Iridium-Catalyzed Cycloisomerization of N-Tethered 1,7-Enynes: Construction of an Azabicyclo[5.1.0]octene System

Article abstract of DOI:10.1021/acs.joc.0c00516

An efficient method for the synthesis of azabicyclo[5.1.0]octenes through cycloisomerization of nitrogen-tethered 1,7-enynes catalyzed by [IrCp*Cl2]2 was developed. With appropriately designed substrates, this method could be easily employed to generate complex fused ring systems such as [6-6-3-7], [5-6-3-7], [7-6-3-7], and [8-6-3-7] ring systems, which enriches the diversity of the cyclopropane-fused polycycle library, and has potential applications in SAR studies of pharmaceutically interesting compounds and total synthesis of natural products.

Full text of DOI:10.1021/acs.joc.0c00516

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Note
Iridium-Catalyzed Cycloisomerization of N-Tethered 1,7-
Enynes: Construction of Azabicyclo [5.1.0] octene System
Sheng Zhao, Zhong-Lin Zang, Siyu Li, Xumei Wen, Chenhui Wang, Jian Guo, and Yun He
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00516 • Publication Date (Web): 17 Jun 2020
Downloaded from pubs.acs.org on June 17, 2020
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Iridium-Catalyzed Cycloisomerization of N-Tethered 1,7-
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8
9
Enynes: Construction of Azabicyclo [5.1.0] octene System
Sheng Zhao,† Zhong-LinZang,‡ Siyu Li,† Xumei Wen,† Chenhui Wang,† Jian Guo*,† and Yun He*,†
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†Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of
Pharmaceutical Sciences, Chongqing University, Chongqing 401331, P.R. China.
‡Key Laboratory of Luminescent and Real-Time Analytical Chemistry, Ministry of Education,
Institute of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering,
Southwest University, Chongqing 400715, P. R. China.
*E-mail: jian.guo@cqu.edu.cn, yun.he@cqu.edu.cn
Ts
N
Ts
Ir 10 mol %
N
CHCl3, 45 
C
19 examples
up to 98%
Iridium-catalyzed cycloisomerization for construction of azabicyclo [5.1.0] octenes
Abstract: An efficient method for the synthesis of azabicyclo [5.1.0] octenes through
cycloismerization of nitrogen-tethered 1,7-enynes catalyzed by [IrCp*Cl2]2 was developed.
With appropriately designed substrates, this method could be easily employed to generate
complex fused ring systems such as [6-6-3-7], [5-6-3-7], [7-6-3-7], and [8-6-3-7] ring systems,
which enriches the diversity of cyclopropane-fused polycycle library, and has potential
applications in SAR studies of pharmaceutically interesting compounds and total synthesis of
natural products.
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Cyclopropane-fused bicycles and polycycles represent a class of privileged scaffolds existing
in numerous bioactive natural products1-3 and synthetic pharmaceutical compounds.4 Their
potential applications as intermediates for natural or biologically active compounds has driven
the exploration for novel synthetic methodologies that can generate these complex cyclic
scaffolds from readily accessible acyclic precursors. Among them, transition metal-catalyzed
cycloisomerization provides a powerful and atom-economical protocol. These complex
polycycle scaffolds could be efficiently constructed in just a single step. There are many reports
on cycloisomerization reactions from 1,6-enyne catalyzed by π-acidic metal catalysts, such as
Pt, Pd, Au, Rh, as well as Ir, for the preparation of hetero-bicyclo [4.1.0] heptene derivatives
(Scheme 1A).5 However, as a class of homologous scaffold of hetero-bicyclo [4.1.0] heptene,
hetero-bicyclo [5.1.0] octene was paid little attention, and there have been few systematic
studies on the construction of this scaffold.
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Scheme 1. Cycloisomerization reactions of enynes to generate hetero-bicyclo [n.1.0] octene
scaffolds.
A. Previous work
Rh
Pt
Ir
R1
R1
R4
R2
R3
Mn
Au
X
...
R2
X
X = NTs, O,
R4
R3
Rh
Au
Mn
Ir
Pt
Fensterbank, 2011
Chatani, 2009
Chung, 2006
Matsubara, 2012
Furstner, 2001
Zhang, 2018
Hayashi, 2011
Echavarren, 2007
Cramer, 2015
...
...
...
...
B. This work
Ts
Ir
Ts
N
N
CHCl3, 45 
C
Considering that these three-dimensional complex bicyclo [5.1.0] octene scaffolds are
promising for structure-activity-relationship studies in drug discovery, we decided to develop
an efficient and general method to construct such azabicyclo [5.1.0] octene scaffolds.
Continuing our efforts in developing efficient methods for natural product synthesis and SAR
studies,6-10 herein we report a novel transformation catalyzed by [IrCp*Cl2]2 to generate the
azabicyclo [5.1.0] octene scaffold. Especially, we meticulously designed precursors to increase
the complexity of ring systems and enrich the diversity of cyclopropane-fused polycycle library.
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To explore the feasibility of the proposed cyclization, we initially examined the reaction with
5
6
enyne 1a and different catalysts, such as [IrMeO(COD)]2, [IrCl(COD)]2, Cu(MeCN)4, AuCl3
7
8
PtCl2, Echavarren’s catalyst and [IrCp Cl2]2 (Full catalyst screening, Table S1, see SI) using
*
9
chloroform as the reaction solvent at 40 °C (Entries 1-7, Table 1). While most catalysts didn’t
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furnish the desired product or just generated trace amount of 2a (Entries 1-3, Table 1). The
catalysts AuCl3, PtCl2, Echavarren’s catalyst and [IrCp
*
Cl2]2 could successfully convert
eneyne 1a into desired azabicyclo [5.1.0] octene 2a (Entries 4-7, Table1). In all of the
catalysts, [IrCp
*
Cl2]2 could get the highest isolated yield (56%) within 5 hours (Entry 7, Table
1
1). The structure of 2a was established by H, 13C {1H} NMR and HRMS spectra, and
supported later by the single-crystal X-ray crystallography of 2e (Figure S1, See SI).
Encouraged by this promising result, we further investigated the influence of temperature,
solvents, and catalyst loading on the yield of 2a. It was suggested that the reaction proceeded
following a parabolic trend depending on the temperature (Entries 8-10, Table 1). It was at 45
ºC that the reaction delivered 2a in the highest yield (82% by NMR and 78% isolated yield;
Entry 9, Table 1). Solvents had a significant impact on the transformation with varying yields
(Entries 11-13, Table1). 1,2-Dichloroethane (DCE) resulted in lower yield, so did
tetrahydrofuran (THF) and toluene, where the majority of starting material 1a remained, even
when the reaction time was extended to 10 hours. At last, chloroform still was found to be the
best among all solvents we screened. Catalyst loading studies showed that decreasing the
amount of [IrCp*Cl2]2 to 5% mol did not impact the yield distinctly, but required longer reaction
time (Entry 14, Table 1). Control experiment was also conducted, which revealed that iridium
catalyst was required, and no product 2a was observed in the absence of [IrCp*Cl2]2 (Entry 15,
Table 1). Finally, the optimal condition was set as [IrCp*Cl2]2 (0.1 equiv) in CHCl3 (0.03 M) at
45 °C.
Table 1. Optimization of reaction conditions.a
Ts
N
Ts
N
catalyst
solvent, temperature
1a
2a
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Temp.
(ºC)
Yieldb
(%)
Entry
Catalyst
Solvent
6
7
8
9
40
c
[IrMeO(COD)]2
[IrCl(COD)]2
Cu(MeCN)4
AuCl3
CHCl3
NR
trace
NR
1
2
3
c
CHCl3
40
40d
25
c
CHCl3
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c
CHCl3
15e
4
5
c
PtCl2
CHCl3
40
40
50e
30e
c
Echavarren’s catalyst
CHCl3
6
c
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
CHCl3
40
40
45
55
45
45
45
56e
7
f
CHCl3
75 (70e)
82 (78e)
74 (68e)
18e,g 40h
76 (56e)
8
f
CHCl3
9
f
CHCl3
10
11
12
THFf
DCEf
Toluenef
12e,g45h
75e
13
14
i
f
[IrCp*Cl2]2
CHCl3
45
45
f
--
CHCl3
NRe
15
aThe reaction was conducted with 1 (0.3 mmol), iridium catalyst (0.1 equiv) for 5 hours. bYield determined by 1H
NMR spectroscopy, using 1,3,5-Trimethoxybenzene as an internal standard. cConcentration, 0.075 M. dno reaction
even at reflux temperature. eIsolated yield. fConcentration, 0.03 M. gStarting material remained and the reaction time
was extended to 10 hours. hBased on recovered starting material. i12 hours, 5% mol of catalyst. [IrOMe(COD)]2 =
(1,5-cyclooctadiene)(methoxy) iridium dimer, [IrCl(COD)]2 = chloro(1,5-cyclo-octadiene) iridium(I) dimer,
Echavarren’s catalyst
= (Acetonitrile)[(2-biphenyl) di-tert-butylphosphine] gold (I) hexafluoroantimonate,
[IrCp*Cl2]2 = (pentamethylcyclo-pentadienyl) iridium dichloride dimer. NR stands for no reaction.
In order to gauge the scope and generality of the cycloisomerization reaction, a number of
substrates with varying olefin moieties were synthesized. Firstly, a series of nitrogen-tethered
1,7-enynes with substituted cyclohexene moieties instead of a terminal alkene were subjected
to the optimized cycloisomerization conditions and the results are summarized in Table 2. The
reactivity of enyne 1 was not affected by the gem dimethyl (2b, 2c) and phenyl (2d)
substitutions on cyclohexyl moieties. The 1,7-enynes with benzene-fused cyclohexene moieties
also proceeded well under the standard conditions, giving rise to the corresponding more
complex fused [6-6-3-7] polycyclic products (2e-2h) in good to excellent yield (72-90%). It is
noteworthy that the ester group in 1i did not disturb the reaction, which afforded an efficient
method to complex cyclic amino acids. The structure of 2e was unequivocally confirmed by
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single-crystal X-ray analysis (Figure S1, See SI).12 Then, in order to enrich the diversity of
products, another series of nitrogen-tethered 1,7-enynes with various substituted olefin moieties
were examined under the optimized cycloisomerization conditions (Table 3). When the
cyclohexyl moiety was changed to cyclopentyl, cycloheptyl or cyclooctyl groups in 1,7-enynes,
the corresponding [5-3-7] (2i), [7-3-7] (2j and 2k) and [8-3-7] (2l and 2m) fused ring systems
were obtained respectively in excellent yields (90-98%). When a phenyl ring was attached to
the terminal carbon of the olefin moiety in the substrates (1n-1p), the reaction still proceeded
well, furnishing the corresponding substituted cyclopropane products (2n-2p) in moderate
yields of 40%-55%. The lower yields compared to those for 2e-2h (74%-90%) were presumably
due to the reduced electron density on the olefin, as one electron-donating carbon substituent
was removed. This also can be supported by substrates 1n-1p, in which phenyl with electron
withdrawing group (EWG) p-bromide resulted in 2n in 40% yield, while phenyl with electron
donating group (EDG) p-OMe resulted in 2o in 55% yield. This protocol also worked with
substrates bearing simple non-cyclic substituents (1q and 1r), resulting in the corresponding
azabicyclo [5.1.0] octenes (2q, 2r) in 75% and 36% yield respectively. The low yield for 2r
was likely due to the steric hindrance of dimethyl group at the terminal carbon of the olefin
moiety. Replacing protecting group Ts with Ns (1s), which could be cleaved easily, resulted in
60% yield, and the reduced yield may be due to electron withdrawing property of the nitro
group. We also examined the cycloisomerization reaction of substrate 1t in which the terminal
alkyne moiety was changed into 2-butyne. However, no reaction occurred (Scheme 2).
Considering that the conditions reported for constructing azabicyclo [4.1.0] heptene from
nitrogen-tethered 1, 6-enyne was not effective for constructing bicyclo [5.1.0] octene,5g we
decided to test in turn whether our protocol would be suitable for constructing azabicyclo [4.1.0]
heptene. The cycloisomerization of 1u proceeded smoothly under the standard reaction
conditions, giving rise to azabicyclo [4.1.0] heptene 2u in 72% yield (Scheme 3). In addition,
to demonstrate the potential synthetic utility of this method, the reaction of 1a was conduced
on a 2 gram scale, providing 2a without loss of yield.
