3 mg); 1H NMR (500 MHz, CDCl3): δ
7.82–7.76 (m, 3H), 7.74 (s, 1H), 7.69–7.64 (m, 2H), 7.49–7.43 (m, 2H), 7.41–7.37 (m, 1H), 7.28 (d, J =
8.0 Hz, 2H), 6.62 (s, 1H), 6.05 (t, J = 4.8 Hz, 1H), 4.00–3.30 (m, 6H), 2.95 (dd, J = 14.8, 2.0 Hz, 1H),
2.56–2.35 (m, 5H); 13C{1H} NMR (125 MHz, CDCl3): δ 173.4, 143.9, 140.8, 138.5, 136.3, 133.2,
132.6, 130.0, 128.6, 128.1, 127.7, 127.1, 126.4, 126.2, 125.9, 124.8, 124.6, 122.9, 120.9, 57.4, 52.8,
47.0, 38.5, 32.7, 21.7; HRMS (ESI) m/z: [M + Na]+ Calcd. for C27H25NO4SNa 482.1397; Found
482.1391.
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Methyl 8-(benzofuran-3-yl)-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3as): The title
compound was prepared following GP-B, purified by flash column chromatography (hexanes/EtOAc =
7:1) on silica gel and obtained as colorless oil in 69% yield (62.0 mg); 1H NMR (500 MHz, CDCl3): δ
7.69–7.66 (m, 2H), 7.49–7.40 (m, 3H), 7.33–7.28 (m, 3H), 7.22–7.18 (m, 1H), 6.65 (s, 1H), 5.92 (t, J =
13
4.8 Hz, 1H), 3.84–3.28 (m, 6H), 2.93 (dd, J = 14.8, 1.9 Hz, 1H), 2.46–2.31 (m, 5H); C{1H} NMR
(125 MHz, CDCl3): δ 172.7, 155.9, 144.1, 142.2, 140.7, 136.2, 130.1, 127.2, 126.1, 124.7, 124.5,
123.4, 122.9, 121.3, 121.1, 120.3, 111.9, 52.9, 50.1, 46.9, 36.9, 32.5, 21.7; HRMS (ESI) m/z: [M + Na]+
Calcd. for C25H23NO5SNa 472.1189; Found 472.1184.
Methyl 8-phenyl-3-(phenylsulfonyl)-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3ba): The
title compound was prepared following GP-B, purified by flash column chromatography
(hexanes/EtOAc = 7:1) on silica gel and obtained as colorless oil in 80% yield (63.2 mg); 1H NMR (500
MHz, CDCl3): δ 7.80–7.76 (m, 2H), 7.61–7.57 (m, 1H), 7.53–7.48 (m, 2H), 7.33–7.23 (m, 5H), 6.59 (s,
1H), 5.96 (t, J = 4.8 Hz, 1H), 3.92–3.45 (m, 6H), 2.88 (dd, J = 14.9, 1.9 Hz, 1H), 2.53–2.28 (m, 2H);
13C{1H} NMR (125 MHz, CDCl3): δ 173.4, 141.2, 140.8, 139.2, 133.1, 129.4, 128.6, 127.3, 127.1,
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126.3, 125.8, 122.5, 121.3, 57.2, 52.8, 47.0, 38.5, 32.6; HRMS (ESI) m/z: [M + Na]+ Calcd. for
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C22H21NO4SNa 418.1084; Found 418.1078.
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Methyl
3-((4-bromophenyl)sulfonyl)-8-phenyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate
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(3ca): The title compound was prepared following GP-B, purified by flash column chromatography
(hexanes/EtOAc = 7:1) on silica gel and obtained as colorless oil in 76% yield (72.0 mg); 1H NMR (500
MHz, CDCl3): δ 7.64 (s, 4H), 7.35–7.24 (m, 5H), 6.54 (s, 1H), 5.98 (t, J = 4.8 Hz, 1H), 3.90–3.35 (m,
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6H), 2.88 (dd, J = 14.9, 2.0 Hz, 1H), 2.52–2.29 (m, 2H); C{1H} NMR (125 MHz, CDCl3): δ 173.3,
141.0, 140.8, 138.3, 132.7, 128.64, 128.57, 128.1, 127.4, 126.3, 126.1, 122.3, 122.2, 57.2, 52.8, 47.0,
38.5, 32.5; HRMS (ESI) m/z: [M + Na]+ Calcd. for C22H20BrNO4SNa 496.0189; Found 496.0186.
