Transition-Metal Controlled Diastereodivergent Radical Cyclization/Azidation Cascade of 1,7-Enynes

Article abstract of DOI:10.1021/acs.joc.6b00655

A strategy for achieving diastereodivergent azidations of enynes has been developed, employing azide transfer from the M-N₃ complex to alkyl radicals. Following this concept, the diastereoselectivity has been switched by modulating the transition metals and the ligands. The Mn(III)-mediated radical cyclization/azidation cascade of 1,7-enynes afforded trans-fused pyrrolo[3,4-c]quinolinones, whereas the Cu(II)/bipyridine system gave cis-products.

Full text of DOI:10.1021/acs.joc.6b00655

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Note
Transition-metal Controlled Diastereodivergent
Radical Cyclization/Azidation Cascade of 1,7-Enynes
Yingying Zhao, Yancheng Hu, Haolong Wang, Xincheng Li, and Boshun Wan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00655 • Publication Date (Web): 29 Apr 2016
Downloaded from http://pubs.acs.org on May 2, 2016
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The Journal of Organic Chemistry
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Transition-metal
Controlled
Diastereodivergent
Radical
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Cyclization/Azidation Cascade of 1,7-Enynes
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Yingying Zhao,‡ Yancheng Hu,‡ Haolong Wang, Xincheng Li* and Boshun Wan*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan
Road, Dalian 116023, China
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*Eꢀmail: xcli@dicp.ac.cn; bswan@dicp.ac.cn
ABSTRACT
A strategy for achieving diastereodivergent azidations of enynes has been developed,
employing azide transfer from MꢀN3 complex to alkyl radicals. Following this
concept, the diastereoselectivity has been switched by modulating the
transitionꢀmetals and the ligands. Mn(III)ꢀmediated radical cyclization/azidation
cascade of 1,7ꢀenynes afforded transꢀfused pyrrolo[3,4ꢀc]quinolinones, whereas
Cu(II)/bipyridine system gave cisꢀproducts.
Diastereodivergent catalysis1, aiming at attaining different diastereomers from the
same substrates solely controlled by distinct catalysts, is the most straightforward and
efficient tool to produce the complete set of diastereomers. This strategy has been
extensively employed to selectively control the formation of stereocenters in
asymmetric catalysis.1b–f On the other hand, azidation of alkenes has emerged as a
promising alternative for the synthesis of useful organic azides, which are valuable
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precursors of numerous nitrogenꢀcontaining compounds2. Therefore, the past decade
has witnessed substantial achievements in this area.3 Despite the impressive advances,
the stereocontrol of the product distribution still remains a notable challenge, which
may be due to the involvement of free radical process. In this context,
diastereodivergent azidations to generate the complete set of diastereomers is of high
demand. In the pioneering works of Kochi,4 Fristad,3d, 5 and Minisci6, it is suggested
that the terminating step of olefin diazidations proceeds through azide transfer from
metal azide complex to alkyl radicals7, namely “ligandꢀtransfer oxidation” process.
Besides, an ironꢀcatalyzed diazidation was disclosed by Xu’s group very recently, in
which azido ligand transfer step was believed to be crucial for its high d.r. value.3f
Intrigued by these seminal works and our interests in azide chemistry8, we speculated
that if a radical reaction was terminated by the azide transfer oxidation step, instead of
free azidyl radical process, the diastereoselectivity possibly could be switched by
modulating the transitionꢀmetals and the ligands.
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In recent years, 1,nꢀenynes, which endowed with both C=C and C ≡ C
unsaturated moieties, are privileged building blocks for assembling elaborate
compounds via radical reaction cascades. For example, Nevado and coꢀworkers9
reported various radicals triggered domino cyclizations of enynes, providing highly
complex azaꢀheterocycles through a radical addition/aryl migration/desulfonylation
cascade pathway (Scheme 1a). Li10, Jiang and Tu11 et al. devoted to exploring the
intriguing radical reactivity of Nꢀtethered 1,7ꢀenynes (Scheme 1b). As our continued
efforts to exploit new reaction patterns of unsaturated precursors,12 we envisioned that
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enynes
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could undergo azidyl radicalꢀtriggered cyclization/the loss of
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N2/tautomerization cascade process to form alkyl radical IV, which can be intercepted
by LnMꢀN3 species3j, leading to alkyl azides with high diastereoselectivity (Scheme
1c). Indeed, Mn(III)ꢀmediated azidations of Nꢀsulfonyl tethered 1,7ꢀenynes 1 afforded
transꢀfused pyrrolo[3,4ꢀc]quinolinones (transꢀ2), whereas Cu(II)/bipyridine system
gave cisꢀproducts (Scheme 1d). Although Li et al. has already reported an analogous
Cuꢀcatalyzed azidation of enynes for the synthesis of cisꢀ2,13 additional multiꢀstep
reactions were required to synthesize azidoꢀbenziodoxolone, which served as the
azide source in the work. Besides, easily handled and commercial available TMSN3
was proven to be ineffective for the reaction. Given the stepꢀeconomy, simple
operation and opposite selectivity of our protocol, we herein demonstrate Mnꢀ and
Cuꢀcontrolled diastereodivergence in radical bicyclization/azidation cascade of
enynes.
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Previous works:
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X = N3, CF3,
SCF3, P(O)Ph2
O
N
O
O
1) radical addition X•
N
X
N
(a)
•
Ph
O
S
O
Ph
X
2) aryl migration
3) desulfonylation
Ph
8
Nevado et al.
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Ph
Ph
X
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•
X = NO2, 1,4-dioxane,
arylsulfonyl, cycloalkane
Highly
Functionalized
Heterocycles
O
(b)
Li et al.
Jiang and Tu et al.
N
R
N
O
R
This work:
R
R
•
R
R
N3
N
N
•
•
O
Azidyl radical-
triggered 6-exo-dig
cyclization
N
N
O
N
O
N
O
+
Ts
1
Ts
Ts
III
Ts
IV
II
R
R
MLn
M = Transition metal
L = Ligand
N
N
N3
N3
N3
(c)
"azide transfer oxidation"
switchable diastereoselectivity
N
O
N
O
Ts
Ts
R
N
R
N
R
N3
N3
O
+
TMSN3
(d)
Mn
Cu
N
N
O
N
Ts
O
Ts
Ts
trans-2
1
cis-2
Scheme 1. Diastereodivergent radical cyclization/azidation cascade of 1,7-enynes.
We commenced our investigations using Nꢀsulfonyl tethered 1,7ꢀenyne 1a as
benchmark substrate and commercial available TMSN3 as azide source. When 3.0
equivalent of Mn(OAc)3•2H2O was employed as the radical initiator, to our delight,
transꢀfused pyrrolo[3,4ꢀc]quinolinones 2a14 was obtained in 53% yield, albeit with
moderate diastereoselectivity (Table 1, entry 1). In contrast, commonly used oxidant
K2S2O8 gave poor results, which possibly was ascribed to the free radical process in
its terminating step (Table 1, entry 2). The utilization of TBPB as oxidant generated
no desired product (Table 1, entry 3). Notably, treatment of 1a with subꢀstoichiometric
Mn(OAc)3•2H2O and 2.0 equivalent of TBPB also produced transꢀ2a in a comparable
yield (Table 1, entry 4), which prompted us to evaluate other transitionꢀmetals. The
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results demonstrated that Fe(II) could execute this reaction, but were inferior to
Mn(III) (Table 1, entry 5). Surprisingly, cisꢀ2a is predominant in the product mixture
when Cu(ClO4)2•6H2O was introduced to the reaction (Table 1, entry 6). After
screening of various oxidants, we were delighted to find that NFSI led to transꢀ2a in
15:1 d.r. and 67% yield (Table 1, entries 7‒11). The introduction of ligands exerted a
negative influence on the results (Table 1, entries 12, 13). In comparison, the
combination of Cu(II) and N,Nꢀbidentate ligand, such as phen and bipy, could
drastically increase the selectivity and cisꢀ2a was observed as the single isomer; the
latter ligand yielded a slightly better result (Table 1, entries 14, 15).
