Catalyst and Additive-Free Diastereoselective 1,3-Dipolar Cycloaddition of Quinolinium Imides with Olefins, Maleimides, and Benzynes: Direct Access to Fused N,N′-Heterocycles with Promising Activity against a Drug-Resistant Malaria Parasite

Article abstract of DOI:10.1021/acs.joc.8b01520

A convenient and eco-friendly synthesis of various fused N-heterocyclic compounds through catalyst and additive-free 1,3 dipolar cycloadditions of quinolinium imides with olefins, maleimides, and benzynes in excellent yields and diastereoselectivities is reported. The thermally controlled diastereoselective [3 + 2] cycloaddition reaction between quinolinium imides and olefins provided cis-isomers at low temperature and trans-isomers at high temperature. A reaction between quinolinium imides with substituted maleimides gave four-ring-fused N-heterocyclic compounds in high yields as a single diastereomer. The aryne precursors also provided four-ring-fused N,N′-heterocyclic compounds in high yields. The in vitro antiplasmodial activity of selected molecules revealed that this class of molecules possesses potential for ongoing studies against malaria.

Full text of DOI:10.1021/acs.joc.8b01520

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Article
A Catalyst and Additive-free Diastereoselective 1,3-Dipolar
Cycloaddition of Quinolinium Imides with Olefins, Maleimides
and Benzynes: Direct Access to Fused N,N´-Heterocycles with
Promising Activity against Drug Resistant Malaria Parasite
Rakesh Kumar, Sandeep Chaudhary, Rohit Kumar, Pooja Upadhyay, Dinkar Sahal, and Upendra Sharma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01520 • Publication Date (Web): 30 Aug 2018
Downloaded from http://pubs.acs.org on August 30, 2018
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A Catalyst and Additive-free Diastereoselective 1,3-Dipolar
Cycloaddition of Quinolinium Imides with Olefins, Maleimides and
Benzynes: Direct Access to Fused N,N´-Heterocycles with Promising
Activity against Drug Resistant Malaria Parasite
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Rakesh Kumar, Sandeep Chaudhary, Rohit Kumar, Pooja Upadhyay, Dinkar Sahal,
†,
Upendra Sharma 
†Natural Product Chemistry and Process Development Division and AcSIR, CSIR-IHBT,
Palampur, India
‡Malaria Drug Discovery Laboratory, International Centre for Genetic Engineering and
Biotechnology, Aruna Asaf Ali Marg, New Delhi, 110067, India
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ABSTRACT: A convenient and eco-friendly synthesis of various fused N-heterocyclic
compounds through catalyst and additive-free 1,3 dipolar cycloadditions of quinolinium imides
with olefins, maleimides, and benzynes in excellent yields and diastereoselectivities is reported.
The thermally controlled diastereoselective [3+2] cycloaddition reaction between quinolinium
imides and olefins provided cis-isomers at low temperature and trans-isomers at high temperature.
A reaction between quinolinium imides with substituted maleimides gave four-ring-fused N-
heterocyclic compounds in high yields as a single diastereomer. The aryne precursors also
provided four-ring-fused N,N´-heterocyclic compounds in high yields. The in vitro antiplasmodial
activity of selected molecules revealed that this class of molecules has shown the potential for
ongoing studies against malaria.