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Table 2. Substrate scope of 1,7-enynes with substituted cyclohexene moieties.a
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7
8
Ts
N
Ts
N
[IrCp*Cl2]2 (0.10 equiv), 45 °C
CHCl3 (0.03 M)
R
R
1
2
9
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Entry
1
1
2
Yield
Ts
N
Ts
N
1a
2a
78%
73%
Ts
N
Ts
N
2
3
4
1b
1c
1d
2b
Ts
N
Ts
N
2c
64%
Ts
N
Ts
N
Ph
Ph
2d
75% (55:45 dr)
Ts
N
Ts
N
R
5
R
7
5
6
7
1e, R = H
2e
2f
79%b
90% b
72% b
1f, R = 5-OMe
1g, R = 7-OMe
2g
MeOOC
Ts
N
Ts
N
8
COOMe
1h
2h
74% b
aUnless otherwise stated, reactions were conducted with 1 (0.3 mmol), [IrCp*Cl2]2 (0.1 equiv) and CHCl3 (0.03M)
at 45 °C for 5 hours. b10 hours.
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Table 3. Substrate scope of 1,7-enynes with varying substituents on the olefins.a
5
6
7
8
Ts
N
Ts
N
[IrCp*Cl2]2 (0.10 equiv), 45 °C
CHCl3 (0.03 M)
1
2
9
Entry
1
1
2
Yield
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13
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Ts
Ts
N
N
1i
1j
2i
2j
93%
90%
Ts
Ts
N
N
2
3
TFTs
TFTs
N
N
1k
1l
2k
2l
97%
98%
97%
Ts
Ts
N
N
4
5
TFTs
TFTs
N
N
1m
2m
Ts
N
N
Ts
R
R
6
7
8
1n, R = H
2n, R = H
2o, R = p-Br
2p, R = p- OMe
50%
40%b
55%
1o, R = p-Br
1p, R = p-OMe
Ts
N
Ts
N
9
1q
Ts
N
2q
2r
75%
36%
Ts
N
10
1r
Ns
Ns
N
N
11
1s
2s
60%
aUnless otherwise stated, reactions were conducted with 1 (0.3 mmol), [IrCp*Cl2]2 (0.1 equiv) and CHCl3 (0.03M)
at 45 °C for 5 hours. b10 hours. TFTs: 4-(trifluoromethyl)benzenesulfonyl.
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Scheme 2. Attempted reaction with substrate 1t bearing a substituent on the alkyne.
5
Ts
6
7
Ts
N
N
[IrCp*Cl2]2
x
8
9
2t
1t
10
11
12
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Scheme 3. Construction of azabicyclo [4.1.0] heptene under optimized reaction conditions.
Ts
Ts
N
[IrCp*Cl2]2 (0.10 equiv)
N
45 °C
CHCl3 (0.03 M), 72%
2u
1u
A plausible mechanism is proposed for this cycloisomerization reaction of 1,7-enynes as
shown in Scheme 4.5c, 5e, 5m, 5h, 5i The alkyne moiety in 1a first coordinates with cationic iridium
(III) to form a transient intermediate I, which undergoes intramolecular cyclization via
nucleophilic addition of the tethered olefin to the coordinated alkyne to provide intermediate
II. Isomerization of II gives rise to iridium alkylidene complex III, which subsequently
undergoes 1,2-hydride shift and elimination to yield the desired product 1b, regenerating the Ir
(II) catalyst, and completing the catalytic cycle.
Scheme 4. Plausible mechanisms.
Ts
N
IrCpCl2
N
Ir(L)
Ts
1a
I
Ts
Ts
N
N
IrCpCl2
+
Ir(L)
1b
II
Ts
1,2-hydrogen migration
and elimination
N
H
Ir(L)
III
In summary, we have developed an efficient method for the synthesis of azabicyclo [5.1.0]
octenes through cycloismerization of nitrogen-tethered 1,7-enynes catalyzed by [IrCp*Cl2]2.
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With the appropriately designed substrates, this method could be employed to efficiently
generate complex fused ring systems such as [6-6-3-7], [5-6-3-7], [7-6-3-7], and [8-6-3-7] ring
systems, which enrich the diversity of cyclopropane-fused polycycle library, and would find
applications in SAR studies and natural product synthesis.
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EXPERIMENTAL SECTION
General Information
Reagents and solvents were purchased from commercial sources (Energy Chemical, Adamas
and J&K). Deuterated solvents were purchased from Cambridge Isotope Laboratories and used
without further purification. Tetrahydrofuran (THF) was dried and distilled from sodium.
Toluene, dichloromethane (DCM), and 1,2-dichloroethane (DCE) were dried and distilled from
calcium hydride. Procedure of dried chloroform: 500 mL commercially available chloroform
washed with tree times of equal water to remove ethanol, and pre-dried by calcium chloride
(CaCl2), then dried and distilled from phosphorus pentoxide. All reactions were monitored by
TLC with silica gel coated plates. H NMR and 13C {1H} NMR spectra were recorded on
1
Agilent 400MR DD2 (400 MHz and 100 MHz) or 600MR DD2 (600 MHz 150 MHz)
spectrometer at ambient temperature. 19F NMR spectra were recorded on Agilent 400MR DD2
(376 MHz) spectrometer at ambient temperature. Chemical shifts were reported in parts per
million (ppm), and the residual solvent peak was used as an internal reference: 1H (chloroform
δ 7.26), 13C {1H} (CDCl3 δ 77.0). Data are reported as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constants (J-
values were in Hz) and integration. High-resolution mass spectra (HRMS) were obtained from
on a Bruker SolariX 7.0 T FT-ICR mass spectrometer with an ESI source. Melting points were
measured on SGW X-4A.
Synthetic Procedures and Characterization Data.
I. General Procedure I for preparation of nitrogen-tethered 1,7-enynes (1a-1d, 1h-1m and
1u) (GP I).6-10
Step 1: A solution of ketone (1.0 equiv), cyanoacetic acid (1.1 equiv) and ammonium acetate
(2.0 equiv) in toluene was heated to reflux at 120 ℃ (oil bath temperature). Generally the
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reaction would complete within 3 hours, as monitored by TLC (ethyl acetate: petroleum ether
= 1 : 10). Solvent (toluene) was then removed under vacuum, and the residue was re-dissolved
in ethyl acetate, washed with water to remove the salt. The corresponding nitriles were obtained
after purification by flash silica column chromatography.
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Step 2: To a dried flask, lithium aluminum hydride (LiAlH4, 1.0 equiv) was slowly added into
dry diethyl ether (1.0 M) under nitrogen atmosphere. The LiAlH4 solution was stirred at 0 °C
and aluminum chloride (AlCl3, 1.0 equiv) was added in batches. After stirring 10 minutes,
nitrile in diethyl ether (1.0 M) was added dropwise to the mixture of LiAlH4 /AlCl3/ether and
stirred over a period of 1.5-2 hours at room temperature. The reaction was quenched by aqueous
potasium hydroxide (10.0 M) at 0 °C. The reaction mixture was then diluted with diethyl ether,
and stirred for 5 minutes. The ether phase was separated from the thick solid, and organic phase
was dried over anhydrous sodium sulphate (Na2SO4), and concentrated to afford the
corresponding primary amines, which were directly used for the next step without further
purification.
Step 3: To a solution of primary amine (1.0 equiv) obtained from step 2 in dichloromethane
(DCM, 0.5 M for amine) and triethylamine (1.5 equiv), was added tosyl chloride (1.2 equiv) in
DCM (0.5 M for amine) at 0 ℃. The reaction mixture was warmed up and stirred at room
temperature. This reaction typically completed within 30 minutes based on TLC analysis and
then diluted with DCM, washed with 0.5 M HCl (aqueous), dried over anhydrous Na2SO4 and
concentrated under vacuum. The residue was purified by flash silica column chromatography
(ethyl acetate : petroleum ether = 1 : 10) to afford Ts-substituted amine.
Step 4: NaH (1.1 equiv) was placed into dry N, N-dimethylformamide (1.0 M for Ts-substituted
amine) in a dried flask slowly under nitrogen atmosphere. The Ts-substituted amine (1.0 equiv,
2.0 M; obtained from Step 3) solution in N, N-dimethylformamide was added dropwise by
syringe at 0 ℃. The resulting mixture was stirred for 15 minutes at the same temperature, then
3-bromopropyne (1.5 equiv) was added. This reaction usually completed within 30 minutes as
monitored by TLC. After the consumption of the Ts-substituted amine, the reaction was
quenched by saturated NH4Cl in water, the solvent was removed under vacuum, and the residue
was dissolved in ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and
concentrated under reduce pressure. The crude product was purified by silica column
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chromatography (ethyl acetate : petroleum ether = 1 : 15) to afford nitrogen-tethered 1,7-enynes
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(1a-1d, 1h-1m)
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II. General Procedure II for the preparation of nitrogen-tethered 1, 7-enynes (1e-1g, 1n-
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1r, and 1t-1u) (GP II).
A solution of primary alcohol (1.0 equiv), triphenylphosphine (2.0 equiv) and 4-methyl-N-
(prop-2-yn-1-yl)benzenesulfonamide (1.2 equiv) in dry terahydrofuran (0.3 M for the primary
alcohol) was stirred at 0 ℃ under nitrogen atmosphere. Diisopropyl azodicarboxylate (DIAD,
2.0 equiv) was added dropwise to the above solution by syringe at the same temperature, and
the resulting mixture was stirred at room temperature for 5 hours. After the complete conversion
of the starting alcohol, the solvent was removed under reduced pressure, and the residue was
dissolved in ethyl acetate (EtOAc), washed with brine, dried over anhydrous Na2SO4 and
concentrated in reduce pressure. The residue was purified by silica column chromatography
(ethyl acetate : petroleum ether = 1 : 15) to afford nitrogen-tethered 1,7-enynes (1e-1g, and 1n-
1t).
N-(2-(Cyclohex-1-en-1-yl)ethyl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (1a). 1a
was synthesized following GPI. (1) Following the general procedures for GPI - Step 3, the
reaction was carried out using 2-(1-cyclohexenyl)ethylamine (5.00 g, 39.70 mmol, 1.0 equiv,
commercially available), toslyl chloride (9.07 g, 47.60 mmol, 1.2 equiv) and triethylamine
(8.26 mL, 59.52 mmol, 1.5 equiv) to produce 1a-1 (9.3 g, 84%) as a white solid. 1H NMR (400
MHz, CDCl3) δ = 7.74 (d, J =8.2, 2H), 7.31 (d, J =8.0, 2H), 5.38 (dt, J =4.0, 2.2, 1H), 4.28 (t,
J =5.6, 1H), 3.00 (q, J =6.3, 2H), 2.43 (s, 3H), 2.05 (t, J =6.7, 2H), 1.99 – 1.94 (m, 2H), 1.69
(d, J =6.3, 2H), 1.52 (q, J =6.3, 4H). (2) Following the general procedures for GPI - Step 4, the
reaction was carried out using 1a-1 (2.5 g, 8.95 mmol, 1.0 equiv, in 4.5 mL DMF), NaH (395
mg in 4.5 mL DMF, 9.745 mmol, 1.1 equiv, 60% in mineral oil), 3-Bromopropyne (2.55 g,
13.43 mmol, 1.5 equiv) to produce 1a as a white solid, m.p. = 74-75 ℃, Rf = 0.5 (silica, EtOAc
: hexane = 1 : 10). 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.1 Hz,
2H), 5.44 (s, 1H), 4.13 (d, J = 2.5 Hz, 2H), 3.25 (t, J = 8.0, 2H), 2.40 (s, 3H), 2.18 (t, J = 7.6
Hz, 2H), 2.01 (t, J = 2.5 Hz, 1H), 1.98 – 1.89 (m, 4H), 1.65 – 1.46 (m, 4H). C {1H} NMR
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(101 MHz, CDCl3) δ 143.5, 134.4, 129.6, 127.8, 123.8, 73.8, 44.9, 36.4, 28.1, 25.4, 23.0, 22.4,