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Table 1. Optimization of the reaction conditions.a
Ph
N3
Ph
N3
Ph
N
N
Transition-metal (30 mol%)
Oxidant (2.0 equiv)
TMSN3, CH3CN, 80 o
C
O
+
N
N
O
N
O
Ts
Ts
Ts
1a
cis-2a
trans-2a
OH
I
O
F
N
F
N
N
N
N
N
2BF4
PhO2S
SO2Ph
N
Cl
Selectfluor
O
BI-OH
NFSI
Bipy
Phen
d.r.b
Entry Transitionꢀmetal
Oxidant
Yieldb [%]
(trans:cis)
1c
2c
3c
4
Mn(OAc)3•2H2O
‒
53 (trans)
25 (trans)
0
5.6:1
‒
K2S2O8
TBPB
TBPB
1.8:1
‒
‒
Mn(OAc)3•2H2O
45 (trans)
8.6:1
5
6
Fe(OAc)2
TBPB
TBPB
30 (trans)
33 (cis)
1:1
Cu(ClO4)2•6H2O
1:3.6
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Mn(OAc)3•2H2O
Mn(OAc)3•2H2O
Mn(OAc)3•2H2O
K2S2O8
TBHP
BIꢀOH
14 (trans)
10 (trans)
38 (trans)
38 (trans)
67 (trans)
2.4:1
6.6:1
5.7:1
7.2:1
15:1
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10
11
Mn(OAc)3•2H2O Selectfluor
Mn(OAc)3•2H2O
NFSI
Mn(OAc)3•2H2O
/ Phen
12
13
14
15
NFSI
NFSI
TBPB
TBPB
39 (trans)
35 (trans)
59 (cis)
4.4:1
4.7:1
Mn(OAc)3•2H2O
/ Bipy
Cu(ClO4)2•6H2O
/Phen
d
‒
Cu(ClO4)2•6H2O
/Bipy
d
64 (cis)
‒
aReaction conditions: 1a (0.10 mmol), Mn(OAc)3•2H2O (30 mol%),
ligand (33 mol% when added), TMSN3 (6.0 equiv), and oxidant (2.0
equiv) in CH3CN (2.0 mL) at 80 oC for 22 h. bDetermined by HPLC
analysis of the crude reaction mixture before isolated. Naphthalene
c
was used as the internal standard. Mn(OAc)3•2H2O or oxidant (3.0
d
equiv) was employed. cisꢀ2a was observed as the single isomer.
TBPB
=
tertꢀButyl peroxybenzoate. TBHP
=
tertꢀButyl
hydroperoxide.
With the optimized conditions in hand, we next explored the scope and
limitations of Mn(III)ꢀ and Cu(II)ꢀmediated radical cyclization/azidation cascade of
enynes 1. As summarized in Table 2, variations of R at the terminal alkyne were first
examined. A wide array of substituted aromatic groups were well tolerated, providing
both transꢀ and cisꢀ2 in moderate to good yields (Table 2, entries 2‒8). The electronic
properties and the positions of the substituents on the phenyl ring had only minimal
influence on the reactivity. For example, electronꢀrich substrates 1b, 1c and 1e
underwent this diastereodivergent reaction smoothly, furnishing the corresponding
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diastereomers with good selectivity, regardless of the steric effects. Electronꢀdeficient
substituents, such as F, Cl and Br, on the phenyl ring were also compatible with the
transformations (Table 2, entries 4, 6‒8). It is worthwhile to mention that treatment of
1g with Cu(II)/bipy/TBPB system only delivered cisꢀisomer in 38% yield and 75%
conversion, which was owing to the poor solubility under the standard conditions.
However, no desired products were observed when submitting butyl substituted enyne
1i to the standard conditions. Substrates possessing different substituents on the
aniline moiety were readily converted into the complete set of diastereomers in high
efficiencies (Table 2, entries 10, 11). Notably, NꢀMs tethered enyne 1l afforded transꢀ
and cisꢀ2l in 64% and 54% yield under the optimized conditions, respectively.
Surprisingly, both Mn(III)ꢀ and Cu(II)ꢀmediated reactions of Nꢀalkyl substrates 1m
and 1n led to the formation of cisꢀproducts. Electronꢀdonating alkyl substituent
presumably changes the inherent properties of the substrates and its less steric
hinderance tends to make the cyclized rings too flexible to facilitate the coordination
of manganese complex and the nitrogen atoms, thus affording the same selectivity.
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Table 2. Substrate scope of diastereodivergent radical cyclization/azidation
cascade of 1,7-enynes.a
Entry
1
Enyne 1
Condition A
Condition B
Entry
8
Enyne 1
Condition A
Condition B
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F
O
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N
Ts
1f
7
14
aCondition A: 1 (0.20 mmol), Mn(OAc)3•2H2O (30 mol%), NFSI (2.0 equiv), TMSN3 (6.0 equiv), CH3CN (4.0 mL), 80
oC for 22 h; d.r. (trans/cis) value was determined by HPLC analysis of the crude reaction mixture before isolated
.
Condition B: 1 (0.20 mmol), Cu(ClO4)2•6H2O (30 mol%), Bipy (33 mol%), TBPB (2.0 equiv), TMSN3 (6.0 equiv),
CH3CN (4.0 mL), 80 oC for 22 h; cisꢀ2 was observed as the single isomer. bMn(OAc)3•2H2O (3.0 equiv) was employed in
c
the reaction. Yield was calculated on the basis of 0.20 mmol of the product and 25% of starting substrate 1g was
recovered. dtransꢀisomer was not observed.
To gain further insights into the diastereodivergent azidation reaction, some
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mechanistic experiments were conducted. Subjecting TEMPO or BHT, wellꢀknown
radical scavengers, to the reaction system led to complete inhibition of this
diastereodivergent process, implying that a free radicalꢀmediated pathway is involved
(Eq. 1). Additionally, when a mixture of LiCl (6.0 equiv), Mn(OAc)3•2H2O (3.0 equiv)
and TMSN3 (1.0 equiv) was introduced to the reaction system, chloroꢀsubstituted
product 3a was observed, explicitly illustrating that Mn(III)ꢀCl complex is formed and
then undergoes chloroꢀligand transfer oxidation process to deliver 3a (Eq. 2). As a
consequence, we believe that LnMꢀN3 species is in situ formed and then involved in
the d.r.ꢀdetermining step, which is in accordance with our initial hypothesis.
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On the basis of these experimental observations, a plausible mechanism is
presented in Scheme 2. Initially, TMSN3 is oxidized by highꢀvalent transitionꢀmetals
to produce a free azidyl radical, which then attacks the alkene moiety of enyne 1,
giving alkyl radical I (pathway a). It is noteworthy that direct azide transfer from
metal azide complex to alkene cannot be ruled out (pathway b). Radicalꢀtriggered
6ꢀexoꢀdig cyclization of I affords vinyl radical II, which can be further trapped by
azidyl group, followed by releasing one molecule of nitrogen to generate aminyl
radical III. The tautomer of III, alkyl radical IV, undergoes innerꢀsphere azide
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transfer oxidation process, rather than free azidyl radical pathway, to deliver the
desired product 2. The oxidation of lowꢀvalent metals Mn(II) and Cu(I) by NFSI and
TBPB regenerates the catalysts.
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Scheme 2. A plausible mechanism.