Methyl
3-((4-nitrophenyl)sulfonyl)-8-phenyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate
(3da): The title compound was prepared following GP-B, purified by flash column chromatography
(hexanes/EtOAc = 7:1) on silica gel and obtained as colorless oil in 71% yield (62.5 mg); 1H NMR (500
MHz, CDCl3): δ 8.36–8.32 (m, 2H), 7.98–7.95 (m, 2H), 7.33–7.24 (m, 5H), 6.55 (s, 1H), 6.00 (t, J =
13
4.7 Hz, 1H), 3.84–3.49 (m, 6H), 2.91 (dd, J = 15.1, 1.9 Hz, 1H), 2.51–2.31 (m, 2H); C{1H} NMR
(125 MHz, CDCl3): δ 173.2, 150.2, 144.9, 140.79, 140.76, 128.7, 128.3, 127.5, 126.5, 126.2, 124.7,
123.6, 121.6, 57.2, 52.8, 47.2, 38.5, 32.5; HRMS (ESI) m/z: [M + Na]+ Calcd. for C22H20N2O6SNa
463.0934; Found 463.0928.
Methyl 3-(methylsulfonyl)-8-phenyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3ea): The
title compound was prepared following GP-B, purified by flash column chromatography
(hexanes/EtOAc = 7:1) on silica gel and obtained as colorless oil in 73% yield (48.7 mg); 1H NMR (500
MHz, CDCl3): δ 7.40–7.32 (m, 4H), 7.30–7.25 (m, 1H), 6.41 (s, 1H), 6.12 (t, J = 4.8 Hz, 1H), 3.94–
3.56 (m, 6H), 2.96–2.88 (m, 4H), 2.79–2.60 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ 173.5,
141.2, 141.1, 128.7, 127.4, 126.4, 125.9, 122.2, 121.6, 57.3, 52.9, 46.7, 39.9, 38.4, 33.6; HRMS (ESI)
m/z: [M + Na]+ Calcd. for C17H19NO4SNa 356.0927; Found 356.0923.
Methyl 5-methyl-8-phenyl-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3fa): The title
compound was prepared following GP-B, purified by flash column chromatography (hexanes/EtOAc =
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7:1) on silica gel and obtained as colorless oil in 82% yield (69.4 mg; mixture of two inseparable
regioisomers; dr ~ 1.5:1); 1H NMR (500 MHz, CDCl3): δ 7.68–7.62 (m, 2H), 7.40–7.23 (m, 7H), 6.57–
6.46 (m, 1H), 5.88–5.78 (m, 1H), 4.61–4.51 (m, 1H), 3.81–3.73 (m, 1H), 3.68–3.63 (m, 3H), 2.96–2.88
(m, 1H), 2.45–2.34 (m, 4H), 2.11–1.94 (m, 1H), 0.96–0.86 (m, 3H); 13C{1H} NMR (125 MHz, CDCl3):
δ 173.6, 173.5, 143.90, 143.85, 141.84, 141.77, 141.2, 141.1, 136.1, 135.9, 130.0, 129.9, 128.7, 128.5,
127.30, 127.25, 126.41, 126.38, 122.2, 121.9, 121.7, 120.1, 119.0, 118.9, 57.1, 57.0, 52.8, 52.7, 50.2,
49.5, 38.9, 38.6, 36.8, 36.6, 21.7, 17.1, 17.0; HRMS (ESI) m/z: [M + Na]+ Calcd. for C24H25NO4SNa
446.1397; Found 446.1389.