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INTRODUCTION
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Heterocyclic compounds are ubiquitously present in nature. Among them, N-heterocyclic
compounds which are widely distributed in natural products and have found broad application as
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pharmaceuticals and agrochemicals. Quinoline is a privileged class of heterocyclic compounds
exhibiting broad range of biological activities including antimalarial, antitumor and anti-HIV.4
Quinoline containing fused N-heterocyclic compounds have also shown significant bioactivities
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and important representatives, such as lutonin A (A), dactolisib (B), pyronaridine (C),
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compound D and compound E, are shown in Fig. 1. Realizing the potential of these heterocycles,
various efforts have been made for their synthesis.10
Azomethine quinolines have not been explored much as a precursor for the synthesis of N-
1
1
heterocyclic compounds as compared to the quinoline N-oxides. Leading examples include the
transition metal catalyzed, direct C-H arylation,12 alkylation,13 and alkenylation14 of N-
iminopyridinium ylides with aryl halides/boronic acids, N‑tosylhydrazones/alkanes/alkyl alcohol
and vinyl iodide, respectively. The cyclizations of N-iminopyridinium ylides with alkenyl halides
and alkynes have also been reported.15
Figure 1. Typical Quinoline Containing Fused N-Heterocyclic Bioactive Molecules
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Also, azomethine imines and nitrones have also been explored for [3+2], [3+3], [4+3] and other
cycloaddition reactions with enol diazoacetate, cyclopropanes, iminooxindoles allenoates,
activated olefins and malemides for the synthesis of N-heterocycles.16 Although,
dihydroisoquinolinium and tetrahydroisoquinolium ylides have been used for the synthesis of N-
heterocycles via cycloaddition reactions,17 the aromatic azomethine imines including N-
iminoquinolinium ylides has not been explored much for the cycloaddition reactions as there is
energy barrier to dearomatization of aromatic azomethine imines.10b, 18 Herein, we disclose the
diastereoselective synthesis of fused N,N´-heterocycles through 1,3-DC reaction of aryl
azomethine imines with activated olefins, maleimides and arynes in good to excellent yields under
catalyst and additive-free conditions (Scheme 1).
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Scheme 1. Synthesis of Fused N-Heterocyclic Molecules
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Results and discussion
Initially, the reaction of N-benzoyliminoquinolinium ylide, 1a with methyl acrylate, 2a in
acetonitrile under a metal-free condition at 50 ℃ was studied. Gratifyingly, this reaction proceeds
with excellent regioselectivity providing only 2-exo isomer in quantitative yield.
Diastereoselectivity was poor as both the diastereomeric products 3a: 4a were formed in 1:1 ratio
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(Table 1, entry 1). Both diastereomers were isolated and characterized ambiguously by 1D, 2D
NMR and 3a with SC-XRD analysis (Scheme 2).18d
Further, we optimized the reaction conditions to get products 3a and 4a, selectively. With
an increase in temperature from 50℃ to 110℃, 4a was formed in excess (entries 1-3), and a further
increase in temperature from 110℃ to 140℃ did not affect the diastereoselectivity (entry 4).
Screening of different solvents revealed a noticeable increase in the diastereoselectivity w.r.t. 4a
in DCE, toluene, DMF, and xylene while there was a decrease in the diastereoselectivity in THF
(entries 10-15). Under the solvent-free condition, only traces of product were observed (entry 16).
The product 4a was formed diastereoselectively (cis: trans = 1:7) in DCE at 110℃ (Table 1, entry
10).
Scheme 2. [3+2] Cycloaddition Reaction of Quinolinium Imides 1 with 2a
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Table 1. Optimization Studya
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S. No.
Solvent
Temp. (℃)
Time (h) Yield (%)
dr (cis/trans)
Conv. (%)
>99
1
2
3
4
5
6
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
toluene
THF
DMF
xylene
EtOH
-
50
100
110
140
rt
110
110
110
110
110
110
110
110
110
rt
24
24
24
24
24
15
15
15
15
15
15
15
15
15
48
15
8
99
>95
>95
84
48
>95
80
40
65
98
90
96
75
74
95
<5
nd
1:1
1:3
>99
>99
94
53
>99
90
50
80
>99
>99
>99
85
1:5.3
1:5.3
1.25:1
1:5.3
1:5.5
1:5.5
1:5
1:7
1:6
1:4
d
7
8e
9f
1
1
1
1
0
1
2
3
1:6.1
1:6.1
2.9:1
-
14
15
16
88
>99
-
110
0
1
7
EtOH
Nd
nd
a
b
reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), solvent (0.5 ml). NMR yield (cis/trans mixture) from crude
c
reaction mixture using tetrachloroethane (TCE) as internal standard. diastereoselective ratio (dr) determined by 1H
d
e
f
NMR. 1a (0.1 mmol), 2a (0.1 mmol). 1a (0.2 mmol), 2a (0.1 mmol). 1a (0.1 mmol), 2a (0.4 mmol).
Further, the reaction was optimized to get the cis-product (3a) selectively (Table S1). The
cis-isomer 3a was formed as a major product (3a:4a, 2.9:1) in ethanol at 25℃ with 95% of yield
(Table 1, entry 15). No conversion was observed at 0℃ and reactants remained as such (entry 17).