Although we have no direct rationale on the coordination modes between
transitionꢀmetal complex and the substrate,
a
tentative model for the
diastereodivergence is depicted (Scheme 3). In the case of Mnꢀmediated reaction,
MnꢀN3 possibly also coordinates with the nitrogen atoms of intermediate IV,
following azide transfer to produce transꢀ2. When Cu was introduced to the reaction,
the pronounced steric repulsion between phenyl and azide group enables the azide
attack on the opposite side, thus providing cisꢀ2.
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Scheme 3. A tentative model for transition-metal controlled diastereodivergence.
In summary, we have developed a strategy for achieving diastereodivergent
azidations of enynes, employing azide transfer from MꢀN3 complex to alkyl radicals.
Following this concept, the diastereoselectivity has been switched by modulating the
transitionꢀmetals and the ligands. Mn(III)ꢀmediated radical cyclization/azidation
cascade of 1,7ꢀenynes afforded transꢀfused pyrrolo[3,4ꢀc]quinolinones, whereas
Cu(II)/bipyridine system gave cisꢀproducts. Further studies on the azide transfer
oxidation mechanism are underway in our laboratory.
EXPERIMENTAL SECTION
General Information. Unless otherwise stated, all manipulations and reactions
were performed under inert atmosphere using standard Schlenk techniques or in an
argonꢀfilled gloveꢀbox. All chemicals were purchased from commercial sources and
were used without further purification. Solvents were treated prior to use according to
the standard methods. Column chromatography was carried out on silica gel (200–300
mesh) using a forced flow of eluent at 0.3–0.5 bar pressure. NMR Spectra were
recorded at room temperature in CDCl3 on 400 MHz spectrometers. The chemical
1
shifts for H NMR were recorded in ppm downfield from tetramethylsilane (TMS)
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with CDCl3 (7.26 ppm) as the internal standard. The chemical shifts for 13C NMR
were recorded in ppm downfield using the central peak of CDCl3 (77.16 ppm) as the
internal standard. Coupling constants (J) are reported in hertz and refer to apparent
peak multiplications. The abbreviations s, d, t, q and m stand for singlet, doublet,
triplet, quartet and multiplet in that order. HRMS data were obtained by ESI on a
QꢀTOF mass spectrometer.
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General procedure for the synthesis of enynes 1
Tsꢀprotected 2ꢀ(phenylethynyl)aniline iii was prepared according to the reported
method15. 60% NaH in mineral oil (2 equiv, 20 mmol, 0.80 g) was slowly added to a
solution of iii (10 mmol) in 40 mL THF and the mixture was stirred 30 minutes at
0 °C, then the methacryloyl chloride (2 equiv, 20 mmol, 2.0 mL) was added, and
stirred overnight. The reaction was quenched with saturated NH4Cl, and the solution
was extracted with ethyl acetate three times. The combined organic phases were dried
with anhydrous Na2SO4, the solvent was concentrated via rotary evaporation. The
crude residue was recrystallized with EtOH to afford 1 as a white or yellow solid.
N-(2-(phenylethynyl)phenyl)-N-tosylmethacrylamide (1a): white solid; 6.0 g (in
16.0 mmol scale); 86% yield; mp 127−128 °C; 1H NMR (400 MHz, CDCl3) δ 7.92 (d,
J = 8.3 Hz, 2H), 7.66 – 7.59 (m, 1H), 7.50 – 7.44 (m, 1H), 7.44 – 7.41 (m, 1H), 7.41 –
7.36 (m, 1H), 7.27 (d, J = 7.5 Hz, 1H), 7.21 (t, J = 7.4 Hz, 2H), 7.05 (d, J = 8.3 Hz,
4H), 5.23 (s, 2H), 2.08 (s, 3H), 1.77 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ
170.6, 144.8, 139.2, 138.9, 136.3, 132.8, 132.7, 131.5, 130.0, 129.2, 129.01, 128.97,
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128.8, 128.1, 123.8, 123.5, 122.09, 94.9, 85.6, 21.5, 19.3. HRMS (ESI) calcd for
C25H22NO3S [M+H]+ 416.1315, found 416.1317.
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N-(2-(o-tolylethynyl)phenyl)-N-tosylmethacrylamide (1b): white solid; 833.0 mg
(in 3.2 mmol scale); 53% yield; mp 125−126 °C; 1H NMR (400 MHz, CDCl3) δ 7.92
(d, J = 8.3 Hz, 2H), 7.57 (dd, J = 7.7, 1.3 Hz, 1H), 7.51 (dd, J = 7.2, 2.0 Hz, 1H), 7.46
– 7.35 (m, 2H), 7.22 – 7.15 (m, 1H), 7.12 (d, J = 7.4 Hz, 1H), 7.07 – 7.00 (m, 3H),
6.91 (d, J = 7.6 Hz, 1H), 5.26 (s, 1H), 5.22 (s, 1H), 2.30 (s, 3H), 2.10 (s, 3H), 1.77 (s,
3H). 13C {1H} NMR (100 MHz, CDCl3) δ 170.5, 144.8, 139.9, 139.2, 138.5, 136.3,
133.0, 132.5, 132.3, 130.0, 129.3, 129.2, 129.0, 128.89, 128.87, 125.5, 124.0, 123.5,
121.9, 94.0, 89.4, 21.5, 20.6, 19.4. HRMS (ESI) calcd for C26H24NO3S [M+H]+
430.1471, found 430.1478.
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N-(2-((2-methoxyphenyl)ethynyl)phenyl)-N-tosylmethacrylamide
(1c):
light
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yellow solid; 1.25 g (in 4.1 mmol scale); 69% yield; mp 114−115 °C; H NMR (400
MHz, CDCl3) δ 7.96 (d, J = 8.2 Hz, 2H), 7.62 – 7.51 (m, 2H), 7.45 – 7.34 (m, 2H),
7.28 – 7.20 (m, 1H), 7.04 (d, J = 8.2 Hz, 2H), 6.86 (dd, J = 7.6, 1.2 Hz, 1H), 6.78 (t, J
= 7.9 Hz, 2H), 5.25 (s, 1H), 5.18 (s, 1H), 3.77 (s, 3H), 2.09 (s, 3H), 1.77 (s, 3H). 13C
{1H} NMR (100 MHz, CDCl3) δ 170.5, 159.9 144.6, 139.2, 138.5, 136.4, 133.7,
133.1, 132.5, 130.3, 130.1, 129.2, 128.9, 128.7, 124.0, 123.1, 120.2, 111.3, 110.2,
91.8, 89.6, 55.5, 21.5, 19.4. HRMS (ESI) calcd for C26H24NO4S [M+H]+ 446.1421,
found 446.1424.
N-(2-((3-fluorophenyl)ethynyl)phenyl)-N-tosylmethacrylamide (1d): white solid;
700 mg (in 1.9 mmol scale); 79% yield; mp 112−113 °C; 1H NMR (400 MHz, CDCl3)
δ 7.92 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.51 – 7.36 (m, 3H), 7.19 (dd, J =
14.0, 7.7 Hz, 1H), 7.10 (d, J = 8.1 Hz, 2H), 7.03 – 6.95 (m, 1H), 6.88 (d, J = 7.6 Hz,
1H), 6.68 (d, J = 9.2 Hz, 1H), 5.25 (s, 1H), 5.23 (s, 1H), 2.14 (s, 3H), 1.76 (s, 3H). 13C
{1H} NMR (100 MHz, CDCl3) δ 170.6, 162.1 (d, J = 246.7 Hz), 144.9, 139.1, 139.1,
136.4, 132.9, 132.7, 130.1, 129.7 (d, J = 8.6 Hz), 129.3 (d, J = 7.9 Hz), 129.0, 127.4
(d, J = 3.0 Hz), 124.0, 123.8, 123.7, 123.0, 118.2 (d, J = 23.0 Hz), 116.2 (d, J = 21.2
Hz), 93.5, 86.4, 21.4, 19.2. 19F NMR (376 MHz, CDCl3) δ ꢀ112.80. HRMS (ESI)
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calcd for C25H21FNO3S [M+H]+ 434.1221, found 434.1229.