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Methyl 4,8-diphenyl-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3ga): The title
compound was prepared following GP-B, purified by flash column chromatography (hexanes/EtOAc =
7:1) on silica gel and obtained as white solid in 73% yield (70.9 mg; mixture of two inseparable
o
1
regioisomers; dr ~ 2:1); mp: 172–175 C; H NMR (500 MHz, CDCl3): δ 7.74–7.66 (m, 2H), 7.36–
7.15 (m, 8H), 7.10–6.96 (m, 2H), 6.82–6.58 (m, 1H), 6.51–6.47 (m, 1H), 5.97–5.67 (m, 2H), 3.68–3.39
(m, 4H), 3.30–3.07 (m, 1H), 2.86–2.39 (m, 5H), 2.21–1.95 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3):
δ 173.5, 172.9, 144.2, 144.0, 142.63, 142.58, 141.5, 141.0, 139.0, 138.6, 136.1, 135.6, 130.2, 130.0,
128.50, 128.45, 128.4, 127.9, 127.6, 127.4, 127.3, 127.0, 126.9, 126.8, 126.7, 126.4, 126.3, 125.8,
123.7, 123.0, 122.9, 121.5, 119.8, 119.7, 58.2, 57.2, 57.0, 56.9, 52.53, 52.49, 39.4, 38.6, 34.2, 33.7,
21.8; HRMS (ESI) m/z: [M + Na]+ Calcd. for C29H27NO4SNa 508.1553; Found 508.1552.
Methyl
1-phenyl-4-tosyl-2,4,4a,5,6,7,8,8a-octahydro-1H-benzo[b]cyclobuta[e]azepine-1-
carboxylate (3ha): The title compound was prepared following GP-B, purified by flash column
chromatography (hexanes/EtOAc = 7:1) on silica gel to obtain a mixture of four inseparable
regioisomers, which was further recrystallized in hexanes/EtOAc to obtain one major regioisomer as
o
1
white solid in 35% yield (32.4 mg); mp: 177–179 C; H NMR (500 MHz, CDCl3): δ 7.65–7.59 (m,
2H), 7.32–7.24 (m, 3H), 7.17–7.07 (m, 4H), 6.40–6.36 (m, 1H), 5.60–5.58 (m, 1H), 3.75 (dd, J = 15.1,
2.4 Hz, 1H), 3.64 (s, 3H), 3.04–2.97 (m, 1H), 2.87 (dd, J = 15.1, 1.6 Hz, 1H), 2.63–2.55 (m, 1H), 2.38
(s, 3H), 2.33–2.22 (m, 1H), 2.06–1.92 (m, 2H), 1.84–1.76 (m, 1H), 1.65–1.58 (m, 1H), 1.28–1.16 (m,
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1H), 1.08–0.95 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ 173.5, 143.1, 140.3, 139.4, 137.6, 132.3,
129.7, 129.5, 128.5, 127.24, 127.15, 126.5, 125.8, 67.4, 57.8, 52.7, 45.4, 38.2, 34.9, 32.7, 26.7, 24.8,
21.8; HRMS (ESI) m/z: [M + Na]+ Calcd. for C27H29NO4SNa 486.1710; Found 486.1705.
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Methyl 9-methyl-8-phenyl-3-tosyl-3-azabicyclo[5.2.0]nona-1,6-diene-8-carboxylate (3ia): The title
compound was prepared following GP-B, purified by flash column chromatography (hexanes/EtOAc =
7:1) on silica gel and obtained as white solid in 74% yield (62.7 mg; one regioisomer); mp: 166–168 oC;
1H NMR (500 MHz, CDCl3): δ 7.69–7.66 (m, 2H), 7.34–7.26 (m, 5H), 7.09 (d, J = 7.0 Hz, 2H), 6.59 (s,
1H), 5.86 (t, J = 4.8 Hz, 1H), 3.98–3.92 (m, 1H), 3.84–3.44 (m, 5H), 2.51–2.28 (m, 5H), 0.70 (d, J = 7.1
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Hz, 3H); C{1H} NMR (125 MHz, CDCl3): δ 174.1, 143.9, 138.9, 137.5, 136.4, 130.0, 128.6, 128.4,
127.5, 127.3, 127.2, 126.4, 122.1, 62.0, 52.7, 47.1, 41.9, 32.5, 21.8, 16.2; HRMS (ESI) m/z: [M + Na]+
Calcd. for C24H25NO4SNa 446.1397; Found 446.1391.