Attempt to get the enantioenriched product by using different chiral ligands did not result in
positive output (Table S2).
With the optimized reaction condition in hand, we studied the substrate scope of N-
benzoyliminoquinolinium ylides with acrylates for the diastereoselective synthesis of the trans
N,N’-heterocyclic compounds (Table 2).
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Table 2 Substrate Scope for trans-Isomers.a
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reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), DCE (1.5 ml), 110 ℃, 15h; in parenthesis H NMR yields of cis/trans
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mixture using tetrachloroethane (TCE) as an internal standard; diastereoselective ratio (dr) determined by H NMR.
b
reaction time 24h.
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The 1,3-DC reactions of 1a with various acrylates afforded the desired trans-products in excellent
yields and good diastereoselectives (Table 2, entry 4a-4e, 68-79%, dr = 1:4-1:7). Trans-
confirmation was also confirmed with SC-XRD analysis of 4b. Reaction of 1a with tri-substituted
olefins, benzyl methacrylate and tert-butyl methacrylate afforded the trans-product 4f (30%, dr =
0
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:2) and 4g (34%, dr = 1:4), respectively. The fluorinated olefins pentafluoropropyl and
heptadecafluorodecyl acrylate also provided the trans-product 4h (72%; 1:4.7) and 4i (69%; 1:5.7),
respectively. Other activated olefins like anthracynylmeth, N-tert-butyl, cyanoethyl cyclohexyl
and 3-hydroxyadamantanyl acrylate were also compatible underdeveloped reaction condition
(Table 2, entry 4j-l, 4n-o, 59-79%, dr = 1:3-1:6.9). The morpholino acrylate gave the product 4m
in 70% yield with the highest diastereoselectivity (1:8.5). Substituted N-benzoyliminoquinolium
ylides reacted successfully with tert-butyl acrylate providing the trans-N,N’-heterocyclic product
in high yield with milder to good diastereoselectivities (Table 2, entry 4p-4s, 58-67%, dr = 1:3-
1:5). The electron withdrawing groups Cl and CF at para-position of benzoyl ring were well
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tolerated. The substituted quinoline ring of N-benzoyliminoquinolinium ylides also reacted with
tert-butyl acrylate to afford corresponding trans-N,N’-heterocyclic products (Table 2, entry 4t-v,
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8-72%, dr = 1:2.8-1:4.2). The reaction of polyaromatic N-benzoyliminobenzo[f]quinolinium
ylide with 2d furnished the trans-N,N’-heterocyclic product 4w in 51% yield with milder
diastereoselectivity (1:3.5). In case of substrates such as N-benzoyliminoisoquinolinium ylide, N-
benzoyliminopyridinium ylide, aliphatic olefins and styrenes either inseparable mixture or no
conversion was observed under current reaction condition.
Next, we explored the substrate scope for the synthesis of cis-N,N’-heterocyclic
compounds. The reaction of 1a with acrylates at rt in ethanol as solvent afforded the desired
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product in good yield and moderate diastereoselectivity (Table 3, entries 3a-e, 32-63%, dr = 2.3:1-
2
.9:1).
Table 3. Substrate Scope for cis-Isomersa
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reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), EtOH (1.5 ml), rt, 48h; in parenthesis H NMR yields of cis/trans
1
mixture by using tetrachloroethane (TCE) as an internal standard; diastereoselective ratio (dr) determined by H NMR.
b
C
reaction time 60h. reaction time 72h at 50 ℃.
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The fluorinated olefins provided the cis-N,N´-heterocyclic products in good yields 3h (53%, dr =
2
:1) and 3i (56%, dr = 2.5:1). The product 3f and 3g were not formed under standard reaction
condition. The 1,3-DC reactions of 1a with other activated olefins such as anthracynylmethyl,
cyanoethyl, cyclohexyl and 3-hydroxyadamantanyl acrylates proceed well providing the desired
cis-N,N’-heterocyclic products 3j, 3l and 3n-o in good yields (49-65%) and diastereoselectivities
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(3:1-3.5:1). While the product 3k, 3m, and 3p were formed in traces and not isolated in pure form.