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N-(2-(p-tolylethynyl)phenyl)-N-tosylmethacrylamide (1e): white solid; 1.2 g (in
3.6 mmol scale); 78% yield; mp 182−183 °C; 1H NMR (400 MHz, CDCl3) δ 7.92 (d,
J = 8.3 Hz, 2H), 7.61 (d, J = 7.6 Hz, 1H), 7.50 – 7.34 (m, 3H), 7.06 (d, J = 8.2 Hz,
2H), 7.02 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.1 Hz, 2H), 5.23 (s, 1H), 5.21 (s, 1H), 2.34
(s, 3H), 2.10 (s, 3H), 1.76 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 170.6, 144.7,
139.2, 139.1, 138.9, 136.4, 132.73, 132.66, 131.5, 130.1, 129.2, 129.0, 128.9, 128.8,
123.8, 123.7, 119.0, 95.3, 85.1, 21.7, 21.5, 19.3. HRMS (ESI) calcd for C26H24NO3S
[M+H]+ 430.1471, found 430.1472.
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N-(2-((4-fluorophenyl)ethynyl)phenyl)-N-tosylmethacrylamide (1f): light yellow
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solid; 1.3 g (in 3.7 mmol scale); 84% yield; mp 184−185 °C; H NMR (400 MHz,
CDCl3) δ 7.91 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.49 – 7.36 (m, 3H), 7.11
– 7.02 (m, 4H), 6.92 (t, J = 8.7 Hz, 2H), 5.25 (s, 1H), 5.23 (s, 1H), 2.13 (s, 3H), 1.76
(s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 170.7, 162.9 (d, J = 250.8 Hz), 144.7,
139.1, 139.0, 136.5, 133.6 (d, J = 8.5 Hz), 132.7, 130.1, 129.3, 129.1, 129.0, 124.0,
123.4, 118.2(d, J = 3.4 Hz), 115.5 (d, J = 22.1 Hz), 93.9, 85.4, 21.5, 19.3. 19F NMR
(376 MHz, CDCl3) δ ꢀ109.80. HRMS (ESI) calcd for C25H21FNO3S [M+H]+ 434.1221,
found 434.1223.
N-(2-((4-chlorophenyl)ethynyl)phenyl)-N-tosylmethacrylamide (1g): white solid;
1.5 g (in 3.4 mmol scale); 98% yield; mp 200−201 °C; 1H NMR (400 MHz, CDCl3) δ
7.91 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 7.8 Hz, 1H), 7.50 – 7.36 (m, 3H), 7.20 (d, J =
8.2 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 8.2 Hz, 2H), 5.24 (s, 1H), 5.23 (s,
1H), 2.13 (s, 3H), 1.75 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 170.7, 144.8,
139.1, 136.4, 135.0, 132.7, 132.7, 130.1, 129.3, 129.3, 129.0, 128.5, 124.0, 123.2,
120.5, 93.7, 86.6, 21.5, 19.2. HRMS (ESI) calcd for C25H21ClNO3S [M+H]+ 450.0925,
found 450.0925.
N-(2-((4-bromophenyl)ethynyl)phenyl)-N-tosylmethacrylamide (1h): white solid;
400 mg (in 1.2 mmol scale); 71% yield; mp 206−207 °C; 1H NMR (400 MHz, CDCl3)
δ 7.93 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 7.9 Hz, 1H), 7.51 – 7.44 (m, 2H), 7.42 (d, J =
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8.1 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.3 Hz, 2H), 6.94 (d, J = 8.4 Hz,
2H), 5.27 (s, 1H), 5.24 (s, 1H), 2.15 (s, 3H), 1.77 (s, 3H). 13C {1H} NMR (100 MHz,
CDCl3) δ 170.7, 144.8, 139.1 136.4, 132.9, 132.7, 131.4, 130.1, 129.3, 129.3, 129.0,
124.1, 123.3, 123.2, 121.0, 93.8, 86.8, 21.5, 19.3. HRMS (ESI) calcd for
C25H21BrNO3S [M+H]+ 494.0420, found 494.0422.
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N-(2-(hex-1-ynyl)phenyl)-N-tosylmethacrylamide (1i): white solid; 476 mg (in 1.7
1
mmol scale); 71% yield; mp 142−143 °C; H NMR (400 MHz, CDCl3) δ 7.92 (d, J =
8.1 Hz, 2H), 7.49 (d, J = 7.6 Hz, 1H), 7.45 – 7.21 (m, 5H), 5.22 (s, 1H), 5.21 (s, 1H),
2.50 (s, 3H), 2.54 – 1.84 (m, 2H), 1.77 (s, 3H), 1.50 – 1.06 (m, 4H), 0.86 (t, J = 6.3
Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 170.5, 144.5, 139.2, 138.8, 136.6,
133.1, 132.2, 130.1, 129.1, 129.0, 128.2, 124.5, 123.4, 96.9, 76.6, 30.2, 22.3, 21.8,
19.3, 19.1, 13.7. HRMS (ESI) calcd for C23H26NO3S [M+H]+ 396.1628, found
396.1631.
N-(4-methyl-2-(phenylethynyl)phenyl)-N-tosylmethacrylamide (1j): white solid;
415 mg (in 2.3 mmol scale); 42% yield; mp 166−167 °C; 1H NMR (400 MHz, CDCl3)
δ 7.93 (d, J = 8.3 Hz, 2H), 7.44 (s, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 7.0 Hz,
1H), 7.20 (t, J = 7.3 Hz, 3H), 7.08 – 7.00 (m, 4H), 5.23 (s, 2H), 2.44 (s, 3H), 2.08 (s,
3H), 1.77 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 170.7, 144.8, 139.6, 139.2,
138.7, 136.4, 133.2, 132.5, 131.4, 130.2, 130.1, 129.0, 128.6, 128.1, 123.7, 122.2,
120.5, 94.2, 85.8, 21.6, 21.5, 19.3. HRMS (ESI) calcd for C26H24NO3S [M+H]+
430.1471, found 430.1473.
N-(4-chloro-2-(phenylethynyl)phenyl)-N-tosylmethacrylamide (1k): white solid;
520 mg (in 2.0 mmol scale); 58% yield; mp 176−177 °C; 1H NMR (400 MHz, CDCl3)
δ 7.91 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 1.8 Hz, 1H), 7.43 – 7.34 (m, 2H), 7.32 – 7.19
(m, 3H), 7.05 (t, J = 7.9 Hz, 4H), 5.30 (s, 1H), 5.25 (s, 1H), 2.09 (s, 3H), 1.79 (s, 3H).
13C {1H} NMR (100 MHz, CDCl3) δ 170.3, 145.1, 139.9, 139.0, 136.1, 134.5, 133.4,
132.7, 131.6, 130.0, 129.7, 129.12, 129.07, 128.2, 124.3, 122.1, 121.7, 95.8, 84.7,
21.5, 19.3. HRMS (ESI) calcd for C25H21ClNO3S [M+H]+ 450.0925, found 450.0929.
N-(methylsulfonyl)-N-(2-(phenylethynyl)phenyl)methacrylamide (1l): light yellow
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solid; 710 mg (in 2.3 mmol scale); 90% yield; mp 127−128 °C; H NMR (400 MHz,
CDCl3) δ 7.58 – 7.50 (m, 4H), 7.46 – 7.36 (m, 5H), 5.35 (s, 1H), 5.33 (s, 1H), 3.52 (s,
3H), 1.89 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.0, 138.9, 138.2, 133.0,
132.5, 131.5, 129.5, 129.4, 129.4, 128.9, 124.6 123.1, 122.0, 95.6, 85.7, 42.4, 19.3.