Methyl (1Z,7E)-9-phenyl-3-tosyl-3-azabicyclo[6.2.0]deca-1,7-diene-9-carboxylate (5a): The title
compound was prepared following GP-B, purified by flash column chromatography (hexanes/EtOAc =
1
15:1 to 7:1) on silica gel and obtained as colorless oil in 61% yield (51.7 mg); H NMR (500 MHz,
CDCl3): δ 7.69–7.65 (m, 2H), 7.37–7.23 (m, 7H), 6.28 (s, 1H), 5.73 (t, J = 6.6 Hz, 1H), 3.90–3.82 (m,
1H), 3.76–3.68 (m, 1H), 3.65 (s, 3H), 3.61 (dd, J = 14.0, 1.9 Hz, 1H), 2.71 (dd, J = 14.0, 1.7 Hz, 1H),
13
2.42 (s, 3H), 2.33–2.24 (m, 1H), 2.19–2.09 (m, 1H), 1.83–1.72 (m, 1H), 1.62–1.52 (m, 1H); C{1H}
NMR (125 MHz, CDCl3): δ 173.4, 143.9, 141.07, 141.06, 136.2, 130.0, 128.7, 127.3, 127.1, 126.7,
122.3, 121.4, 118.2, 57.7, 52.6, 48.0, 38.8, 25.3, 22.6, 21.7; HRMS (ESI) m/z: [M + Na]+ Calcd. for
C24H25NO4SNa 446.1397; Found 446.1389.
Methyl (1Z,7E)-9-(p-tolyl)-3-tosyl-3-azabicyclo[6.2.0]deca-1,7-diene-9-carboxylate (5b): The title
compound was prepared following GP-B, purified by flash column chromatography (hexanes/EtOAc =
1
15:1 to 7:1) on silica gel and obtained as colorless oil in 65% yield (57.0 mg); H NMR (500 MHz,
CDCl3): δ 7.67 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.1
Hz, 2H), 6.27 (s, 1H), 5.72 (t, J = 6.7 Hz, 1H), 3.89–3.81 (m, 1H), 3.75–3.68 (m, 1H), 3.64 (s, 3H), 3.59
(dd, J = 13.9, 1.8 Hz, 1H), 2.68 (dd, J = 13.9, 1.8 Hz, 1H), 2.42 (s, 3H), 2.34–2.24 (m, 4H), 2.17–2.09
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(m, 1H), 1.82–1.72 (m, 1H), 1.60–1.52 (m, 1H); C{1H} NMR (125 MHz, CDCl3): δ 173.6, 143.9,
141.3, 138.1, 137.1, 136.2, 130.0, 129.4, 127.1, 126.6, 122.1, 121.4, 118.4, 57.4, 52.6, 48.0, 38.8, 25.2,
22.6, 21.7, 21.2; HRMS (ESI) m/z: [M + Na]+ Calcd. for C25H27NO4SNa 460.1553; Found 460.1547.
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Methyl
(1Z,7E)-9-([1,1'-biphenyl]-4-yl)-3-tosyl-3-azabicyclo[6.2.0]deca-1,7-diene-9-carboxylate
9
(5c): The title compound was prepared following GP-B, purified by flash column chromatography
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(hexanes/EtOAc = 15:1 to 7:1) on silica gel and obtained as colorless oil in 68% yield (68.0 mg); H
NMR (500 MHz, CDCl3): δ 7.70–7.66 (m, 2H), 7.58–7.52 (m, 4H), 7.45–7.40 (m, 4H), 7.36–7.32 (m,
1H), 7.31–7.28 (m, 2H), 6.31 (s, 1H), 5.77 (t, J = 6.5 Hz, 1H), 3.91–3.84 (m, 1H), 3.78–3.70 (m, 1H),
3.68 (s, 3H), 3.64 (dd, J = 14.0, 1.8 Hz, 1H), 2.75 (dd, J = 14.0, 1.8 Hz, 1H), 2.41 (s, 3H), 2.35–2.26 (m,
1H), 2.20–2.12 (m, 1H), 1.84–1.74 (m, 1H), 1.64–1.55 (m, 1H); C{1H} NMR (125 MHz, CDCl3): δ
13
173.4, 143.9, 141.1, 140.7, 140.3, 140.1, 136.2, 130.0, 128.9, 127.5, 127.4, 127.2, 127.1, 122.3, 121.5,
118.2, 57.5, 52.7, 48.0, 38.8, 25.4, 22.6, 21.7; HRMS (ESI) m/z: [M + Na]+ Calcd. for C30H29NO4SNa
522.1710; Found 522.1702.