21.7. HRMS (ESI) m/z: [M + H]+ Calcd for C18H24NO2S 318.1522, found 318.1525.
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N-(2-(6,6-Dimethylcyclohex-1-en-1-yl)ethyl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfon-
amide(1b).6-10 (1) Following the general procedures for GPI - Step 1, 2,2-dimethylcyclohexan-
1-one (1.0 g, 7.9 mmol, 1.0 equiv), cyanoacetic acid (742 mg, 8.73 mmol, 1.1 equiv), NH4OAc
(1.22 g, 15.8 mmol, 2.0 equiv) and toluene (10.0 mL) were added to a 25.0 mL round bottom
flask to give the corresponding nitrile (940 mg, 80%, yellow liquid, ethyl acetate: petroleum
ether = 1:10, Rf = 0.7). (2) Following the general procedures for GPI - Step 2, the reaction was
carried out using the purified nitrile to afford the amine (800 mg, yellow liquid). (3) Following
the general procedures for GPI - Step 3, the reaction was carried out using 2-(6,6-
dimethylcyclohex-1-en-1-yl) ethan-1-amine (500 mg, 3.26 mmol, 1.0 equiv), toslyl chloride
(745 mg, 3.91 mmol, 1.2 equiv) and triethylamine (680 μL, 4.9 mmol, 1.5 equiv) and DCM
(15.0 mL) to produce tosyl-substituted amine (Ts-amine) (730 mg, 73%) as a colorless oil. (4)
Following the general procedures for GP I- Step 4, the reaction was carried out using Ts-amine
(250 mg, 0.81 mmol, 1.0 equiv, in 2.0 mL DMF), NaH (36 mg, 0.89 mmol, 1.1 equiv, 60% in
mineral oil, in 3.0 mL DMF), 3-Bromopropyne (145 mg, 1.22 mmol, 1.5 equiv) to produce 1b
a colorless oil, Rf = 0.5 (silica, EtOAc : hexane = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.72 (d,
J = 8.1 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 5.34 (t, J = 3.9 Hz, 1H), 4.15 (d, J = 2.5 Hz, 2H),
3.33 – 3.15 (m, 2H), 2.41 (s, 3H), 2.28 – 2.15 (m, 2H), 2.04 (t, J = 2.5 Hz, 1H), 1.99 – 1.84 (m,
2H), 1.54 (s, 7H), 1.47 – 1.36 (m, 2H), 0.98 (s, 6H). 13C {1H} NMR (101 MHz, CDCl3) 143.4,
141.3, 136.0, 129.4, 127.6, 123.0, 76.7, 73.6, 47.1, 39.3, 36.5, 34.1, 29.4, 28.0, 25.9, 21.5, 19.1.
HRMS (ESI) m/z: [M + H]+ Calcd for C20H28NO2S 346.1835, found 346.1838.
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N-(2-(4,4-Dimethylcyclohex-1-en-1-yl)ethyl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfon-
amide (1c). (1) Synthesis of 2-(4,4-dimethylcyclohex-1-en-1-yl) aceto-nitrile (1c-1).
Following the general procedures for GPI - Step 1, 4, 4-dimethylcyclohexan-1-one (1.0 g, 7.9
mmol, 1.0 equiv), cyanoacetic acid (742 mg, 8.73 mmol, 1.1 equiv), NH4OAc (1.22 g, 15.8
mmol, 2.0 equiv) and toluene (10.0 mL) were added to a 25.0 mL round bottom flask to give
the corresponding nitrile 1c-1 (850 mg, 72%, yellow liquid, ethyl acetate: petroleum ether =
1:10, Rf = 0.7) . 1H NMR (400 MHz, CDCl3) δ 5.64 (tq, J = 3.6, 1.7 Hz, 1H), 2.96 (d, J = 2.5
Hz, 2H), 2.05 – 1.90 (m, 2H), 1.78 (dt, J = 4.1, 2.1 Hz, 2H), 1.36 (td, J = 6.4, 1.4 Hz, 2H), 0.86
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(d, J = 1.8 Hz, 6H). C {1H} NMR (101 MHz, CDCl3) δ 125.5, 125.0, 117.6, 38.8, 34.9, 28.1,
27.8, 27.8, 27.8, 27.7, 25.7, 25.1. HRMS (ESI) m/z: [M + Na]+ Calcd for C10H15NNa 172.1097,
found 172.1098. Then following the general procedures for GPI - Step 2, the reaction was
carried out using the purified nitrile to afford the amine (650 mg, yellow liquid). (2) Synthesis
of 4-methyl-N-(2-(1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)ethyl) benzene-sulfonamide (1c-2).
Following the general procedures for GPI - Step 3, the reaction was carried out using the amine
(500 mg, 3.26 mmol, 1.0 equiv), toslyl chloride (745 mg, 3.91 mmol, 1.2 equiv) and
triethylamine (680 μL, 4.9 mmol, 1.5 equiv) and DCM (15.0 mL) to produce 1c-2 (760 mg,
76%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.3 Hz, 2H), 7.29 (d, J =
8.0 Hz, 2H), 5.31 – 5.20 (m, 1H), 4.45 (t, J = 5.8 Hz, 2H), 2.98 (q, J = 6.5 Hz, 2H), 2.41 (s,
3H), 2.06 (t, J = 6.7 Hz, 2H), 1.72 (d, J = 4.4 Hz, 4H), 1.25 (t, J = 6.4 Hz, 2H), 0.83 (s, 6H).
13C {1H} NMR (101 MHz, CDCl3) δ 143.3, 136.7, 132.0, 129.7, 127.1, 123.7, 40.6, 39.1, 36.8,
35.3, 28.3, 28.1, 25.3, 21.5. HRMS (ESI) m/z: [M + H]+ Calcd for C17H26NO2S, 308.1679,
found 308.1682. Then following the general procedures for GPI - Step 4, the reaction vessel
was charged with 1c-2 (250 mg, 0.81 mmol, 1.0 equiv in 3.0 mL DMF), NaH (36 mg, 0.89
mmol, 1.1 equiv, 60% in mineral oil, in 2.0 mL DMF), 3-bromopropyne (145 mg, 1.22 mmol,
1.5 equiv) to produce 1c (250 mg, 90%) a white solid, Rf = 0.5 (silica, EtOAc : hexane = 1 :
10). 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 5.35 (s,
1H), 4.12 (d, J = 2.5 Hz, 2H), 3.25 (t, J = 7.5 Hz, 2H), 2.39 (s, 3H), 2.19 (t, J = 7.6 Hz, 2H),
2.00 (t, J = 2.5 Hz, 1H), 1.97 – 1.89 (m, 1H), 1.71 – 1.77 (m, 2H), 1.32 (t, J = 6.4 Hz, 2H),
0.86 (s, 6H). 13C {1H} NMR (101 MHz, CDCl3) δ 143.3, 135.8, 132.6, 129.3, 127.5, 122.6,
76.4, 73.7, 44.6, 39.1, 36.0, 35.5, 35.4, 28.3, 28.1, 25.6, 21.4. HRMS (ESI) m/z: [M + H]+ Calcd
for C20H28NO2S 346.1835, found 346.1834.
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4-Methyl-N-(prop-2-yn-1-yl)-N-(2-(1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)ethyl) benzene
sulfonamide (1d). (1) Synthesis of 2-(1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)acetonitrile (1d-
1). Following the general procedures for GPI - Step 1, the reaction was carried out using 4-
phenylcyclohexan-1-one (2.0 g, 11.5 mmol, 1.0 equiv), cyanoacetic acid (1.1 g, 12.64 mmol,
1.1 equiv), NH4OAc (1.77 g, 23.0 mmol, 2.0 equiv) and toluene (10.0 mL) in a 25.0 mL round
bottom flask to obtain the nitrile (1.55 g, 68%, yellow liquid, ethyl acetate : petroleum ether =
1
1 : 10, Rf = 0.7) (1d-1). H NMR (400 MHz, CDCl3) δ 7.39 – 7.29 (m, 2H), 7.29 – 7.19 (m,
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3H), 5.90 (dd, J = 3.5, 1.8 Hz, 1H), 3.06 (s, 2H), 2.85 – 2.75 (m, 1H), 2.44 – 2.34 (m, 1H), 2.34
– 2.20 (m, 2H), 2.09-2.19 (m, 1H), 2.08-1.98 (m, 1H), 1.78 – 1.90 (m, 1H). 13C {1H} NMR (101
MHz, CDCl3) δ 145.9, 128.4, 128.3, 126.9, 126.7, 126.6, 126.6, 126.1, 125.7, 117.5, 39.2, 33.0,
29.4, 28.5, 25.2. HRMS (ESI) m/z: [M + Na]+ Calcd for C14H15NNa 220.1097, found 220.1097.
(2) Synthesis of 4-methyl-N-(2-(1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)ethyl) benzene-
sulfonamide (1d-2). Following the general procedures for GPI - Step 2, the reaction was carried
out using the purified nitrile to afford the corresponding amine (1.2 g, yellow liquid). Then
following the general procedures for GP I- Step 3, the reaction was carried out using the amine
(500 mg, 2.4 mmol, 1.0 equiv), toslyl chloride (568 mg, 2.98 mmol, 1.2 equiv) and
triethylamine (500 μL, 2.6 mmol, 1.5 equiv) and DCM (15.0 mL) to produce (1d-2) (670 mg,
79%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.2 Hz, 2H), 7.36-7.24(m,
4H), 7.24-7.15 (m, 3H), 5.52 – 5.43 (m, 1H), 4.61 (t, J = 5.8 Hz, 1H), 3.04 (q, J = 6.4 Hz, 2H),
2.73 – 2.62 (m, 1H), 2.43 (s, 3H), 2.30 – 2.20 (m, 1H), 2.17-2.03 (m, 3H), 2.00 – 1.80 (m, 3H),
1.67 (ddt, J = 17.4, 11.9, 5.7 Hz, 2H). 13C {1H} NMR (101 MHz, CDCl3) δ 146.7, 143.4, 136.8,
133.4, 129.7, 128.4, 127.2, 126.8, 126.1, 124.3, 40.6, 39.8, 37.0, 33.3, 29.7, 28.1, 21.6. HRMS
(ESI) m/z: [M + Na]+ Calcd for C21H25NaNO2S, 378.1498, found 378.1495. (3) The reaction
was carried out using 1d-2 (300 mg, 0.85 mmol, 1.0 equiv, in 2.0 mL DMF), NaH (38 mg, 0.94
mmol, 1.1 equiv, 60% in mineral oil, in 3.0 mL DMF), 3-bromopropyne (152 mg, 1.28 mmol,
1.5 equiv) to produce 1d (305 mg, 92%) a white solid. Rf = 0.5 (silica, EtOAc : hexane = 1 :
10). 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H), 7.25 – 7.34 (m, 4H), 7.24 – 7.15
(m, 3H), 5.56 (s, 1H), 4.17 (t, J = 3.0 Hz, 2H), 3.31 (td, J = 7.2, 2.2 Hz, 2H), 2.81 – 2.66 (m,
1H), 2.42 (s, 3H), 2.32 – 2.22 (m, 3H), 2.22 – 2.10 (m, 2H), 2.10 – 2.06 (m, 1H), 2.05 – 2.00
(m, 1H), 1.99-1.91 (m, 1H), 1.76 (td, J = 11.8, 5.2 Hz, 1H). 13C {1H} NMR (101 MHz, CDCl3)
δ 147.0, 143.4, 135.9, 134.2, 129.5, 128.4, 127.7, 126.9, 126.0, 123.3, 73.8, 44.7, 39.9, 36.2,
35.7, 33.6, 29.9, 28.6, 21.6. HRMS (ESI) m/z: [M + Na]+ Calcd for C24H27NaNO2S 416.1655,
found 416.1651.
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N-(2-(3,4-dihydronaphthalen-2-yl)ethyl)-4-methyl-N-(prop-2-yn-1yl)benzenesulfon-
amide (1e). The primary alcohol was prepared with a reported procedure.11 Then following the
general procedures for GPII, the reaction was carried out using primary alcohol (1.5 g, 8.6
mmol, 1.0 equiv 20.0 mL), triphenylphosphine (4.5 g, 17.24 mmol, 2.0 equiv) and 4-methyl-
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N-(prop-2-yn-1-yl)benzenesulfonamide (2.16 g, 10.32 mmol, 1.2 equiv) and DIAD (3.5 g, 17.2,
2.0 equiv) to afford nitrogen-tethered 1,7-enynes 1e as a white solid, m.p. 78-79 ℃.1H NMR
(400 MHz, CDCl3) δ 7.72 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.17 – 7.04 (m, 3H),
6.96 (d, J = 7.0 Hz, 1H), 6.25 (s, 1H), 4.17 (d, J = 2.5 Hz, 2H), 3.38 (t, J = 8.2 Hz, 2H), 2.80
(t, J = 8.2 Hz, 2H), 2.48 (d, J = 7.5 Hz, 2H), 2.41 (s, 3H), 2.26 (t, J = 8.1 Hz, 2H), 2.05 (t, J =
2.5 Hz, 1H). 13C {1H} NMR (101 MHz, CDCl3) δ 143.7, 137.9, 135.9, 134.7, 134.4, 129.6,
127.1, 127.4, 126.7, 126.6, 125.7, 124.7, 77.5, 77.2, 76.8, 76.7, 74.0, 44.7, 36.5, 35.9, 28.1,
27.0, 21.7. HRMS (ESI) m/z: [M + H]+ Calcd for C22H24NO2S 366.1522, found 366.1524.