HRMS (ESI) calcd for C19H18NO3S [M+H]+ 340.1002, found 340.1002.
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N-methyl-N-(2-(phenylethynyl)phenyl)methacrylamide (1m): known compound10a;
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white solid; 200 mg (in 3.4 mmol scale); 21% yield; mp 85−86 °C; H NMR (400
MHz, CDCl3) δ 7.59 – 7.48 (m, 3H), 7.39 – 7.27 (m, 5H), 7.18 (d, J = 7.6 Hz, 1H),
5.03 (s, 1H), 5.00 (s, 1H), 3.38 (s, 3H), 1.84 (s, 3H). 13C {1H} NMR (100 MHz,
CDCl3) δ 172.4, 146.5, 140.5, 133.0, 131.8, 129.4, 128.9, 128.6, 128.3, 127.6, 122.7,
122.4, 119.1, 94.9, 85.8, 37.0, 20.3. HRMS (ESI) calcd for C19H18NO [M+H]+
276.1383, found 276.1387.
N-benzyl-N-(2-(phenylethynyl)phenyl)methacrylamide (1n): white solid; 261 mg
(in 1.2 mmol scale); 62% yield; mp 178−179 °C; 1H NMR (400 MHz, CDCl3) δ 7.55
– 7.44 (m, 3H), 7.34 – 7.23 (m, 5H), 7.22 – 7.09 (m, 5H), 6.86 (d, J = 7.4 Hz, 1H),
5.51 (d, J = 14.3 Hz, 1H), 5.02 (s, 1H), 4.98 (s, 1H), 4.60 (d, J = 14.3 Hz, 1H), 1.86 (s,
3H). 13C {1H} NMR (100 MHz, CDCl3) δ 171.8, 144.3, 140.3, 137.0, 132.7, 131.5,
129.1, 129.0, 128.7, 128.6, 128.3, 128.1, 127.3, 127.2, 122.6, 122.4, 119.0, 94.7, 86.1,
52.3, 20.1. HRMS (ESI) calcd for C25H22NO [M+H]+ 352.1696, found 352.1702.
Representative procedure for the synthesis of trans-product
To a sealed tube were added enynes 1 (0.2 mmol), Mn(OAc)3•2H2O (30 mol%),
NFSI (2 equiv.), and MeCN (4 mL) in sequence. Subsequently TMSN3 (6 equiv.) was
introduced. The resulting dark solution was stirred at 80 oC for 22 h. Upon completion,
remove the solvent and purification by flash chromatography on silica gel (petroleum
ether/EtOAc: 5/1) afforded the desired products transꢀ2.
trans-9b-azido-3a-methyl-1-phenyl-5-tosyl-5,9b-dihydro-3H-pyrrolo[3,4-c]quinol
1
in-4(3aH)-one (trans-2a): white solid; 55.3 mg; 59% yield; mp 178−179 °C; H
NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.2 Hz, 1H), 7.76 (d,
J = 7.0 Hz, 2H), 7. 59 – 7.44 (m, 4H), 7.35 (d, J = 8.3 Hz, 2H), 7.19 – 7.10 (m, 2H),
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4.05 (d, J = 16.4 Hz, 1H), 3.89 (d, J = 16.4 Hz, 1H), 2.45 (s, 3H), 0.80 (s, 3H). 13C
{1H} NMR (100 MHz, CDCl3) δ 170.3, 168.7, 145.6, 137.5, 135.3, 133.7, 131.4,
129.9, 129.7, 129.2, 129.1, 128.0, 126.32, 126.29, 126.26, 126.0, 79.7, 63.4, 57.5,
21.9, 20.9. HRMS (ESI) calcd for C25H22N5O3S [M+H]+ 472.1438, found 472.1439.
trans-9b-azido-3a-methyl-1-o-tolyl-5-tosyl-5,9b-dihydro-3H-pyrrolo[3,4-c]quinoli
n-4(3aH)-one (trans-2b): white solid; 57.5 mg; 59% yield; mp 156−157 °C; 1H NMR
(400 MHz, CDCl3) δ 7.95 (dd, J = 10.5, 8.7 Hz, 3H), 7.47 – 7.30 (m, 7H), 7.08 (t, J =
7.6 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 4.07 (d, J = 16.0 Hz, 1H), 3.96 (d, J = 15.9 Hz,
1H), 2.45 (s, 3H), 2.37 (s, 3H), 0.94 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ
170.3, 169.7, 145.6, 137.3, 136.8, 135.4, 133.8, 131.7, 130.1, 129.8, 129.6, 129.2,
127.3, 126.4, 125.8, 125.4, 125.1, 79.7, 63.6, 56.5, 21.9, 20.8, 20.4. HRMS (ESI)
calcd for C26H24N5O3S [M+H]+ 486.1594, found 486.1594.
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trans-9b-azido-1-(2-methoxyphenyl)-3a-methyl-5-tosyl-5,9b-dihydro-3H-pyrrolo[
3,4-c]quinolin-4(3aH)-one (trans-2c): white solid; 48.4 mg; 49% yield; mp
158−159 °C; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.2
Hz, 1H), 7.57 – 7.50 (m, 1H), 7.47 – 7.40 (m, 1H), 7.35 (d, J = 8.2 Hz, 2H), 7.14 –
7.02 (m, 3H), 6.98 (d, J = 7.6 Hz, 1H), 4.10 (d, J = 15.4 Hz, 1H), 3.86 – 3.80 (m, 4H),
2.46 (s, 3H), 0.82 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 170.6, 169.7, 157.2,
145.5, 136.9, 135.8, 132.5, 129.7, 129.5, 129.3, 126.2, 125.6, 125.3, 124.8, 121.6,
111.4, 78.4, 65.7, 63.0, 56.2, 21.9, 19.9. HRMS (ESI) calcd for C26H24N5O4S [M+H]+
502.1544, found 502.1549.
trans-9b-azido-1-(3-fluorophenyl)-3a-methyl-5-tosyl-5,9b-dihydro-3H-pyrrolo[3,
4-c]quinolin-4(3aH)-one (trans-2d): white solid; 63.1 mg; 65% yield; mp
173−174 °C; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.2
Hz, 1H), 7.58 – 7.46 (m, 1H), 7.35 (d, J = 8.3 Hz, 2H), 7.31 – 7.26 (m, 1H), 7.19 –
7.11 (m, 2H), 4.05 (d, J = 16.5 Hz, 1H), 3.91 (d, J = 16.5 Hz, 1H), 2.45 (s, 3H), 0.79
(s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 170.1, 167.6, 163.0 (d, J = 248.6 Hz),
145.7, 137.5, 135.8 (d, J = 7.3 Hz), 135.3, 130.8 (d, J = 8.1 Hz), 129.94, 129.85,
129.2, 126.4, 126.1, 125.8, 123.7 (d, J = 3.2 Hz), 118.5 (d, J = 21.2 Hz), 115.2 (d, J =
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23.1 Hz), 79.8, 63.5, 57.5, 21.9, 21.0. 19F NMR (376 MHz, CDCl3) δ ꢀ110.76. HRMS
(ESI) calcd for C25H21FN5O3S [M+H]+ 490.1344, found 490.1342.