Methyl (1Z,7E)-9-(4-fluorophenyl)-3-tosyl-3-azabicyclo[6.2.0]deca-1,7-diene-9-carboxylate (5d):
The title compound was prepared following GP-B, purified by flash column chromatography
1
(hexanes/EtOAc = 15:1 to 7:1) on silica gel and obtained as colorless oil in 60% yield (53.0 mg); H
NMR (500 MHz, CDCl3): δ 7.70–7.65 (m, 2H), 7.35–7.27 (m, 4H), 7.03–6.96 (m, 2H), 6.30 (s, 1H),
5.72 (t, J = 6.6 Hz, 1H), 3.89–3.83 (m, 1H), 3.74–3.64 (m, 4H), 3.60 (dd, J = 13.9, 1.8 Hz, 1H), 2.67
(dd, J = 14.0, 1.8 Hz, 1H), 2.42 (s, 3H), 2.33–2.24 (m, 1H), 2.19–2.10 (m, 1H), 1.82–1.73 (m, 1H),
1.62–1.53 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 173.2, 162.0 (d, J = 246.2 Hz), 143.9, 141.0,
136.8 (d, J = 3.4 Hz), 136.1, 130.0, 128.5 (d, J = 7.5 Hz), 127.1, 122.3, 121.6, 117.8, 115.5 (d, J = 21.2
Hz), 57.0, 52.7, 47.9, 38.8, 25.4, 22.5, 21.7; HRMS (ESI) m/z: [M + Na]+ Calcd. for C24H24FNO4SNa
464.1302; Found 464.1298.
Methyl (1Z,7E)-9-(4-chlorophenyl)-3-tosyl-3-azabicyclo[6.2.0]deca-1,7-diene-9-carboxylate (5e):
The title compound was prepared following GP-B, purified by flash column chromatography
1
(hexanes/EtOAc = 15:1 to 7:1) on silica gel and obtained as colorless oil in 58% yield (53.0 mg); H
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NMR (500 MHz, CDCl3): δ 7.69–7.65 (m, 2H), 7.32–7.25 (m, 6H), 6.30 (s, 1H), 5.71 (t, J = 6.6 Hz,
1H), 3.89–3.82 (m, 1H), 3.71–3.63 (m, 4H), 3.60 (dd, J = 14.0, 1.8 Hz, 1H), 2.66 (dd, J = 13.9, 1.8 Hz,
1H), 2.42 (s, 3H), 2.33–2.25 (m, 1H), 2.19–2.10 (m, 1H), 1.82–1.73 (m, 1H), 1.62–1.53 (m, 1H);
13C{1H} NMR (125 MHz, CDCl3): δ 173.0, 144.0, 140.7, 139.6, 136.1, 133.2, 130.0, 128.8, 128.2,
127.1, 122.4, 121.6, 117.6, 57.2, 52.8, 47.9, 38.8, 25.4, 22.6, 21.7; HRMS (ESI) m/z: [M + Na]+ Calcd.
for C24H24ClNO4SNa 480.1007; Found 480.0999.
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Methyl (1Z,7E)-9-(4-bromophenyl)-3-tosyl-3-azabicyclo[6.2.0]deca-1,7-diene-9-carboxylate (5f):
The title compound was prepared following GP-B, purified by flash column chromatography
1
(hexanes/EtOAc = 15:1 to 7:1) on silica gel and obtained as colorless oil in 55% yield (55.3 mg); H
NMR (500 MHz, CDCl3): δ 7.69–7.65 (m, 2H), 7.45–7.42 (m, 2H), 7.31–7.28 (m, 2H), 7.24–7.20 (m,
2H), 6.30 (s, 1H), 5.70 (t, J = 6.6 Hz, 1H), 3.88–3.82 (m, 1H), 3.70–3.63 (s, 4H), 3.60 (dd, J = 14.0, 1.8
Hz, 1H), 2.66 (dd, J = 13.9, 1.8 Hz, 1H), 2.42 (s, 3H), 2.33–2.25 (m, 1H), 2.19–2.10 (m, 1H), 1.82–1.73
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(m, 1H), 1.63–1.53 (m, 1H); C{1H} NMR (125 MHz, CDCl3): δ 172.9, 144.0, 140.7, 140.2, 136.1,
131.8, 130.0, 128.6, 127.1, 122.5, 121.7, 121.3, 117.6, 57.2, 52.8, 47.9, 38.7, 25.4, 22.6, 21.7; HRMS
(ESI) m/z: [M + Na]+ Calcd. for C24H24BrNO4SNa 524.0502; Found 524.0490.