N-(2-(5-methoxy-3,4-dihydronaphthalen-1-yl)ethyl)-4-methyl-N-(prop-2-yn-1-yl)benz-
enesulfonamide (1f). The primary alcohol was prepared with a reported procedure.11 Then
following the general procedures for GPII, the reaction was carried out using primary alcohol
(1.75 g, 8.6 mmol, 1.0 equiv, in 20.0 mL THF), triphenylphosphine (4.5 g, 17.24 mmol, 2.0
equiv) and 4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (2.16 g, 10.32 mmol, 1.2 equiv)
and DIAD (3.5 g, 17.2, 2.0 equiv) to afford nitrogen-tethered 1,7-enynes 1f as a white solid. Rf
= 0.5 (silica, EtOAc : hexane = 1 : 5). 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.1 Hz, 2H),
7.26 (d, J = 8.1 Hz, 2H), 7.09 (t, J = 7.9 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 7.5 Hz,
1H), 6.22 (s, 1H), 4.17 (d, J = 2.5 Hz, 2H), 3.81 (s, 3H), 3.39 (t, J = 7.4 Hz, 2H), 2.80 (t, J =
8.4 Hz, 2H), 2.47 (t, J = 7.4 Hz, 2H), 2.40 (s, 3H), 2.23 (t, J = 8.4 Hz, 2H), 2.07 (t, J = 2.5 Hz,
1H). 13C {1H} NMR (101 MHz, CDCl3) δ 150.9, 138.4, 132.7, 130.6, 130.2, 124.3, 122.5, 121.5,
119.1, 116.8, 113.5, 104.1, 71.4, 68.8, 50.3, 39.3, 31.3, 30.6, 21.1, 16.4, 15.0. HRMS (ESI)
m/z: [M + H]+ Calcd for C23H26NO3S 396.1628, found 396.1633.
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N-(2-(7-Methoxy-3,4-dihydronaphthalen-1-yl)ethyl)-4-methyl-N-(prop-2-yn-1-yl)benz-
enesulfonamide (1g). The primary alcohol was prepared with a reported procedure.11 Then
following the general procedures for GPII, the reaction was carried out using primary alcohol
(1.75 g, 8.6 mmol, 1.0 equiv in 20.0 mL THF), triphenylphosphine (4.5 g, 17.24 mmol, 2.0
equiv) and 4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (2.16 g, 10.32 mmol, 1.2 equiv)
and DIAD (3.5 g, 17.2, 2.0 equiv) to afford nitrogen-tethered 1,7-enynes 1g as a white solid. Rf
= 0.5 (silica, EtOAc : hexane = 1 : 5). 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.9 Hz, 2H),
7.27 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.2 Hz, 1H), 6.64 (dd, J = 8.2, 2.6 Hz, 1H), 6.55 (d, J =
2.8 Hz, 1H), 6.22 (s, 1H), 4.17 (d, J = 2.5 Hz, 1H), 3.77 (s, 3H), 3.38 (t, J = 7.4 Hz, 2H), 2.73
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(t, J = 8.1 Hz, 2H), 2.48 (t, J = 7.5 Hz, 2H), 2.41 (s, 3H), 2.24 (t, J = 8.1 Hz, 2H), 2.12 – 1.93
(m, 1H). 13C {1H} NMR (101 MHz, CDCl3) δ158.2, 143.5, 138.5, 135.7, 135.2, 129.5, 127.9,
127.6, 126.6, 124.5, 111.5, 111.3, 76.5, 73.9, 55.3, 44.5, 36.4, 35.8, 27.2, 27.1, 21.5. HRMS
(ESI) m/z: [M + H]+ Calcd for C23H26NO3S 396.1628, found 396.1631.
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Methyl
(S)-3-(3,4-dihydronaphthalen-1-yl)-2-((4-methyl-N-(prop-2-yn-1-yl)phenyl)
sulfonamido)propanoate (1h). The corresponding tosyl amine was synthesis by our previous
reported. 6-10 Then following the general procedures for GPI – step 4, the reaction was carried
out using Ts-amine (200 mg, 0.52 mmol, 1.0 equiv, in 2.0 mL DMF), NaH (23 mg, 0.57 mmol,
1.1 equiv, 60% in mineral oil, in 2.0 mL DMF), 3-bromopropyne (95 mg, 0.78 mmol, 1.5 equiv)
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to produce 1h as a faint yellow solid. Rf = 0.5 (silica, EtOAc : hexane = 1:5). H NMR (400
MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 2H), 7.19 – 6.99 (m, 5H), 6.98 – 6.83 (m, 1H), 6.28 (s,
1H), 4.73 (t, J = 7.6 Hz, 1H), 4.39 – 4.19 (m, 2H), 3.55 (s, 3H), 2.83 (dd, J = 14.3, 7.1 Hz, 1H),
2.75 (t, J = 8.1 Hz, 2H), 2.67 (dd, J = 14.3, 8.2 Hz, 1H), 2.34 (s, 3H), 2.26 – 2.04 (m, 3H). 13C
{1H} NMR (101 MHz, CDCl3) δ 171.0, 143.6, 136.6, 135.3, 134.5, 134.1, 129.3, 127.7, 127.2,
126.7, 126.5, 126.4, 125.7, 79.3, 72.7, 57.5, 52.1, 38.2, 33.9, 27.9, 26.5, 21.5. HRMS (ESI)
m/z: [M + Na]+ Calcd for C24H25NNaO4S 446.1397, found 446.1405.
N-(2-(Cyclopent-1-en-1-yl)ethyl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (1i).
(1) Following the general procedures for GPI - Step 1, the reaction was carried out using
cyclopentanone (3.0 g, 35.7 mmol, 1.0 equiv), cyanoacetic acid (3.34 g, 39.29 mmol, 1.1 equiv),
NH4OAc (5.5 g, 35.7 mmol, 2.0 equiv) and toluene (20.0 mL) in a 50 mL round bottom flask
to give the corresponding nitrile (2.5 g, 65%, yellow liquid, ethyl acetate: petroleum ether =
1:10, Rf = 0.7). (2) Following the general procedures for GPI - Step 2, the reaction was carried
out using the purified nitrile to afford the amine (1.8 g, yellow liquid). (3) Following the general
procedures for GPI - Step 3, the reaction was carried out using the amine (1.0 g, 9.0 mmol, 1.0
equiv, in 10.0 mL DCM), toslyl chloride (2.06 g, 10.8 mmol, 1.2 equiv) and triethylamine (1.87
mL, 13.5 mmol, 1.5 equiv) to produce tosly substituted amine (Ts-amine) (1.7 g, 71%). (4)
Following the general procedures for GPI - Step 4, the reaction was carried out using the Ts-
amine (1.0 g, 3.78 mmol, 1.0 equiv, in 4.0 mL DMF), NaH (166 mg, 4.15 mmol, 1.1 equiv,
60% in mineral oil, in 5.0 mL DMF), 3-bromopropyne (675 mg, 5.66 mmol, 1.5 equiv) to
produce 1i (980 mg, 86%) as a colorless oil. Rf = 0.5 (silica, EtOAc : hexane = 1 : 10). 1H NMR
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(400 MHz, CDCl3 δ 7.70 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 5.39 (s, 1H), 4.12 (d, J
= 2.5 Hz, 2H), 3.29 (t, J = 7.5 Hz, 2H), 2.39 (s, 3H), 2.33 (t, J = 7.7 Hz, 2H), 2.15-2.30 (m,
4H), 2.01 (s, 1H), 1.82 (p, J = 7.5 Hz, 1H). 13C {1H} NMR (101 MHz, CDCl3) δ143.5, 140.6,
135.8, 129.4, 127.7, 125.7, 76.5, 73.8, 44.6, 36.2, 34.8, 32.5, 29.4, 23.3, 21.6. HRMS (ESI)
m/z: [M + H]+ Calcd for C17H22NO2S 304.1366, found 304.1367.
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N-(2-(Cyclohept-1-en-1-yl)ethyl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (1j).
(1) Following the general procedures for GPI - Step 1, the reaction was carried out using
cycloheptanone (2.0 g, 17.9 mmol, 1.0 equiv), cyanoacetic acid (1.7 g, 19.64 mmol, 1.1 equiv),
NH4OAc (2.7 g, 35.7 mmol, 2.0 equiv) and toluene (15.0 mL) in a 25.0 mL round bottom flask
to give the corresponding nitrile (2.25 g, 85%, yellow liquid, ethyl acetate: petroleum ether = 1
: 10, Rf = 0.7). (2) Following the general procedures for GPI - Step 2, the reaction was carried
out using the purified nitrile to afford the amine (1.5 g, yellow liquid). (3) Following the general
procedures for GPI - Step 3, the reaction was carried out using the amine (1.0 g, 7.2 mmol, 1.0
equiv, in 15.0 mL DCM), toslyl chloride (1.65 g, 8.6 mmol, 1.2 equiv) and triethylamine (1.5.0
mL, 10.8 mmol, 1.5 equiv) to produce tosyl protected amine (Ts-amine) (1.6 g, 76%). (4)
Following the general procedures for GPI - Step 4, the reaction was carried out using Ts-amine
(1.0 g, 3.4 mmol, 1.0 equiv, in 4.0 mL DMF), NaH (150 mg, 3.75 mmol, 1.1 equiv, 60% in
mineral oil, in 5.0 mL DMF), 3-bromopropyne (610 mg, 5.11 mmol, 1.5 equiv) to produce 1j
(990 mg, 88%) as a colorless oil, Rf = 0.5 (silica, EtOAc : hexane = 1:10). 1H NMR (400 MHz,
CDCl3 δ 7.70 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 5.58 (t, J = 6.4 Hz, 1H), 4.12 (d, J
= 2.6 Hz, 2H), 3.28 – 3.14 (m, 2H), 2.40 (s, 3H), 2.22 (t, J = 8.0 Hz 2H), 2.12 – 2.06 (m, 2H),
2.06 – 1.99 (m, 3H), 1.66-1.74 (m, 2H), 1.50 – 1.39 (m, 4H). 13C {1H} NMR (101 MHz, CDCl3)
δ 143.5, 140.9, 136.2, 129.5, 128.8, 127.8, 73.7, 45.2, 38.6, 36.4, 32.6, 32.5, 28.5, 27.2, 26.8,
21.6. HRMS (ESI) m/z: [M + H]+ Calcd for C19H26NO2S 332.1679, found 332.1682.
N-(2-(Cyclohept-1-en-1-yl)ethyl)-N-(prop-2-yn-1-yl)-4-(trifluoromethyl) benzenesulfon-
amide (1k). (1) Following the general procedures for GPI – Step 3, the reaction was carried out
using 2-(cyclohept-1-en-1-yl) ethan-1-amine (500 mg, 3.6 mmol, 1.0 equiv), 4-(trifluoromethyl)
benzene-1-sulfonyl chloride (1.05 g, 4.3 mmol, 1.2 equiv, in 10.0 mL DCM) and triethylamine
(0.75.0 mL, 5.4 mmol, 1.5 equiv) to produce the 4-trifluoromethyl-tosyl-amine (TFTs-
amine)(850 g, 68%). (2) Following the general procedures for GPI - Step 4, the reaction was
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carried out using the TFTs-amine (800 mg, 2.3 mmol, 1.0 equiv, in 2.0 mL DMF), NaH (102
mg, 2.5 mmol, 1.1 equiv, 60% in mineral oil, in 2.0 mL DMF), 3-bromopropyne (411 mg, 3.45
mmol, 1.5 equiv) to produce 1k (730 mg, 83%) as a colorless oil, Rf = 0.5 (silica, EtOAc :
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hexane = 1 : 10). H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.3 Hz,
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2H), 5.60 (t, J = 6.4 Hz, 1H), 4.17 (d, J = 2.5 Hz, 2H), 3.29 – 3.15 (m, 2H), 2.24 (t, J = 7.6 Hz,
2H), 2.12 – 2.08 (m, 2H), 2.05 (q, J = 6.2 Hz, 2H), 2.00 (t, J = 2.5 Hz, 1H), 1.70 (ddt, J = 8.5,
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6.1, 2.8 Hz, 2H), 1.46 (tdd, J = 11.7, 8.3, 5.8 Hz, 4H). C {1H} NMR (101 MHz, CDCl3) δ
142.6, 140.4, 134.3 (q, JC-F = 132), 133.8, 129.1, 128.1, 125.9(q, JC-F = 16), 123.3(q, JC-F
=
1088), 76.1, 74.0, 45.1, 38.4, 36.2, 32.5, 32.3, 28.3, 27.0, 26.7. 19F NMR (376 MHz, CDCl3) δ
-63.1 (s, 3 F). HRMS (ESI) m/z: [M + Na]+ Calcd for C19H22F3NNaO2S 408.1216, found
408.1219.