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n-4(3aH)-one (trans-2e): white solid; 56.0 mg; 60% yield; mp 181−182 °C; 1H NMR
(400 MHz, CDCl3) δ 8.01 (d, J = 8.3 Hz, 2H), 7.92 (d, J = 8.2 Hz, 1H), 7.67 (d, J =
8.0 Hz, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.33 (t, J = 8.4 Hz, 4H), 7.22 (d, J = 7.5 Hz, 1H),
7.13 (t, J = 7.5 Hz, 1H), 4.02 (d, J = 16.3 Hz, 1H), 3.87 (d, J = 16.3 Hz, 1H), 2.45 (s,
3H), 2.44 (s, 3H), 0.78 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 170.4, 168.3,
145.5, 141.8, 137.5, 135.2, 130.7, 129.9, 129.7, 129.6, 129.1, 127.9, 126.5, 126.20,
126.17, 126.1, 79.7, 63.2, 57.4, 21.8, 21.6, 20.9. HRMS (ESI) calcd for C26H24N5O3S
[M+H]+ 486.1594, found 486.1596.
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trans-9b-azido-1-(4-fluorophenyl)-3a-methyl-5-tosyl-5,9b-dihydro-3H-pyrrolo[3,
4-c]quinolin-4(3aH)-one (trans-2f): white solid; 64.5 mg; 66% yield; mp
190−191 °C; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.3 Hz, 2H), 7.94 (d, J = 8.3
Hz, 1H), 7.79 (dd, J = 8.6, 5.3 Hz, 2H), 7.52 – 7.45 (m, 1H), 7.35 (d, J = 8.2 Hz, 2H),
7.22 (t, J = 8.5 Hz, 2H), 7.15 (d, J = 3.9 Hz, 2H), 4.04 (d, J = 16.5 Hz, 1H), 3.88 (d, J
= 16.4 Hz, 1H), 2.45 (s, 3H), 0.78 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 170.2,
167.4, 164.6 (d, J = 252.9 Hz), 145.7, 137.5, 135.2, 130.2 (d, J = 8.6 Hz), 123.0,
129.8, 129.2, 126.4 (d, J = 8.1 Hz), 126.3, 125.8, 116.4 (d, J = 22.0 Hz), 79.8, 63.4,
57.6, 21.9, 21.0. 19F NMR (376 MHz, CDCl3) δ ꢀ107.78. HRMS (ESI) calcd for
C25H21FN5O3S [M+H]+ 490.1344, found 490.1346.
trans-9b-azido-1-(4-chlorophenyl)-3a-methyl-5-tosyl-5,9b-dihydro-3H-pyrrolo[3,
4-c]quinolin-4(3aH)-one (trans-2g): white solid; 65.0 mg; 64% yield; mp
184−185 °C; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.3
Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.53 – 7.46 (m, 3H), 7.35 (d, J = 8.2 Hz, 2H), 7.18
– 7.12 (m, 2H), 4.04 (d, J = 16.5 Hz, 1H), 3.89 (d, J = 16.5 Hz, 1H), 2.44 (s, 3H), 0.78
(s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 170.2, 167.6, 145.7, 137.7, 137.5, 135.2,
132.1, 129.94, 129.85, 129.5, 129.4, 129.2, 126.41, 126.35, 126.2, 125.8, 79.8, 63.5,
57.5, 21.9, 21.0. HRMS (ESI) calcd for C25H21ClN5O3S [M+H]+ 506.1048, found
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506.1049.
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trans-9b-azido-1-(4-bromophenyl)-3a-methyl-5-tosyl-5,9b-dihydro-3H-pyrrolo[3,
4-c]quinolin-4(3aH)-one (trans-2h): white solid; 56.1 mg; 57% yield; mp
172−173 °C; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.3 Hz, 2H), 7.94 (d, J = 8.2
Hz, 1H), 7.70 – 7.63 (m, 4H), 7.52 – 7.46 (m, 1H), 7.35 (d, J = 8.2 Hz, 2H), 7.20 –
7.12 (m, 2H), 4.03 (d, J = 16.6 Hz, 1H), 3.89 (d, J = 16.5 Hz, 1H), 2.45 (s, 3H), 0.78
(s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 170.1, 167.7, 145.7, 137.5, 135.2, 132.5,
132.4, 130.0, 129.9, 129.5, 129.2, 126.42, 126.36, 126.2, 126.1, 125.8, 79.8, 63.6,
57.5, 21.9, 21.0. HRMS (ESI) calcd for C25H21BrN5O3S [M+H]+ 550.0543, found
550.0546.
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trans-9b-azido-3a,8-dimethyl-1-phenyl-5-tosyl-5,9b-dihydro-3H-pyrrolo[3,4-c]qui
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nolin-4(3aH)-one (trans-2j): white solid; 62.6 mg; 65% yield; mp 145−146 °C; H
NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 6.7 Hz, 3H), 7.58 –
7.49 (m, 3H), 7.35 (d, J = 8.2 Hz, 2H), 7.04 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 7.3 Hz,
1H), 4.02 (d, J = 16.3 Hz, 1H), 3.87 (d, J = 16.3 Hz, 1H), 2.44 (d, J = 8.1 Hz, 6H),
0.79 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 170.5, 168.9, 145.6, 140.1, 137.4,
135.4, 133.7, 131.3, 129.9, 129.14, 129.07, 128.0, 127.0, 126.8, 125.9, 123.2, 79.7,
63.4, 57.4, 21.9, 21.8, 20.9. HRMS (ESI) calcd for C26H24N5O3S [M+H]+ 486.1594,
found 486.1597.
trans-9b-azido-8-chloro-3a-methyl-1-phenyl-5-tosyl-5,9b-dihydro-3H-pyrrolo[3,4
-c]quinolin-4(3aH)-one (trans-2k): white solid; 72.7 mg; 72% yield; mp 153−154 °C;
1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 1.4 Hz, 1H), 7.77
– 7.71 (m, 2H), 7.61 – 7.49 (m, 3H), 7.36 (d, J = 8.2 Hz, 2H), 7.16 – 7.04 (m, 2H),
4.04 (d, J = 16.5 Hz, 1H), 3.90 (d, J = 16.4 Hz, 1H), 2.45 (s, 3H), 0.82 (s, 3H). 13C
{1H} NMR (100 MHz, CDCl3) δ 167.0, 168.2, 145.9, 138.5, 135.5, 134.9, 133.4,
131.5, 130.0, 129.2, 127.9, 126.7, 126.5, 126.2, 124.9, 79.3, 63.4, 57.4 21.9, 21.0.
HRMS (ESI) calcd for C25H21ClN5O3S [M+H]+ 506.1048, found 506.1058.
trans-9b-azido-3a-methyl-5-(methylsulfonyl)-1-phenyl-5,9b-dihydro-3H-pyrrolo[
3,4-c]quinolin-4(3aH)-one (trans-2l): white solid; 50.6 mg; 64% yield; mp
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177−178 °C; 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 6.9 Hz, 2H), 7.71 (d, J = 8.2
Hz, 1H), 7.63 – 7.52 (m, 3H), 7.47 – 7.41 (m, 1H), 7.22 (dd, J = 7.7, 1.3 Hz, 1H),
7.13 (t, J = 7.5 Hz, 1H), 4.33 (d, J = 16.3 Hz, 1H), 4.06 (d, J = 16.3 Hz, 1H), 3.59 (s,
3H), 0.86 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 171.9, 168.7, 136.8, 133.7,
131.5, 129.8, 129.2, 127.9, 126.5, 126.3, 126.0, 125.8, 79.7, 63.5, 57.6, 42.8, 20.7.