Methyl (1Z,7E)-9-(4-iodophenyl)-3-tosyl-3-azabicyclo[6.2.0]deca-1,7-diene-9-carboxylate (5g): The
title compound was prepared following GP-B, purified by flash column chromatography
1
(hexanes/EtOAc = 15:1 to 7:1) on silica gel and obtained as colorless oil in 52% yield (57.0 mg); H
NMR (500 MHz, CDCl3): δ 7.70–7.61 (m, 4H), 7.30 (d, J = 8.0 Hz, 2H), 7.12–7.07 (m, 2H), 6.29 (s,
1H), 5.69 (t, J = 6.6 Hz, 1H), 3.88–3.81 (m, 1H), 3.72–3.62 (m, 4H), 3.60 (dd, J = 14.0, 1.8 Hz, 1H),
2.65 (dd, J = 13.9, 1.8 Hz, 1H), 2.43 (s, 3H), 2.33–2.25 (m, 1H), 2.19–2.09 (m, 1H), 1.82–1.73 (m, 1H),
1.62–1.53 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 172.9, 144.0, 140.9, 140.6, 137.7, 136.1,
130.0, 128.9, 127.1, 122.4, 121.7, 117.6, 92.9, 57.3, 52.8, 47.9, 38.7, 25.4, 22.6, 21.7; HRMS (ESI) m/z:
[M + Na]+ Calcd. for C24H24INO4SNa 572.0363; Found 572.0358.
Methyl (1Z,7E)-9-(3-chlorophenyl)-3-tosyl-3-azabicyclo[6.2.0]deca-1,7-diene-9-carboxylate (5h):
The title compound was prepared following GP-B, purified by flash column chromatography
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1
(hexanes/EtOAc = 15:1 to 7:1) on silica gel and obtained as colorless oil in 38% yield (34.8 mg); H
NMR (500 MHz, CDCl3): δ 7.69–7.66 (m, 2H), 7.33–7.28 (m, 3H), 7.26–7.20 (m, 3H), 6.30 (s, 1H),
5.72 (t, J = 6.4 Hz, 1H), 3.89–3.83 (m, 1H), 3.71–3.64 (m, 4H), 3.61 (dd, J = 14.0, 1.8 Hz, 1H), 2.68
(dd, J = 14.0, 1.8 Hz, 1H), 2.42 (s, 3H), 2.34–2.25 (m, 1H), 2.20–2.11 (m, 1H), 1.82–1.72 (m, 1H),
1.64–1.56 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 172.9, 144.0, 143.2, 140.4, 136.1, 134.5,
130.0, 129.9, 127.6, 127.1, 127.0, 125.0, 122.7, 121.7, 117.5, 57.4, 52.8, 47.9, 38.8, 25.5, 22.6, 21.7;
HRMS (ESI) m/z: [M + Na]+ Calcd. for C24H24ClNO4SNa 480.1007; Found 480.1003.
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Methyl (1Z,7E)-9-(naphthalen-2-yl)-3-tosyl-3-azabicyclo[6.2.0]deca-1,7-diene-9-carboxylate (5i):
The title compound was prepared following GP-B, purified by flash column chromatography
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(hexanes/EtOAc = 15:1 to 7:1) on silica gel and obtained as colorless oil in 47% yield (44.5 mg); H
NMR (500 MHz, CDCl3): δ 7.83–7.77 (m, 4H), 7.69–7.64 (m, 2H), 7.50–7.40 (m, 3H), 7.29–7.25 (m,
2H), 6.30 (s, 1H), 5.82 (t, J = 6.6 Hz, 1H), 3.91–3.84 (m, 1H), 3.78–3.64 (m, 5H), 2.79 (dd, J = 14.0, 1.8
Hz, 1H), 2.42–2.30 (m, 4H), 2.24–2.16 (m, 1H), 1.87–1.78 (m, 1H), 1.68–1.59 (m, 1H); 13C{1H} NMR
(125 MHz, CDCl3): δ 173.4, 143.9, 141.0, 138.4, 136.1, 133.2, 132.6, 130.0, 128.6, 128.1, 127.7, 127.1,
126.4, 126.2, 125.3, 125.0, 122.4, 121.6, 118.1, 57.9, 52.7, 48.0, 38.7, 25.5, 22.8, 21.7; HRMS (ESI)
m/z: [M + Na]+ Calcd. for C28H27NO4SNa 496.1553; Found 496.1550.