(E)-N-(2-(Cyclooct-1-en-1-yl)ethyl)-4-methyl-N-(prop-2-yn-1-yl) benzenesulfonamide (1l).
(1) Following the general procedures for GPI - Step 1, the reaction was carried out using
cyclooctanone (2.5 g, 19.84 mmol, 1.0 equiv), cyanoacetic acid (1.86 g, 21.83 mmol, 1.1 equiv),
NH4OAc (3.05 g, 39.7 mmol, 2.0 equiv) and toluene (15.0 mL) were added to a 25.0 mL round
bottom flask to give the corresponding nitrile (2.4 g, 80%, yellow liquid, ethyl acetate:
petroleum ether = 1:10, Rf = 0.7). (2) Following the general procedures for GPI - Step 2, the
reaction was carried out using the purified nitrile to afford the amine (1.9 g, yellow liquid). (3)
Following the general procedures for GPI - Step 3, the reaction was carried out using the amine
(1.0 g, 6.5 mmol, 1.0 equiv, in 10.0 mL DCM), toslyl chloride (1.5 g, 7.8 mmol, 1.2 equiv) and
triethylamine (1.4.0 mL, 9.8 mmol, 1.5 equiv), tosyl substituted amine (Ts-amine) (1.4 g, 70%).
(4) Following the general procedures for GPI - Step 4, the reaction was carried out using the
reaction vessel was charged with the Ts-amine (1.0 g, 3.25 mmol, 1.0 equiv, in 4.0 mL DMF),
NaH (145 mg, 3.58 mmol, 1.1 equiv, 60% in mineral oil, in 5.0 mL DMF), 3-bromopropyne
(580 mg, 4.88 mmol, 1.5 equiv) to produce 1l (905 mg, 80%) as a colorless oil, Rf = 0.5 (silica,
EtOAc : hexane = 1:10). 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.3 Hz, 2H), 7.27 (d, J =
8.0 Hz, 2H), 5.39 (t, J = 8.1 Hz, 1H), 4.13 (d, J = 2.5 Hz, 2H), 3.34 – 3.15 (m, 2H), 2.40 (s,
3H), 2.28 – 2.18 (m, 2H), 2.13 (dd, J = 7.3, 4.5 Hz, 2H), 1.99-2.09 (m, 3H), 1.52 – 1.34 (m,
8H). 13C {1H} NMR (101 MHz, CDCl3)δ 143.3, 137.1, 136.0, 129.4, 127.7, 126.6, 73.6, 45.3,
36.2, 35.4, 29.8, 28.6, 28.5, 26.5, 26.4, 26.1, 21.5. HRMS (ESI) m/z: [M + Na]+ Calcd for
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C20H27NNaO2S 368.1655, found 368.1656.
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benzenesulfonamide (1m). (1) Following the general procedures for GPI - Step 3, the reaction
was carried out using the amine (500 mg, 3.25 mmol, 1.0 equiv, in 10.0 mL DCM, amine used
in synthesis of 1m), 4-(trifluoromethyl)benzene-1-sulfonyl chloride (960 mg, 3.9 mmol, 1.2
equiv) and triethylamine (0.7 mL, 4.9 mmol, 1.5 equiv) to produce 4-trifluoromethyl-tosyl
protected amine (TFTs-amine) (620 mg, 53%) as a white solid. (2) Following the general
procedures for GPI - Step 4, the reaction was carried out using the TFTs-amine (500 mg, 1.38
mmol, 1.0 equiv, in 4.0 mL DMF), NaH (61 mg, 1.52 mmol, 1.1 equiv, 60% in mineral oil, in
5.0 mL DMF), 3-bromopropyne (250 mg, 2.1 mmol, 1.5 equiv) to produce 1m (500 mg, 90%)
as a white solid, m.p. 182-183, Rf = 0.5 (silica, EtOAc : hexane = 1:10). 1H NMR (400 MHz,
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Chloroform-d) H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 8.2 Hz,
2H), 5.41 (t, J = 8.1 Hz, 1H), 4.18 (d, J = 2.5 Hz, 2H), 3.30 (t, J = 8, 2H), 2.26 (t, J = 7.7 Hz,
2H), 2.16 – 2.11 (m, 2H), 2.03-2.10 (m, 2H), 2.01 (t, J = 2.5 Hz, 1H), 1.55 – 1.39 (m, 8H). 13C
{1H} NMR (101 MHz, CDCl3) δ 142.6, 136.7, 134.3(q, JC-F = 128), 128.1, 127.0, 126.0 (q, JC-
= 16, 1C), 123.3(q, JC-F =1084), 121.9, 119.2, 76.1, 74.0, 45.3, 36.2, 35.4, 29.7, 28.6, 28.4,
F
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26.5, 26.4, 26.1. F NMR (376 MHz, CDCl3) δ -63.1 (s, 3 F). HRMS (ESI) m/z: [M + Na]+
Calcd for C20H24F3NNaO2S 422.1372, found 422.1373.
(E)-4-Methyl-N-(4-phenylbut-3-en-1-yl)-N-(prop-2-yn-1-yl)benzenesulfonamide
(1n).
Firstly the primary alcohol was prepared with a reported procedure.11 Then following the
general procedures for GPII, the reaction was carried out using primary alcohol (500 mg, 3.4
mmol, 1.0 equiv, in 10.0 mL THF), triphenylphosphine (1.77g, 6.77 mmol, 2.0 equiv) and 4-
methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (855 mg, 4.08 mmol, 1.2 equiv) and DIAD (1.4
g, 6.77 mmol, 2.0 equiv) to afford nitrogen-tethered 1,7-enynes 1n (615 mg, 53%) as a white
solid. m.p. 75-76 ℃. 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.9 Hz, 2H), 7.36 – 7.13 (m,
7H), 6.44 (d, J = 15.8 Hz, 1H), 6.12 (dt, J = 15.1, 7.0 Hz, 1H), 4.16 (d, J = 2.5 Hz, 2H), 3.33
(t, J = 7.3 Hz, 2H), 2.50 (q, J = 7.2 Hz, 2H), 2.40 (s, 3H), 2.06 (t, J = 2.3 Hz, 1H). 13C {1H}
NMR (101 MHz, CDCl3) δ 143.5, 137.1, 135.9, 132.4, 129.5, 128.5, 127.7, 127.3, 126.1, 126.1,
76.7, 73.8, 46.1, 36.6, 31.6, 21.5. HRMS (ESI) m/z: [M + H]+ Calcd for C20H22NO2S 340.1366,
found 340.1371.
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(E)-N-(4-(4-Bromophenyl)but-3-en-1-yl)-4-methyl-N-(prop-2-yn-1yl)benzenesulfon-
amide (1o). Firstly the primary alcohol was prepared with a reported procedure.11 Then
following the general procedures for GPII, the reaction was carried out using primary alcohol
(770 mg,3.4 mmol, 1.0 equiv, in 10.0 mL THF), triphenylphosphine (1.77g, 6.77 mmol, 2.0
equiv) and 4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (855 mg, 4.08 mmol, 1.2 equiv)
and DIAD (1.4 g, 6.77 mmol, 2.0 equiv) to afford nitrogen-tethered 1,7-enynes 1o (705 mg,
50%) as a white solid. m.p. 104-105 ℃. 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.9 Hz, 2H),
7.40 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 9.5 Hz, 1H), 7.17 (d, J = 8.1 Hz, 2H), 6.38 (d, J = 15.9
Hz, 1H), 6.12 (dt, J = 15.8, 7.0 Hz, 1H), 4.15 (d, J = 2.5 Hz, 2H), 3.33 (t, J = 7.2 Hz, 2H), 2.49
(q, J = 7.2 Hz, 2H), 2.40 (s, 3H), 2.05 (t, J = 2.5 Hz, 1H). 13C {1H} NMR (101 MHz, CDCl3)
δ 143.5, 136.1, 135.9, 131.6, 131.2, 129.5, 127.6, 127.0, 121.00, 73.9, 45.9, 36.6, 31.5, 21.5.
HRMS (ESI) m/z: [M + H]+ Calcd for C20H21BrNO2S 418.0471, found 418.0485.
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(E)-N-(4-(4-Methoxyphenyl)but-3-en-1-yl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfon-
amide (1p). Firstly the primary alcohol was prepared with a reported procedure.11 Then
following the general procedures for GPII, the reaction was carried out using primary alcohol
(500 mg, 2.8 mmol, 1.0 equiv, in 10.0 mL THF), triphenylphosphine (1.47g, 5.61 mmol, 2.0
equiv) and 4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (700 mg, 3.36 mmol, 1.2 equiv)
and DIAD (1.1 g, 5.61 mmol, 2.0 equiv) to afford nitrogen-tethered 1,7-enynes 1p (650 mg,
63%) as a white solid. m.p. 114-115 ℃.1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz,
2H), 7.25 (dd, J = 8.3, 5.8 Hz, 4H), 6.90 – 6.71 (m, 2H), 6.38 (d, J = 15.8 Hz, 1H), 5.97 (dt, J
= 15.8, 7.0 Hz, 1H), 4.16 (d, J = 2.5 Hz, 2H), 3.78 (s, 3H), 3.32 (t, J = 7.3 Hz, 2H), 2.47 (q, J
= 7.2, 6.8 Hz, 2H), 2.39 (s, 3H), 2.06 (t, J = 2.5 Hz, 1H). 13C {1H} NMR (101 MHz, CDCl3) δ
159.0, 143.5, 135.9, 131.7, 130.0, 129.5, 127.7, 127.2, 123.8, 113.9, 73.8, 55.3, 46.2, 36.6, 31.6,
21.5. HRMS (ESI) m/z: [M + H]+ Calcd for C21H24NO3S 370.1471, found 370.1479.
4-Methyl-N-(3-methylbut-3-en-1-yl)-N-(prop-2-yn-1-yl)benzenesulfonamideb
(1q).
Following the general procedures for GPII, the reaction was carried out using 3-methyl-3-
buten-1-ol (500 mg, 5.8 mmol, 1.0 equiv, in 20.0 mL THF), triphenylphosphine (3.0 g, 11.62
mmol, 2.0 equiv) and 4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (1.45 g, 6.96 mmol,
1.2 equiv) and DIAD (2.4 g, 11.62 mmol, 2.0 equiv) to afford nitrogen-tethered 1,7-enynes 1q
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(700 mg, 44%) as a colorless oil. H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.1 Hz, 2H), 7.28
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4-Methyl-N-(4-methylpent-3-en-1-yl)-N-(prop-2-yn-1-yl)
benzenesulfonamide
(1r).
Following the general procedures for GPII, the reaction was carried out using 4-methylpent-3-
en-1-ol (200 mg, 2.0 mmol, 1.0 equiv, in 10.0 mL THF), triphenylphosphine (1.05 g, 4.0 mmol,
2.0 equiv) and 4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (1.0 g, 4.8 mmol, 1.2 equiv)
and diisopropyl azodicarboxylate (DIAD, 810 mg, 4.0 mmol, 2.0 equiv) to afford nitrogen-
tethered 1,7-enynes 1r (310 mg, 54%) as a colorless oil. Rf = 0.7 (silica, EtOAc : hexane =
1:10). 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 5.09-
5.00 (m, 1H), 4.13 (d, J = 2.5 Hz, 2H), 3.16 (t, J = 4.0, 2H), 2.40 (s, 3H), 2.25 (q, J = 7.5 Hz,
2H), 2.02 (t, J = 2.5 Hz, 1H), 1.66 (s, 3H), 1.59 (s, 3H). 13C {1H} NMR (101 MHz, CDCl3) δ
143.4, 136.0, 134.5, 129.4, 129.4, 127.6, 119.8, 73.6, 46.1, 36.4, 26.7, 25.7, 21.5, 17.8. HRMS
(ESI) m/z: [M + H]+ Calcd for C16H22NO2S 292.1366, found 292.1364.