Substitution on quinoline and benzoyl rings of 1 did not affect the outcome of the reaction afforded
corresponding desired products (3q-w) in low to good yields (11-62%) with moderate
diastereoselectivities (1.5:1-4:1).
Maleimides are well known as dipolarophile in the 1,3-DC reactions.16e, 19 When we carried
out the reaction of 1a with maleimide (5a) in DCE at 110℃ for 24h the endo selective product 6a
was observed in 95% of yield with >99:1 (cis: trans) diastereoselectivity (Table S3). The
tetracyclic endo-N-heterocyclic product 6a was characterized by 1D, 2D NMR, and ESI-MS data.
Further optimization revealed that the desired product 6a could be obtained in 90% of isolated
yield with >99:1(cis: trans) diastereoselectivity under milder reaction condition using water as
solvent at 50 ℃ for 24h (Table S3).
Substrate scope of the 1,3-DC reaction between 1 and 5 was studied using water as solvent
at 50 ℃ for 24h (Table 4). The methyl substituents at C-6 and C-7 position of quinoline ring of 1
were well tolerated and gave the cis-selective tetracyclic products 6b-c in 90% and 70% yields,
respectively. The polyaromatic N-benzoyliminoquinolinium ylide also provided the product 6d in
6
5% yield. The electron withdrawing substituents such as -CF and -Cl at the para-position of the
3
benzoyl ring of 1 provided the cis-products 6e and 6f in high yields. Similarly, the methyl
substituents at para-, meta- and ortho-position of benzoyl ring of 1 provided the desired products
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g-i in high yields (72%-91%). The N-benzoyliminoisoquinolinium ylide also reacted to afford the
desired product 6j in 60% yield. The N-protected maleimides were also successfully reacted with
1a for the synthesis of the N,N´-tetrahetrocyclic products.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 4. Substrate Scope for endo-Isomersa
a
reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), H
2
O (1.5 ml), 50 ℃, 24h; diastereoselective ratio (dr) determined
1
by H NMR.
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5
6
Different substituents at para- or meta-position of the of N-phenyl maleimide were well tolerated
providing the desired products 6l-s in high yields (82%-90%) with excellent cis-
diastereoselectivities (>99:1). The di-substituted maleimides with electron withdrawing and
electron donating groups were also reacted successively and providing the desired cis-products
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
u-w in high yields (82-90%). In case of an ortho-substituent inseparable mixture of product, 6t
was obtained (dr = 80:20) in 60% of isolated yield. It is interesting to note that a steric factor may
cause the exo-product formation or cis and trans- product formation, and there may be an axial
chirality due to H-bonding between H-atoms of ortho-substituted methyl and oxygen atoms of
maleimide ring which may restrict the rotation around single bond while in case of 6s no mixture
was observed. Other than N-aryl maleimides the N-alkyl maleimides also smoothly undergo the
1
,3-DC reactions with 1a and provided the products 6x-y in high yields as a single isomer.
Scheme 3. Proposed Transition States for Folded Isomer of 1,3-DC Reaction between 1a
with N-Substituted Maleimides
The 1,3-DCs reaction between 1a and N-phenylmaleimide provided the folded four-ring-fused
heterocyclic product 6k which was conformed through SC-XRD analysis. On the basis of the
folded structure of 6k favorable transition states TS1 and TS2 were drawn which showed the edge
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to face interaction between two orthogonal arene rings of 1a and N-phenylmaleimide. Other than
orthogonal π-interaction of two arene rings, the oxygen atoms of the maleimide can also favor the
folded structure through interactions with arene ring of 1a. However, the TS3 and TS4 were not
favorable for the observed folded structure (Scheme 3).16f, 20
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 5. Substrate Scope of N-Aryne Precursorsa
areaction conditions: 1 (0.3 mmol), 7 (0.45 mmol), 18-crown ether (2 equiv), KF (2 equiv), ACN (1.5 ml), rt, overnight.
Next, benzyne precursor 7a was reacted the with 1a in the presence of 18-crown ether
and KF using acetonitrile as a solvent at room temperature (Table 5). Delightfully, the cyclic
product 8a was obtained in good yield which was characterized by NMR and SC-XRD analysis.