HRMS (ESI) calcd for C19H18N5O3S [M+H]+ 396.1125, found 396.1124
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Representative procedure for the synthesis of cis-product
To a sealed tube were added enynes 1 (0.2 mmol), Cu(ClO4)2•6H2O (30 mol%),
bipyridine (33 mol%), and MeCN (4 mL) in sequence. Subsequently TBPB (2 equiv.)
and TMSN3 (6 equiv.) were introduced to the mixture. The resulting dark solution
o
was stirred at 80 C for 22 h. Upon completion, the reaction was quenched by
saturated NaHCO3 and extracted with ethyl acetate three times. The combined organic
layers were dried with anhydrous Na2SO4. Then remove the solvent and purification
by flash chromatography on silica gel (petroleum ether/EtOAc: 10/1) afforded the
desired products cisꢀ2.
cis-9b-azido-3a-methyl-1-phenyl-5-tosyl-5,9b-dihydro-3H-pyrrolo[3,4-c]quinolin-
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4(3aH)-one (cis-2a): known compound13; yellow oil; 55.3 mg; 59% yield; H NMR
(400 MHz, CDCl3) δ 7.81 (d, J = 7.2 Hz, 1H), 7.73 – 7.66 (m, 3H), 7.61 (d, J = 7.5 Hz,
2H), 7.50 – 7.41 (m, 2H), 7.40 – 7.32 (m, 3H), 7.21 (d, J = 8.1 Hz, 2H), 4.32 (d, J =
16.5 Hz, 1H), 3.79 (d, J = 16.5 Hz, 1H), 2.42 (s, 3H), 1.22 (s, 3H). 13C {1H} NMR
(100 MHz, CDCl3) δ 172.8, 170.3, 145.7, 134.9, 133.0, 132.5, 131.4, 129.8, 129.40,
129.36, 128.8, 128.5, 128.2, 126.6, 124.1, 122.7, 78.6, 69.3, 61.1, 21.9, 14.2.
cis-9b-azido-3a-methyl-1-o-tolyl-5-tosyl-5,9b-dihydro-3H-pyrrolo[3,4-c]quinolin-
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4(3aH)-one (cis-2b): white solid; 52.8 mg; 54% yield; mp 154−155 °C; H NMR
(400 MHz, CDCl3) δ 7.94 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.2 Hz, 1H), 7.46 – 7.38 (m,
2H), 7.30 (d, J = 8.2 Hz, 2H), 7.27 – 7.25 (m, 2H), 7.24 – 7.19 (m, 2H), 7.12 – 7.06
(m, 1H), 4.43 (d, J = 16.4 Hz, 1H), 3.98 (d, J = 16.4 Hz, 1H), 2.43 (s, 3H), 2.40 (s,
3H), 1.32 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.9, 171.0, 145.7, 138.6,
135.8, 133.4, 131.8, 131.7, 130.0, 129.7, 129.1, 128.32, 128.28, 126.4, 125.4, 122.9,
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121.8, 79.4, 70.1, 59.6, 21.9, 20.8, 15.8. HRMS (ESI) calcd for C26H24N5O3S [M+H]+
486.1594, found 486.1596.
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cis-9b-azido-1-(2-methoxyphenyl)-3a-methyl-5-tosyl-5,9b-dihydro-3H-pyrrolo[3,
4-c]quinolin-4(3aH)-one (cis-2c): white solid; 43.5 mg; 44% yield; mp 140−141 °C;
1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.1 Hz, 1H), 7.44
– 7.35 (m, 3H), 7.31 – 7.26 (m, 3H), 7.22 – 7.16 (m, 1H), 6.95 (t, J = 7.5 Hz, 1H),
6.78 (d, J = 8.3 Hz, 1H), 4.37 (d, J = 16.8 Hz, 1H), 3.84 (d, J = 16.8 Hz, 1H), 3.48 (s,
3H), 2.40 (s, 3H), 1.31 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 173.0, 171.7,
157.3, 145.5, 135.8, 133.2, 132.0, 130.8, 129.6, 129.03, 128.98, 128.0, 125.7, 123.5,
122.0, 121.4, 120.7, 110.9, 80.0, 71.4, 59.9, 54.9, 21.8, 15.6. HRMS (ESI) calcd for
C26H24N5O4S [M+H]+ 502.1544, found 502.1545.
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cis-9b-azido-1-(3-fluorophenyl)-3a-methyl-5-tosyl-5,9b-dihydro-3H-pyrrolo[3,4-c
]quinolin-4(3aH)-one (cis-2d): white solid; 76.5 mg; 78% yield; mp 161−162 °C; 1H
NMR (400 MHz, CDCl3) δ 7.81 (dd, J = 7.8, 1.4 Hz, 1H), 7.70 (d, J = 8.3 Hz, 3H),
7.53 – 7.45 (m, 1H), 7.42 – 7.34 (m, 3H), 7.35 – 7.27 (m, 1H), 7.23 (d, J = 8.2 Hz,
2H), 7.18 – 7.11 (m, 1H), 4.35 (d, J = 16.7 Hz, 1H), 3.80 (d, J = 16.7 Hz, 1H), 2.44 (s,
3H), 1.22 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.7, 169.3, 162.7 (d, J =
247.3 Hz), 145.9, 134.9, 134.4 (d, J = 7.6 Hz), 133.0, 130.5 (d, J = 8.1 Hz), 130.0,
129.4, 128.4, 126.8, 123.9 (d, J = 3.0 Hz), 123.7, 122.9, 118.6 (d, J = 21.2 Hz), 115.3
(d, J = 23.4 Hz), 78.5, 69.3, 61.3, 21.9, 14.2. 19F NMR (376 MHz, CDCl3) δ ꢀ111.32.
HRMS (ESI) calcd for C25H21FN5O3S [M+H]+ 490.1344, found 490.1346.
cis-9b-azido-3a-methyl-1-p-tolyl-5-tosyl-5,9b-dihydro-3H-pyrrolo[3,4-c]quinolin-
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4(3aH)-one (cis-2e): white solid; 53.2 mg; 55% yield; mp 145−146 °C; H NMR
(400 MHz, CDCl3) δ 7.82 (d, J = 7.7 Hz, 1H), 7.69 (t, J = 8.3 Hz, 3H), 7.52 (d, J = 7.9
Hz, 2H), 7.47 (t, J = 7.8 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 8.2 Hz, 2H),
7.15 (d, J = 8.1 Hz, 2H), 4.29 (d, J = 16.4 Hz, 1H), 3.76 (d, J = 16.4 Hz, 1H), 2.43 (s,
3H), 2.36 (s, 3H), 1.20 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.9, 170.2,
145.7, 141.9, 134.9, 133.0, 129.7, 129.70, 129.56, 129.5, 129.4, 128.6, 128.2, 126.6,
124.3, 122.8, 78.6, 69.1, 61.1, 21.9, 21.6, 14.2. HRMS (ESI) calcd for C26H24N5O3S
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[M+H]+ 486.1594, found 486.1603.
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]quinolin-4(3aH)-one (cis-2f): white solid; 61.6 mg; 63% yield; mp 201−202 °C; H
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NMR (400 MHz, CDCl3) δ 7.79 (dd, J = 7.8, 1.2 Hz, 1H), 7.70 (t, J = 8.6 Hz, 3H),
7.63 (dd, J = 8.8, 5.4 Hz, 2H), 7.52 – 7.45 (m, 1H), 7.39 (dd, J = 11.1, 4.1 Hz, 1H),
7.22 (d, J = 8.2 Hz, 2H), 7.03 (t, J = 8.6 Hz, 2H), 4.33 (d, J = 16.5 Hz, 1H), 3.79 (d, J
= 16.5 Hz, 1H), 2.43 (s, 3H), 1.22 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.8,
169.2, 164.6 (d, J = 253.1 Hz), 145.8, 135.0, 133.0, 130.5 (d, J = 8.7 Hz), 129.9,
129.4 (d, J = 3.8 Hz), 128.4, 126.7, 124.0, 122.8, 116.0 (d, J = 21.8 Hz), 78.6, 69.3,
61.4, 21.9, 14.2. HRMS (ESI) calcd for C25H21FN5O3S [M+H]+ 490.1344, found
490.1349.