N-(2-(cyclohex-1-en-1-yl)ethyl)-4-nitro-N-(prop-2-yn-1-yl)benzenesulfonamide (1s)
Following the general procedures for GPI - Step 4, the reaction was carried out using 1a-1 (1.5
g, 4.8 mmol, 1.0 equiv, in 4.5 mL DMF), NaH (215 mg in 4.5 mL DMF, 5.3 mmol, 1.1 equiv,
60% in mineral oil), 3-bromoprop-1-yne (860 mg, 7.2 mmol, 1.5 equiv) to produce 1s (1.3 g,
80%) as a yellow solid, m.p. = 89-90℃, Rf = 0.6 (silica, EtOAc : hexane = 1 : 10). 1H NMR
(400 MHz, CDCl3) 8.35 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 5.49 (s, 1H), 4.21 (t, J =
2.1 Hz, 2H), 3.30 (t, J = 7.5 Hz, 2H), 2.23 (t, J = 7.6 Hz, 2H), 2.02 (s, 1H), 1.97 (p, J = 7.0, 5.7
Hz, 5H), 1.62 (ddt, J = 9.2, 6.5, 3.3 Hz, 2H), 1.55 (tt, J = 9.5, 4.5 Hz, 2H). 13C {1H} NMR (101
MHz, CDCl3) δ 150.1, 144.9, 133.7, 128.9, 124.2, 124.1, 77.3, 75.9, 74.3, 44.9, 36.3, 36.2, 28.0,
25.2, 22.8, 22.2. HRMS (ESI) m/z: [M + Na]+ Calcd for C17H21NaN2O4S 71.1041, found
371.1036.
N-(But-2-yn-1-yl)-N-(2-(cyclohex-1-en-1-yl)ethyl)-4-methylbenzenesulfonamide
(1t).
Following the general procedures for GPI - Step 4, the reaction was carried out using 1a-1 (2.0
g, 7.16 mmol, 1.0 equiv, in 4.5 mL DMF), NaH (315 mg in 4.5 mL DMF, 7.88 mmol, 1.1 equiv,
60% in mineral oil), 1-bromobut-2-yne (1.4 g, 10.74 mmol, 1.5 equiv) to produce 1s as a white
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solid, m.p. = 70-71 ℃, Rf = 0.6 (silica, EtOAc : hexane = 1 : 10). 1H NMR (400 MHz, CDCl3)
δ 7.71 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H), 5.43 (s, 1H), 4.05 (q, J = 2.5 Hz, 2H), 3.21
(t, J = 7.6 Hz, 2H), 2.40 (s, 3H), 2.16 (t, J = 7.6 Hz, 2H), 1.95 (dq, J = 13.4, 7.0, 6.5 Hz, 4H),
1.65 – 1.56 (m, 2H), 1.53 (q, J = 4.3, 3.4 Hz, 4H). 13C {1H} NMR (101 MHz, CDCl3) δ 143.0,
136.1, 134.3, 129.2, 127.8, 123.4, 81.4, 71.8, 44.7, 36.7, 36.3, 28.0, 25.2, 22.8, 22.2, 21.5, 3.2.
HRMS (ESI) m/z: [M + H]+ Calcd for C19H26NO2S 332.1679, found 332.1675.
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N-Cinnamyl-4-methyl-N-(prop-2-yn-1-yl) benzenesulfonamide (1u). Following the general
procedures for GPII, the reaction was carried out using (E)-cinnamyl alcohol (500 mg, 3.72
mmol, 1.0 equiv, in 10.0 mL THF), triphenylphosphine (1.95 g, 7.45 mmol, 2.0 equiv) and 4-
methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (935 mg, 4.45 mmol, 1.2 equiv) and
diisopropyl azodicarboxylate (DIAD, 1.5 g, 7.45 mmol, 2.0 equiv) to afford nitrogen-tethered
1,7-enynes 1u (880 mg, 73%) as a white solid. mp 64-65 ℃.1H NMR (400 MHz, CDCl3) δ
7.76 (d, J = 7.9 Hz, 2H), 7.39 – 7.16 (m, 7H), 6.56 (d, J = 15.8 Hz, 1H), 6.07 (dt, J = 15.9, 6.9
Hz, 1H), 4.12 (d, J = 2.5 Hz, 2H), 3.98 (d, J = 6.8 Hz, 2H), 2.43 (s, 3H), 2.04 (t, J = 2.0 Hz,
1H). 13C {1H} NMR (101 MHz, CDCl3) δ 143.6, 136.1, 134.9, 129.5, 128.6, 128.0, 127.8, 126.5,
122.9, 73.8, 48.6, 35.9, 21.5. Data are consistent with the previous reported.5p,5m,5o
III. General Procedure III for construction of azabicyclo[5.1.0]octane ring system. (GP
III)
To a dried Schlenk tube with rubber plug, was charged with 1a-1u (0.3 mmol, 1.0 equiv),
[IrCp*Cl2]2 (0.03 mmol, 0.1 equiv), and replaced with nitrogen 3 times. Then dried chloroform
(0.03M) was added by syringe. The mixture was heated at 50 ℃ via oil bath with magnetic
stirrer for 5-10 hours, until the starting material disappeared, concentrated and purified by flash
silica column chromatography (ethyl acetate: petroleum ether = 1 : 20 ~ 1 : 15) to afford 2a-
2u.
3-Tosyl-2,3,5a,5b,6,7,8,9-octahydro-1H-benzo[1,3]cyclopropa[1,2-d]azepine (2a). White
solid, m.p. 74−75 ℃, Rf = 0.5 (silica gel, petroleum ether : EtOAc = 10 : 1). 76.5 mg, 78%.
1HNMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.21 (d, J =
9.7 Hz, 1H), 5.01 (dd, J = 9.7, 4.6 Hz, 1H), 3.50 (dd, J = 13.3, 8.4 Hz, 1H), 3.34 (dd, J = 13.3,
8.9 Hz, 1H), 2.03 (ddd, J = 15.2, 9.0, 1.7 Hz, 1H), 1.86 (dq, J = 13.2, 6.1 Hz, 1H), 1.74 (dt, J
= 13.2, 5.2 Hz, 1H), 1.66 – 1.46 (m, 3H), 1.38 (ddd, J = 13.7, 9.0, 5.2 Hz, 1H), 1.36 – 1.16 (m,
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1H), 1.16 – 0.96 (m, 1H), 0.91 (t, J = 4.9 Hz, 1H), 0.66 (ddd, J = 7.1, 5.1, 1.5 Hz, 1H).13C {1H}
NMR (101 MHz, CDCl3) δ 143.6 136.4, 129.8, 127.1, 123.4, 112.5, 45.5, 37.8, 31.2, 27.9, 26.9,
25.8, 23.7, 21.7, 21.1. HRMS (ESI) m/z: [M + H]+ Calcd for C18H24NO2S 318.1522, found
318.1524. 2.0 g scale reaction provided 1.5 g (75%) of desired product.
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9,9-Dimethyl-3-tosyl-2,3,5a,5b,6,7,8,9-octahydro-1H-benzo[1,3]cyclopropa[1,2-d]azepine
1
(2b). Cololess oil, Rf = 0.6 (silica gel, petroleum ether : EtOAc = 10 : 1). 75.8 mg, 73%. H
NMR (400 MHz, Chloroform-d) δ 7.66 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.21 (d,
J = 9.6 Hz, 1H), 5.08 (dd, J = 9.6, 6.2 Hz, 1H), 3.66 (ddd, J = 14.2, 6.9, 2.0 Hz, 1H), 3.00 (dd,
J = 13.9, 11.0 Hz, 1H), 2.41 (s, 3H), 2.17 – 2.06 (m, 1H), 1.89 (dtd, J = 14.8, 7.6, 2.5 Hz, 1H),
1.66 (dd, J = 15.3, 6.9 Hz, 1H), 1.60 – 1.47 (m, 1H), 1.37 – 1.14 (m, 2H), 1.09 – 0.86 (m, 6H),
0.78 (s, 4H).13C {1H} NMR (101 MHz, Chloroform-d) δ 143.5, 129.8, 127.0, 123.7, 113.2,
46.3, 36.3, 36.1, 31.8, 31.2, 29.6, 28.5, 27.1, 26.0, 22.5, 21.6, 17.7. HRMS (ESI) m/z: [M + H]+
Calcd for C20H28NO2S 346.1838, found 346.1835.
7,7-Dimethyl-3-tosyl-2,3,5a,5b,6,7,8,9-octahydro-1H-benzo[1,3]cyclopropa[1,2-d]azepine
(2c). Colorless oil, Rf = 0.6 (silica gel, petroleum ether : EtOAc = 10:1). 66.5 mg, 64% .1H
NMR (400 MHz, CDCl3) δ 7.68 – 7.61 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.19 (d, J
= 9.7 Hz, 1H), 5.03 (dd, J = 9.7, 4.8 Hz, 1H), 3.50 (dd, J = 13.4, 8.3, 1H), 3.29 (dd, J = 13.3,
9.0 Hz, 1H), 2.41 (d, J = 4.6 Hz, 3H), 2.04 (dd, J = 15.1, 9.2, 1H), 1.74 (ddd, J = 13.6, 5.3, 2.1
Hz, 1H), 1.63 (ddd, J = 14.2, 7.7, 3.4 Hz, 2H), 1.44 (td, J = 13.5, 5.6 Hz, 1H), 1.20 – 1.13 (m,
1H), 1.06 (dp, J = 11.3, 2.7 Hz, 1H), 0.85 (td, J = 13.6, 5.2 Hz, 1H), 0.75 (s, 6H), 0.61 (ddd, J
= 9.0, 5.0, 2.2 Hz, 1H). 13C {1H} NMR (101 MHz, CDCl3) δ 143.5, 136.1, 129.7, 126.9, 123.1,
112.1, 45.5, 38.2, 37.4, 33.1, 31.7, 28.0, 26.8, 26.5, 25.9, 25.8, 25.3, 21.6. HRMS (ESI) m/z:
[M + H]+ Calcd for C20H28NO2S 346.1835, found346.1838.
7-Phenyl-3-tosyl-2,3,5a,5b,6,7,8,9-octahydro-1H-benzo[1,3]cyclopropa[1,2-d]azepine
(2d). Colorless oil, Rf = 0.6 (silica gel, petroleum ether : EtOAc = 10 : 1). The dr value was
determined by crude reaction residue. 88.9 mg, 75%. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J
= 8.3, 2H), 7.34 – 7.22(m, 4H), 7.20 – 7.08 (m, 3H), 6.26 (d, J = 9.7 Hz, 1H), 5.05 (ddd, J =
23.1, 9.7, 4.5 Hz, 1H), 3.56 (td, J = 13.1, 7.8 Hz, 1H), 3.36 (ddd, J = 38.1, 13.3, 9.0 Hz, 1H),
2.43 (s, 3H), 2.39 – 2.19 (m, 1H), 2.11 (ddd, J = 13.7, 9.5, 6.9 Hz, 2H), 1.88 – 1.46 (m, 5H),
1.22 (dtd, J = 24.5, 11.8, 4.5 Hz, 1H), 1.07 (dt, J = 10.3, 4.9 Hz, 1H), 0.93-0.76 (m, 1H). 13C
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{1H} NMR (101 MHz, CDCl3) δ 147.0, 146.7, 143.5, 136.0, 129.7, 128.3, 126.8, 126.7, 125.9,
123.8, 123.2, 112.3, 111.5, 45.4, 45.3, 40.9, 37.5, 37.2, 33.3, 31.8, 31.3, 31.0, 29.3, 29.2, 27.9,
27.8, 27.5, 27.0, 26.3, 26.0, 25.8, 21.5. HRMS (ESI) m/z: [M + H]+ Calcd for C24H28NO2S
394.1835, found 394.1828.
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3-Tosyl-4,5,6,7,11b,11c-hexahydro-3H-naphtho[2',1':1,3]cyclopropa[1,2-d]azepine (2e).