The symmetrical 4,5-dimethoxy benzyne and napthyl benzyne afforded 85% and 80% of the
products 8b and 8c, respectively. The 1,3-DC reaction of 3-methoxy benzyne precursor with 1a
provided the desired heterocyclic product 8d as a single isomer in 70% yield. The reaction of 4-
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2
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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5
5
5
5
5
5
5
6
methoxybenzyne precursor with 1a provided product 8e in 48% of yield along with an
uncharacterized side product. Other substituted N-benzoyliminoquinolinium ylides were also well
tolerated underdeveloped reaction condition providing the corresponding cyclic products (Table
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
, entries 8f-j) in milder to good yields. Mechanistically, this reaction proceeds through well-
known concerted [3+2] cycloaddition reaction to form the fused-four-ring N,N’-heterocycles
Scheme 4).11g, 21
(
Scheme 4. [3+2] Cycloaddition Reaction of 1a with Benzyne Precursor 7a
The green chemistry parameters of all four developed methodologies were also
calculated. Atom economy is 100% for the synthesis of 3a, 4a, and 6a whereas for 8a it is 31.72%.
Atom efficiency is 63.21, 78.75, 90 and 31.72 for 3a, 4a, 6a and 8a, respectively. Similarly, carbon
efficiency was also calculated for 3a, 4a, 6a, and 8a and it is found as 52.78, 66.67, 75 and 34.66,
respectively. One of the important green metrics is reaction mass efficiency which was also
calculated 3a (50.24), 4a (62.7), 6a (70.46), and 8a (19.26). The optimum efficiency is same as
the reaction mass efficiency for 3a, 4a, and 6a. While for the 8a the optimum efficiency is 51.47.
Other green parameters like process mass intensity, mass productivity, E-factor solvent intensity
and water intensity were also calculated (Table S4). The assessment of the above four reactions by
green metrics showed that the synthesis of the 6a is the greenest whereas the synthesis of 8a is the
least green.16f
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Antiplasmodial Activity: Twenty molecules were evaluated for their SYBR Green microtiter
2
2
plate based in vitro antiplasmodial activity against the chloroquine-sensitive 3D7 and resistant
INDO strains of Plasmodium falciparum. As shown in Table 6, compounds 3j and 4j and 8h
showed the highest promise against both chloroquine sensitive P. falciparum Pf 3D7 and
chloroquine resistant T P. falciparum PfINDO. Thus the 3D7/INDO IC50s (µM) were 0.47/0.40
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(3j), 0.47/0.49 (4j) and 0.85/0.93 (8h). Unlike the resistance index of 12.5 for chloroquine, the
resistance indices for 3j ,4j and 8h were 1, 0.82 and 0.9, respectively. It was interesting to observe
that except 4h, 4k, 4m and 6v which exhibited high double digit IC50s against PfINDO, all other
compounds showed IC50s (µM) in the range of 1.08 and 5.74. Similarly, except for compounds 3b,
3e, 4h, 4k, 4m and 6v which showed high double digit IC50s against Pf3D7, all other compounds
exhibited IC50s (µM) in the range of 1.04 and 6.28. Compounds 3b and 3e which were far more
active against PfINDO than against Pf3D7 showed resistance indices of <0.08 and <0.05
respectively. These two molecules have properties that may challenge the chloroquine-resistant
strain over the chloroquine-sensitive strain with great selectivity. However, further studies
concerning mechanisms of drug uptake and expulsion will be needed to address these possibilities.
Table 6: Comparative Antiplasmodial Potency and Resistance Indices for 20 Molecules.