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cis-9b-azido-1-(4-chlorophenyl)-3a-methyl-5-tosyl-5,9b-dihydro-3H-pyrrolo[3,4-c
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]quinolin-4(3aH)-one (cis-2g): white solid; 37.9 mg; 38% yield; mp 179−180 °C; H
NMR (400 MHz, CDCl3) δ 7.79 (dd, J = 7.8, 1.0 Hz, 1H), 7.74 – 7.67 (m, 3H), 7.56
(d, J = 8.6 Hz, 2H), 7.51 – 7.45 (m, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.6 Hz,
2H), 7.23 (d, J = 8.2 Hz, 2H), 4.34 (d, J = 16.6 Hz, 1H), 3.80 (d, J = 16.6 Hz, 1H),
2.43 (s, 3H), 1.22 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.8, 169.4, 145.8,
137.8, 135.0, 133.0, 130.9, 130.0, 129.6, 129.42, 129.37, 129.2, 128.3, 126.7, 123.9,
122.8, 78.5, 69.5, 61.3, 21.9, 14.2. HRMS (ESI) calcd for C25H21ClN5O3S [M+H]+
506.1048, found 506.1052.
cis-9b-azido-1-(4-bromophenyl)-3a-methyl-5-tosyl-5,9b-dihydro-3H-pyrrolo[3,4-
c]quinolin-4(3aH)-one (cis-2h): white solid; 50.8 mg; 46% yield; mp 183−184 °C;
1H NMR (400 MHz, CDCl3) δ 7.78 (dd, J = 7.8, 1.1 Hz, 1H), 7.70 (t, J = 9.1 Hz, 3H),
7.52 – 7.45 (m, 5H), 7.38 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 8.2 Hz, 2H), 4.33 (d, J =
16.6 Hz, 1H), 3.79 (d, J = 16.6 Hz, 1H), 2.44 (s, 3H), 1.22 (s, 3H). 13C {1H} NMR
(100 MHz, CDCl3) δ 172.8, 169.5, 145.9, 135.0, 133.0, 132.1, 131.3, 130.0, 129.7,
129.43, 129.38, 128.4, 126.8, 126.3, 123.8, 122.8, 78.5, 69.5, 61.3, 21.9, 14.2. HRMS
(ESI) calcd for C25H21BrN5O3S [M+H]+ 550.0543, found 550.0547.
cis-9b-azido-3a,8-dimethyl-1-phenyl-5-tosyl-5,9b-dihydro-3H-pyrrolo[3,4-c]quin
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olin-4(3aH)-one (cis-2j): white solid; 64.8 mg; 67% yield; mp 208−209 °C; 1H NMR
(400 MHz, CDCl3) δ 7.70 – 7.64 (m, 4H), 7.63 (s, 1H), 7.52 (s, 1H), 7.45 (t, J = 7.3
Hz, 1H), 7.36 (t, J = 7.6 Hz, 2H), 7.19 (t, J = 8.6 Hz, 3H), 4.27 (d, J = 16.4 Hz, 1H),
3.76 (d, J = 16.5 Hz, 1H), 2.43 (d, J = 4.6 Hz, 6H), 1.20 (s, 3H). 13C {1H} NMR (100
MHz, CDCl3) δ 172.9, 170.5, 145.7, 140.1, 134.9, 132.8, 132.6, 131.4, 129.4, 129.3,
128.8, 128.3, 128.2, 127.5, 123.3, 121.0, 78.5, 69.0, 60.9, 21.9, 21.59, 14.3. HRMS
(ESI) calcd for C26H24N5O3S [M+H]+ 486.1594, found 486.1600.
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quinolin-4(3aH)-one (cis-2k): white solid; 58.8 mg; 58% yield; mp 216−217 °C; H
NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.69 (d,
J = 8.3 Hz, 2H), 7.61 – 7.56 (m, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.40 – 7.33 (m, 3H),
7.22 (d, J = 8.2 Hz, 2H), 4.35 (d, J = 16.6 Hz, 1H), 3.78 (d, J = 16.6 Hz, 1H), 2.43 (s,
3H), 1.22 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.5, 169.9, 146.0, 135.5,
134.5, 133.8, 132.2, 131.6, 129.7, 129.5, 129.4, 128.9, 128.1, 126.8, 122.9, 122.6,
78.3, 69.4, 61.1, 21.9, 14.1. HRMS (ESI) calcd for C25H21ClN5O3S [M+H]+ 506.1048,
found 506.1050.
cis-9b-azido-3a-methyl-5-(methylsulfonyl)-1-phenyl-5,9b-dihydro-3H-pyrrolo[3,4
-c]quinolin-4(3aH)-one (cis-2l): white solid; 42.0 mg; 53% yield; mp 149−150 °C;
1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.4 Hz, 1H), 7.59 (d, J = 7.4 Hz, 2H), 7.47
– 7.27 (m, 6H), 4.70 (d, J = 16.3 Hz, 1H), 4.01 (d, J = 16.3 Hz, 1H), 3.39 (s, 3H), 1.34
(s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 174.8, 171.4, 132.6, 132.4, 131.4, 129.8,
128.8, 128.6, 128.0, 126.7, 124.2, 122.0, 78.5, 69.40, 61.8, 43.5, 14.3. HRMS (ESI)
calcd for C19H18N5O3S [M+H]+ 396.1125, found 396.1125.
cis-9b-azido-3a,5-dimethyl-1-phenyl-5,9b-dihydro-3H-pyrrolo[3,4-c]quinolin-4(3
aH)-one (cis-2m): known compound13; light yellow solid; 56.7 mg; 86% yield; mp
109−110 °C; 1H NMR (400 MHz, CDCl3) δ 7.58 – 7.51 (m, 3H), 7.43 – 7.36 (m, 2H),
7.30 (t, J = 7.5 Hz, 2H), 7.14 – 7.09 (m, 1H), 7.06 (d, J = 8.2 Hz, 1H), 4.62 (d, J =
16.1 Hz, 1H), 3.95 (d, J = 16.1 Hz, 1H), 3.36 (s, 3H), 1.41 (s, 3H). 13C {1H} NMR
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(100 MHz, CDCl3) δ 171.2, 171.0, 138.3, 133.5, 130.7, 130.4, 129.3, 128.4, 128.3,
123.6, 119.5, 114.8, 78.9, 68.6, 56.2, 30.5, 16.0.
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cis-9b-azido-5-benzyl-3a-methyl-1-phenyl-5,9b-dihydro-3H-pyrrolo[3,4-c]quinoli
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n-4(3aH)-one (cis-2n): known compound13; yellow oil; 61.1 mg; 75% yield; H
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NMR (400 MHz, CDCl3) δ 7.57 – 7.49 (m, 3H), 7.38 (t, J = 7.4 Hz, 1H), 7.29 (t, J =
7.6 Hz, 2H), 7.23 – 7.14 (m, 4H), 7.10 – 7.02 (m, 3H), 6.94 (d, J = 8.2 Hz, 1H), 5.37
(d, J = 16.1 Hz, 1H), 5.06 (d, J = 16.2 Hz, 1H), 4.79 (d, J = 16.0 Hz, 1H), 4.01 (d, J =
13
16.0 Hz, 1H), 1.49 (s, 3H). C {1H} NMR (100 MHz, CDCl3) δ 171.5, 171.3, 137.3,
136.0, 133.4, 130.8, 130.3, 129.5, 128.9, 128.5, 128.4, 127.3, 126.3, 123.7, 119.8,
115.9, 79.1, 68.6, 56.5, 46.3, 15.9.
AUTHOR INFORMATION
Corresponding author
* X. L.: xcli@dicp.ac.cn
* B. W.: bswan@dicp.ac.cn
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China (21572225) for
financial support.
ASSOCIATED CONTENT
Supporting information
The Supporting Information is available free of charge on the ACS Publications
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website. Details of mechanistic studies, Xꢀray structure, NMR spectra (PDF).
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