Methyl 8-((4-methyl-N-(propa-1,2-dien-1-yl)phenyl)sulfonamido)-2-phenylocta-2,3-dienoate (7):
The title compound was prepared following GP-B, purified by flash column chromatography
(hexanes/EtOAc = 15:1 to 7:1) on silica gel and obtained as light-yellow oil in 56% yield (49.0 mg); 1H
NMR (500 MHz, CDCl3): δ 7.69–7.66 (m, 2H), 7.50–7.46 (m, 2H), 7.37–7.28 (m, 5H), 6.81 (t, J = 6.2
Hz, 1H), 5.79 (t, J = 7.0 Hz, 1H), 5.26 (d, J = 6.3 Hz, 2H), 3.81 (s, 3H), 3.09 (t, J = 7.0 Hz, 2H), 2.42 (s,
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3H), 2.26–2.20 (m, 2H), 1.67–1.59 (m, 2H), 1.58–1.50 (m, 2H); C{1H} NMR (125 MHz, CDCl3): δ
211.7, 201.5, 167.0, 143.8, 135.4, 133.0, 129.9, 128.5, 128.4, 127.7, 127.3, 103.3, 100.3, 96.0, 87.7,
52.4, 46.3, 27.8, 27.5, 25.8, 21.7; HRMS (ESI) m/z: [M + Na]+ Calcd. for C25H27NO4SNa 460.1553;
Found 460.1546.
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Gram-Scale Synthesis. A solution of phenyl diazoacetate 2a (1761.8 mg, 10.0 mmol, 2.0 equiv) in
CH2Cl2 (25.0 mL) was added dropwise into a solution of allenyne 1a (1306.5 mg, 5.0 mmol, 1.0 equiv)
and Cu(PPh3)3Br (465.2 mg, 0.5 mmol, 10 mol %) in CH2Cl2 (25.0 mL) via a constant pressure
dropping funnel over 2 h at rt under N2. Then the resulting mixture was continued at rt for 12 h
(monitored by TLC). The mixture was concentrated under reduced pressure and purified by flash
column chromatography (eluent: hexanes/EtOAc = 7:1) on silica gel to afford the corresponding product
3aa in 72% yield (1474.2 mg).
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Radical Inhibition Experiments. A solution of phenyl diazoacetate 2a (70.5 mg, 0.4 mmol, 2.0
equiv) in CH2Cl2 (1.0 mL) was injected into a solution of allenyne 1a (52.3 mg, 0.2 mmol, 1.0 equiv),
Cu(PPh3)3Br (18.6 mg, 0.02 mmol, 10 mol %) and additive (BHT 44.1 mg or TEMPO 31.2 mg, 0.2
mmol, 1.0 equiv) in CH2Cl2 (1.0 mL) via a syringe pump over 2 h at rt. Then the resulting mixture was
continued at rt for 12 h (monitored by TLC). The solution was concentrated under reduced pressure and
purified by flash column chromatography (eluent: hexanes/EtOAc = 7:1) on silica gel to afford the
corresponding product 3aa in 80% yield (BHT, 65.5 mg) or 84% yield (TEMPO, 68.8 mg).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
http://pubs.acs.org.
Figures of copies of 1H and 13C NMR spectra and single crystal X-ray structures (PDF)
Crystal data for 3al, 3ga, 3ha, 3ia (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: psy880124@mail.nankai.edu.cn
Author Contributions
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The Journal of Organic Chemistry
§M.H. and N.C. contributed equally to this work.
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ORCID
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Hongguang Li: 0000-0002-6579-7300
Ming Lang: 0000-0002-0758-5465
Jian Wang: 0000-0002-3298-6367
Shiyong Peng: 0000-0002-2387-5868
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the Natural Science Foundation of Guangdong Province (No. 2018A030310680), the
Research Foundation of Department of Education of Guangdong Province (No. 2017KQNCX204,
2018KTSCX236), the Science Foundation for Young Teachers of Wuyi University (No. 2019td09), and
the College Students Innovation and Entrepreneurship Training Program of Wuyi University (No.
201911349309) for their financial support.
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