White solid, m.p. 110-111 °C, Rf = 0.5 (silica gel, petroleum ether : EtOAc = 10 : 1). 86.7 mg,
79%. 1H NMR (400 MHz, CDCl3) δ7.71 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.17 (d,
J = 7.4 Hz, 1H), 7.10 (t, J = 7.3 Hz, 1H), 7.05 (td, J = 7.1, 1.4 Hz, 1H), 7.00 (d, J = 7.3 Hz,
1H), 6.37 (d, J = 9.8 Hz, 1H), 5.04 (dd, J = 9.8, 4.8 Hz, 1H), 3.66 – 3.49 (m, 2H), 2.61 (ddd, J
= 16.3, 5.8, 2.0 Hz, 1H), 2.52-2.41 (m, 4H), 2.23 (ddd, J = 15.4, 8.6, 2.2 Hz, 1H), 2.06 (ddd, J
= 13.2, 6.3, 2.0 Hz, 1H), 1.86 (ddd, J = 15.3, 7.8, 1.8 Hz, 1H), 1.75 (t, J = 4.6 Hz, 1H), 1.68 (d,
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J = 4.2 Hz, 1H), 1.48 (td, J = 13.3, 5.7 Hz, 1H). C {1H} NMR (101 MHz, CDCl3) δ 143.8,
137.6, 133.1, 130.0, 128.1, 128.2, 127.1, 126.2, 125.3, 124.5, 110.2, 46.0, 35.4, 33.6, 31.5, 26.5,
26.5, 24.1, 21.7. HRMS (ESI) m/z: [M + H]+ Calcd for C22H24NO2S 366.1522, found 366.1525.
8-Methoxy-3-tosyl-4,5,6,7,11b,11c-hexahydro-3H-naphtho[2',1':1,3]cyclopropa[1,2-
d]azepine (2f). White solid, m.p. 153-154 ℃, Rf = 0.5 (silica gel, petroleum ether : EtOAc =
10 : 1). 107.0 mg, 90%. 1H NMR (400 MHz, CDCl3) δ 7.75 – 7.60 (d, J = 8.0 Hz, 2H), 7.34 (d,
J = 8.0 Hz, 2H), 6.91 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), 6.61 (dd, J = 8.2, 2.7 Hz,
1H), 6.36 (d, J = 9.8 Hz, 1H), 5.03 (dd, J = 9.8, 4.8 Hz, 1H), 3.77 (s, 3H), 3.69 – 3.46 (m, 2H),
2.55 (ddd, J = 16.2, 5.7, 1.9 Hz, 1H), 2.45 (s, 3H), 2.39 (td, J = 16.1, 14.9, 6.1 Hz, 1H), 2.22
(ddd, J = 15.3, 8.3, 2.4 Hz, 1H), 2.08 – 2.00 (m, 1H), 1.84 (ddd, J = 15.4, 7.6, 2.0 Hz, 1H),
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1.74 (t, J = 4.6 Hz, 1H). 1.63 (d, J = 4.1 Hz, 1H), 1.46 (td, J = 13.3, 5.6 Hz, 1H). C {1H}
NMR (101 MHz, CDCl3) δ 158.1, 143.8, 138.8, 136.2, 130.0, 129.4, 127.1, 125.2, 124.5, 113.6,
110.9, 110.1, 55.4, 46.0, 35.4, 33.9, 31.6, 26.9, 25.6, 24.1, 21.7. HRMS (ESI) m/z: [M + H]+
Calcd for C23H26NO3S 396.1628, found 396.1630.
10-Methoxy-3-tosyl-4,5,6,7,11b,11c-hexahydro-3H-naphtho[2',1':1,3]cyclopropa[1,2-
d]azepine (2g). White solid, m.p. 146-145 ℃, Rf = 0.5 (silica gel, petroleum ether : EtOAc =
10 : 1). 85.6 mg, 72%. 1H NMR (400 MHz, CDCl3) δ 7.82 – 7.67 (m, 2H), 7.34 (d, J = 8.0 Hz,
2H), 6.91 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), 6.61 (dd, J = 8.2, 2.7 Hz, 1H), 6.36 (d,
J = 9.8 Hz, 1H), 5.03 (dd, J = 9.8, 4.8 Hz, 1H), 3.77 (s, 3H), 3.66 – 3.47 (m, 2H), 2.55 (ddd, J
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= 16.2, 5.7, 1.9 Hz, 1H), 2.45 (s, 3H), 2.40 (dd, J = 13.7, 6.1 Hz, 1H), 2.22 (ddd, J = 15.3, 8.3,
2.4 Hz, 1H), 2.09 – 1.99 (m, 1H), 1.84 (ddd, J = 15.4, 7.6, 2.0 Hz, 1H), 1.74 (t, J = 4.6 Hz,
1H), 1.63 (d, J = 4.1 Hz, 1H), 1.46 (td, J = 13.3, 5.6 Hz, 1H). 13C {1H} NMR (101 MHz,
CDCl3) δ 158.1, 143.8, 138.8, 136.2, 130.0, 129.4, 127.1, 125.2, 124.5, 113.6, 110.9, 110.1,
55.4, 46.0, 35.4, 33.9, 31.55, 26.9, 25.6, 24.1, 21.7. HRMS (ESI) m/z: [M + H]+ Calcd for
C23H26NO3S 396.1628, found 396.1633.
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Methyl(4S)-3-tosyl-4,5,6,7,11b,11c-hexahydro-3H-naphtho[2',1':1,3]cyclopropa[1,2-
d]azepine-4-carboxylate (2h). White solid, m.p. 62-63 ℃, Rf = 0.6 (silica gel, petroleum ether
: EtOAc = 5 : 1). 93.9 mg, 74%. 1H NMR (400 MHz, CDCl3 δ 7.71 (d, J = 8.2 Hz, 2H), 7.35
(d, J = 8.1 Hz, 2H), 7.06 (dtd, J = 18.0, 7.3, 1.6 Hz, 2H), 7.00 – 6.93 (m, 2H), 6.37 (d, J = 10.0
Hz, 1H), 5.07 (dd, J = 10.0, 4.7 Hz, 1H), 4.87 (dt, J = 7.0, 1.9 Hz, 1H), 3.66 (s, 3H), 2.66 (dd,
J = 15.6, 7.2 Hz, 1H), 2.56 (ddd, J = 16.5, 5.5, 2.1 Hz, 1H), 2.46 (s, 3H), 2.37 (td, J = 16.3,
15.1, 6.0 Hz, 1H), 2.11 – 2.03 (m, 2H), 1.96 (ddd, J = 13.4, 6.1, 2.0 Hz, 1H), 1.77 (t, J = 4.5
Hz, 1H), 1.53 (td, J = 13.5, 5.5 Hz, 1H), 1.46 (d, J = 4.3 Hz, 1H). 13C {1H} NMR (101 MHz,
CDCl3) δ 170.9, 144.0, 137.2, 135.9, 132.7, 129.8, 128.3, 128.0, 127.2, 126.0, 125.2, 121.2,
109.9, 92.7, 58.5, 52.1, 36.9, 33.5, 27.5, 26.7, 26.6, 23.5, 21.6. HRMS (ESI) m/z: [M + Na]+
Calcd for C24H25NaNO4S 446.1397, found 446.1405.
3-Tosyl-1,2,3,5a,5b,6,7,8-octahydrocyclopenta[1,3]cyclopropa[1,2-d]azepine
(2i)
Colorless oil, Rf = 0.5 (silica gel, petroleum ether : EtOAc = 10 : 1). 84.8 mg, 93%. 1H NMR
(400 MHz, CDCl3) δ 7.65 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.26 (d, J = 9.7 Hz,
1H), 4.96 (dd, J = 9.7, 5.2 Hz, 1H), 3.71 (ddd, J = 13.7, 7.3, 1.9 Hz, 1H), 3.01 (dd, J = 13.6,
10.3 Hz, 1H), 2.40 (s, 3H), 2.15 (ddd, J = 15.1, 10.4, 1.9 Hz, 1H), 1.89 (dd, J = 15.1, 7.2 Hz,
1H), 1.71 (dddd, J = 18.8, 11.6, 8.2, 4.9 Hz, 3H), 1.53 (dt, J = 12.8, 8.0 Hz, 1H), 1.42 (td, J =
11.6, 8.3 Hz, 1H), 1.18 – 1.08 (m, 1H), 1.05 (q, J = 4.1 Hz, 1H), 0.91 (t, J = 3.8 Hz, 1H). 13C
{1H} NMR (101 MHz, Chloroform-d) δ 143.5, 136.3, 129.7, 126.8, 124.7, 111.9, 47.6, 36.4,
34.8, 33.1, 33.0, 28.0, 22.0, 21.5, 21.2. HRMS (ESI) m/z: [M + H]+ Calcd for C17H22NO2S
304.1366, found 304.1366.
3-Tosyl-1,2,3,5a,5b,6,7,8,9,10-decahydrocyclohepta[1,3]cyclopropa[1,2-d]azepine
(2j).
White solid, m.p. 117-118 ℃, Rf = 0.6 (silica gel, petroleum ether : EtOAc = 10 : 1). 89.7 mg,
90%. 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.19 (d,
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J = 9.8 Hz, 1H), 4.95 (dd, J = 9.8, 4.3 Hz, 1H), 3.51 (dd, J = 13.2, 8.1 Hz, 1H), 3.42 (dd, J =
13.2, 8.8 Hz, 1H), 2.22 – 2.05 (m, 2H), 1.90 (dd, J = 14.5, 7.0 Hz, 1H), 1.81 – 1.71 (m, 1H),
1.71 – 1.61 (m, 1H), 1.59 – 1.49 (m, 2H), 1.42 (dd, J = 15.4, 8.9 Hz, 1H), 1.38 – 1.28 (m, 1H),
1.28 – 1.01 (m, 3H), 1.01 – 0.79 (m, 3H), 0.56 (dt, J = 10.5, 5.5 Hz, 1H). 13C {1H} NMR (101
MHz, CDCl3) δ 143.6, 136.3, 129.8, 127.1, 122.7, 111.8, 45.8, 36.1, 34.3, 32.4, 31.8, 31.7, 29.5,
26.4, 21.7. HRMS (ESI) m/z: [M + H]+ Calcd for C19H26NO2S 332.1679, found 332.1681.
3-((4-(Trifluoromethyl)phenyl)sulfonyl)-1,2,3,5a,5b,6,7,8,9,10-decahydrocyclohepta[1,3]
cyclopropa[1,2-d]azepine (2k). White solid, m.p. 68-69 ℃, Rf = 0.6 (silica gel, petroleum ether
: EtOAc = 10 : 1). 118.8 mg, 97%. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.2 Hz, 2H), 7.76
(d, J = 8.2 Hz, 2H), 6.16 (d, J = 9.7 Hz, 1H), 5.05 (dd, J = 9.7, 4.2 Hz, 1H), 3.59 – 3.41 (m,
2H), 2.23 – 2.04 (m, 2H), 1.87 (dd, J = 14.5, 7.0 Hz, 1H), 1.81 – 1.71 (m, 1H), 1.71 – 1.60 (m,
1H), 1.59 – 1.50 (m, 1H), 1.50 – 1.37 (m, 1H), 1.37 – 1.27 (m, 1H), 1.27 – 1.16 (m, 1H), 1.16
– 1.01 (m, 2H), 1.01 – 0.78 (m, 4H), 0.57 (dt, J = 10.5, 5.5 Hz, 1H).13C {1H} NMR (101 MHz,
CDCl3) δ 142.5, 134.4(q, JC-F = 132), 127.6, 126.3(q, JC-F = 16), 123.3(q, JC-F = 1084), 121.8,
113.6, 45.8, 35.8, 34.1, 34.0, 32.2, 31.6, 31.4, 29.3, 26.2. 19F NMR (376 MHz, CDCl3) δ -63.1
(s, 3 F). HRMS (ESI) m/z: [M + Na]+ Calcd for C19H22F3NNaO2S 408.1216, found 408.1221.
3-Tosyl-2,3,5a,5b,6,7,8,9,10,11-decahydro-1H-cycloocta[1,3]cyclopropa[1,2-d]azepine
(2l). White solid, m.p. 89-90 ℃, Rf = 0.6 (silica gel, petroleum ether : EtOAc = 10 : 1). 101.8
mg, 98%. 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.61 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz,
2H), 6.20 (d, J = 9.7 Hz, 1H), 4.98 (dd, J = 9.7, 4.3 Hz, 1H), 3.55 – 3.35 (m, 2H), 2.42 (s, 3H),
2.18 (ddd, J = 15.4, 8.1, 1.8 Hz, 1H), 2.05 (dq, J = 14.6, 3.5 Hz, 1H), 1.84 (dt, J = 14.8, 3.8
Hz, 1H), 1.54 – 1.19 (m, 8H), 1.00 – 0.87 (m, 2H), 0.57 (t, J = 4.8 Hz, 1H), 0.36 (ddd, J = 11.7,
5.1, 3.4 Hz, 1H). 13C {1H} NMR (101 MHz, CDCl3) δ 143.6, 129.8, 127.1, 122.7, 112.2, 45.5,
33.9, 32.0, 31.1, 29.2, 29.1, 28.1, 27.1, 26.5, 26.2, 25.7, 21.7. HRMS (ESI) m/z: [M + H]+ Calcd
for C20H28NO2S 346.1835, found 346.1836.
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3-((4-(Trifluoromethyl)phenyl)sulfonyl)-2,3,5a,5b,6,7,8,9,10,11-decahydro-1H-cycloocta
[1,3]cyclopropa[1,2-d]azepine (2m). White solid, m.p. 67-68 ℃, Rf = 0.6 (silica gel, petroleum
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ether : EtOAc = 10 : 1). 116.1 mg, 97%. H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.1 Hz,
2H), 7.78 (d, J = 8.1 Hz, 2H), 6.17 (d, J = 9.6 Hz, 1H), 5.08 (dd, J = 9.6, 4.2 Hz, 1H), 3.59 –
3.32 (m, 2H), 2.28 – 2.12 (m, 1H), 2.04 (dq, J = 14.6, 3.4 Hz, 1H), 1.80 (dt, J = 14.9, 3.8 Hz,
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1H), 1.57 – 1.16 (m, 8H), 1.01 – 0.76 (m, 3H), 0.57 (t, J = 4.8 Hz, 1H), 0.37 (dt, J = 11.9, 4.2
Hz, 1H).13C {1H} NMR (101 MHz, CDCl3) δ 142.7, 134.4(q, JC-F = 132), 127.5, 126.4(q, JC-F
= 16), 123.4(q, JC-F = 1084), 122.0, 114.1, 45.7, 33.9, 31.9, 31.0, 29.1, 28.9, 28.1, 26.9, 26.4,
26.2, 25.6. 19F NMR (376 MHz, CDCl3) δ -63.1 (s, 3 F). HRMS (ESI) m/z: [M + Na]+ Calcd
for C20H24F3NNaO2S, 422.1376, found 422.1372 .
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8-Phenyl-4-tosyl-4-azabicyclo[5.1.0]oct-2-ene (2n). White solid, m.p. 79-80 ℃, Rf = 0.5
(silica gel, petroleum ether : EtOAc = 10 : 1), 51.0 mg, 50%. 1H NMR (400 MHz, CDCl3 δ 7.69
(d, J = 8.0 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 7.22 (t, J = 7.5 Hz, 2H), 7.12 (dd, J = 8.5, 5.9
Hz, 1H), 6.95 (d, J = 7.4 Hz, 2H), 6.36 (d, J = 9.8 Hz, 1H), 5.10 (dd, J = 9.8, 4.3 Hz, 1H), 3.62
(dd, J = 13.5, 8.7 Hz, 1H), 3.46 (dd, J = 13.4, 8.2 Hz, 1H), 2.49 – 2.33 (m, 4H), 1.74 – 1.50
(m, 5H). 13C {1H} NMR (101 MHz, CDCl3) δ 143.8, 142.3, 136.3, 129.9, 128.5, 127.0, 125.7,
125.3, 124.4, 110.2, 47.5, 33.6, 28.9, 28.9, 26.8, 21.7. HRMS (ESI) m/z: [M + H]+ Calcd for
C20H22NO2S 340.1366, found 340.1375.
8-(4-Bromophenyl)-4-tosyl-4-azabicyclo[5.1.0]oct-2-ene (2o). White solid, m.p. 88-89 ℃, Rf
= 0.5 (silica gel, petroleum ether : EtOAc = 10 : 1). 50.2 mg, 40%. 1H NMR (400 MHz, CDCl3)
δ 7.67 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.2 Hz, 4H), 6.87 – 6.73 (m, 2H), 6.35 (d, J = 9.8 Hz,
1H), 5.06 (dd, J = 9.8, 4.2 Hz, 1H), 3.61 (dd, J = 13.4, 8.7 Hz, 1H), 3.42 (dd, J = 13.4, 8.3 Hz,
1H), 2.43 (s, 4H), 1.76 – 1.42 (m, 4H). 13C {1H} NMR (101 MHz, CDCl3) δ 143.7, 141.2, 135.9,
131.3, 129.8, 126.9, 126.9, 124.4, 119.0, 109.5, 47.3, 32.9, 28.9, 28.7, 26.7, 21.6. HRMS (ESI)
m/z: [M + H]+ Calcd for C20H21BrNO2S 418.0471, found 418.0480.
8-(4-Methoxyphenyl)-4-tosyl-4-azabicyclo[5.1.0]oct-2-ene (2p). White solid, m.p. 72-73 ℃,
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Rf = 0.5 (silica gel, petroleum ether : EtOAc = 10 : 1). 61.3 mg, 55%. H NMR (400 MHz,
CDCl3) δ 7.69 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 6.79 (d,
J = 8.7 Hz, 2H), 6.35 (d, J = 9.8 Hz, 1H), 5.11 (dd, J = 9.8, 4.4 Hz, 1H), 3.76 (s, 3H), 3.61 (dd,
J = 13.2, 8.8 Hz, 1H), 3.53 – 3.31 (m, 1H), 2.45 (s, 4H), 1.77 – 1.62 (m, 1H), 1.63 – 1.53 (m,
2H), 1.47 (dt, J = 9.6, 5.0 Hz, 1H).13C {1H} NMR (101 MHz, CDCl3) δ 157.7, 143.6, 136.0,
134.1, 129.8, 126.9, 126.2, 124.0, 113.8, 110.3, 55.3, 47.4, 32.6, 28.7, 28.3, 26.1, 21.6. HRMS
(ESI) m/z: [M + H]+ Calcd for C21H24NO3S, 370.1471, found 370.1478. 157.65, 143.63, 135.99,
1-Methyl-4-tosyl-4-azabicyclo[5.1.0]oct-2-ene (2q). White solid, m.p. 153-154 ℃, Rf = 0.6
(silica gel, petroleum ether : EtOAc = 10:1). 84.8 mg, 75%. 1H NMR (400 MHz, CDCl3) δ 7.66
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(d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.24 (d, J = 9.7 Hz, 1H), 4.96 (dd, J = 9.8, 4.8
Hz, 1H), 3.63 – 3.49 (m, 1H), 3.25 (dd, J = 13.5, 9.4 Hz, 1H), 2.42 (s, 2H), 2.02 (ddd, J = 15.2,
9.4, 1.7 Hz, 1H), 1.72 – 1.57 (m, 1H), 1.00 (s, 3H), 0.63 (dd, J = 9.2, 3.9 Hz, 1H), 0.26 (t, J =
4.4 Hz, 1H). 13C {1H} NMR (101 MHz, CDCl3) δ 143.5, 136.2, 129.7, 126.9, 123.8, 112.1,
68.6, 45.7, 35.0, 25.8, 23.1, 22.5, 22.4, 22.4, 22.1, 21.5. HRMS (ESI) m/z: [M + Na]+ Calcd for
C15H19NaNO2S 300.1029, found 300.1028.
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8,8-Dimethyl-4-tosyl-4-azabicyclo[5.1.0]oct-2-ene (2r). White solid, m.p. 61-62 ℃, Rf = 0.6
(silica gel, petroleum ether : EtOAc = 10:1). 31.6 mg, 36%. 1H NMR (400 MHz, CDCl3) δ 7.77
– 7.59 (m, 2H), 7.30 (d, J = 8.1 Hz, 2H), 6.23 (d, J = 9.7 Hz, 1H), 5.04 (dd, J = 9.7, 4.3 Hz,
1H), 3.55 – 3.30 (m, 2H), 2.42 (s, 3H), 2.33 – 2.18 (m, 1H), 1.56 – 1.45 (m, 1H), 1.37 – 1.16
(m, 3H), 1.02 – 0.84 (m, 5H), 0.41 (ddd, J = 11.7, 6.7, 4.9 Hz, 1H). 13C {1H} NMR (101 MHz,
CDCl3) δ 143.6, 136.5, 129.8, 127.0, 123.5, 112.2, 47.3, 29.0, 27.1, 25.0, 21.7. HRMS (ESI)
m/z: [M + H]+ Calcd for C16H22NO2S 292.1366, found 292.1364.
3-((4-Nitrophenyl)sulfonyl)-2,3,5a,5b,6,7,8,9-octahydro-1H-benzo[1,3]cyclopropa[1,2-
d]azepine (2s)
yellow solid, m.p.110-111 ℃, Rf = 0.6 (silica gel, petroleum ether : EtOAc = 10:1). 62.7 mg,
60%. 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.5 Hz, 2H), 6.17 (d,
J = 9.5 Hz, 1H), 5.15 (dd, J = 9.6, 4.5 Hz, 1H), 3.62 – 3.48 (m, 1H), 3.42 (dd, J = 13.2, 8.7 Hz,
1H), 2.02 (dd, J = 15.3, 8.6 Hz, 1H), 1.86 (dq, J = 13.2, 6.2 Hz, 1H), 1.68 (dt, J = 13.2, 5.2 Hz,
1H), 1.64 – 1.48 (m, 5H), 1.45 – 0.93 (m, 6H), 0.89 (t, J = 5.0 Hz, 1H), 0.69 (t, J = 6.4 Hz, 1H).
13C {1H} NMR (101 MHz, CDCl3) δ 150.0, 144.7, 128.1, 124.4, 122.2, 115.2, 77.3, 77.0, 76.7,
45.6, 37.4, 30.8, 27.7, 26.5, 25.4, 23.4, 21.4, 20.8. HRMS (ESI) m/z: [M + Na]+ Calcd for
C17H20NaN2O4S 371.1036, found 371.1034.
7-Phenyl-3-tosyl-3-azabicyclo[4.1.0]hept-4-ene (2u). White solid, m.p. 80-81 ℃, Rf = 0.5
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(silica gel, petroleum ether : EtOAc = 10 : 1). 73.2 mg, 72%. H NMR (400 MHz, CDCl3) δ
7.70 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.22 (t, J = 7.5 Hz, 2H), 7.14 (t, J = 7.3 Hz,
1H), 6.84 – 6.77 (m, 2H), 6.44 (d, J = 8.0 Hz, 1H), 5.52 (dd, J = 8.0, 5.4 Hz, 1H), 4.04 (d, J =
12.0 Hz, 1H), 3.17 (dd, J = 12.1, 2.9 Hz, 1H), 2.48 (s, 3H), 1.91 (ddd, J = 8.0, 5.5, 2.5 Hz, 1H),
1.63 (t, J = 4.5 Hz, 1H), 1.47 (ddd, J = 9.1, 5.4, 3.9 Hz, 1H). 13C {1H} NMR (101 MHz, CDCl3)
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δ 143.8, 140.5, 134.8, 139.9, 128.3, 127.1, 125.9, 125.2, 121.4, 111.1, 40.2, 31.1, 28.9, 21.5,
19.3. Data are consistent with the previous reported.5p,5m,5o
Supporting Information
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Catalysts screening, NMR spectra and X-ray analysis.
Crystal data for 2e (CIF)
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Associated Content
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Author Information
Corresponding Author:
*E-mail for Jian Guo: jian.guo@cqu.edu.cn.
*E-mail for Yun He: yun.he@cqu.edu.cn.
ORCID
Jian Guo: 0000-0003-2162-9337
Yun He: 0000-0002-5322-7300
Notes
The authors declare no competing financial interest.
Acknowledgment
We are grateful for the financial support from the Natural Science Foundation of Chongqing,
China (cstc2019jcyj-zdxmX0021, and cstc2019jcyj-msxmX0057) and the Fundamental
Research Funds for the Central Universities (2020CDJQY-A041). We would also like to thank
Analytical and Testing Center of Chongqing University for X-ray single crystal structural
analyses.
Notes and references
1. Wessjohann, L. A.; Brandt, W.; Thiemann, T. Biosynthesis and Metabolism of
Cyclopropane Rings in Natural Compounds. Chem. Rev. 2003, 103, 1625−1647.
2. (a) Label, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Stereoselective
Cyclopropanation Reactions. Chem. Rev. 2003, 103, 977−1050. (b) Ebner, C.; Carreira, E.
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