Entry
IC Pf INDO (µM)
IC Pf3D7 (µM)
Compound
50
50
RI
1
2
3
4
5
6
7
8
9
CQ
3b
3d
3e
0.50
5.74
3.19
3.29
1.98
0.47
1.81
1.23
5.53
0.04
>71.75
3.85
12.5
<0.08
0.83
<0.05
0.69
1.00
1.06
1.17
0.88
>60.90
2.87
3h
3j
0.47
3o
3w
4a
1.71
1.06
6.28
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1
1
1
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1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
6
1
1
1
1
0
1
2
3
4d
4h
4j
2.79
>55.26
0.40
5.58
>55.26
0.49
0.5
1
0.82
1
4k
4m
4o
4t
>66.58
>64.19
1.60
>66.58
>64.19
1.92
14
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
5
6
0.83
0.34
0.92
1
1.52
4.44
17
4w
6v
6x
8c
1.08
1.17
1
1
2
2
8
9
0
1
>44.84
1.46
>44.84
1.04
1.4
0.73
0.90
1.47
2.00
8h
0.85
0.93
CONCLUSIONS
In conclusion, a catalyst and additive-free method for 1,3-DC reaction of quinolinium imides with
activated olefins, maleimides and benzynes for the diastereoselective synthesis N-containing
heterocyclic molecules under the ambient condition is reported. Calculations of green metrics
revealed that developed methodologies are environment-friendly. Experimental evaluation
showed that several compounds had low micromolar IC50s against P. falciparum in human red
blood cell culture. Compounds 3j, 4j and 8h were the most potent with submicromolar IC50s.
Unlike chloroquine which showed a resistance index of 12.5, most of the quinolines studied by us
exhibited their resistance indices around 1. A redeeming feature of our study was that 3b and 3e
which exhibited resistance indices of <0.08 and <0.05 respectively were more active against the
chloroquine-resistant INDO strain than against the chloroquine-sensitive 3D7 strain. Our results
indicate that this class of molecules has the potential to be developed as antimalarial agents.
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EXPERIMENTAL SECTION
Reagent Information. Unless otherwise stated, all reactions were carried out under an air
atmosphere in screw cap reaction vials. All solvents were bought from Aldrich in sure-seal bottle
and used as such. All chemicals were bought from Sigma Aldrich, Alfa-aesar and TCI. For column
chromatography, silica gel (230-400 mesh) from Merck was used. A gradient elution using n-
hexane and ethyl acetate was performed based on Merck aluminum TLC sheets (silica gel 60F254).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
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4
4
4
4
4
5
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Analytical Information. The melting points were recorded on a Bronsted Electro thermal 9100.
1
13
All isolated compounds are characterized by H NMR, C NMR, LC-MS and IR. In addition, all
the compounds are further characterized by HRMS. Mass spectra were recorded on Water Q-ToF-
1
13
Micro mass. Copies of H, C NMR can be found in the NMR supporting information. IR was
analyzed by Shimadzu IR Prestige-21with ZnSe Single reflection ATR accessory. Nuclear
magnetic resonance spectra were recorded either on a Bruker-Avance 600 or 300 MHz instrument.
1
All H NMR experiments are reported in units, parts per million (ppm) and were measured relative
to the signals for residual chloroform (7.26) and acetone (2.05, 2.84) in the deuterated solvents.
13
All C NMR spectra were reported in ppm relative to deuterated chloroform (77.23), and acetone
1
(29.84, 206.26) and all were obtained with H decoupling. Optimization studies were done by
NMR, and NMR yield was calculated by using TCE as an internal standard. Enantiomeric ratios
were calculated by HPLC (Shimadzu LC-solution) using Daicel CHIRACEL OD-H column.
23
Procedure for the Synthesis of Substituted N-Benzoyliminoquinolinium Ylides. To an oven-
dried a 10 ml screw cap reaction vial charged with a spin vane magnetic stir-bar, quinoline was
added (0.100 mL, 1.24 mmol) and O-(2,4-dinitrophenyl)hydroxylamine (272 mg, 1.36 mmol) were
added to 0.5 mL of a (1:1) mixture of H
2
O and THF. The mixture was stirred at 40 °C for 12 h
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6
after that benzoyl chloride (0.215 mL, 1.84 mmol) was added slowly and stir for 30 minutes. The
reaction was poured into aqueous NaOH (2.5 N, 6 mL) at room temperature, after 4 h, the reaction
was diluted with 5 mL of H
organic phases were washed once with 5 mL of 2.5 N NaOH. The organic phase was dried over
Na SO4, filtered, and concentrated under reduced pressure affording desired products.
2
O and extracted three times with 10 mL of CHCl . The combined
3
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
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4
5
6
7
8
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
General Procedure for Diastereoselective Synthesis of trans-N,N´-Heterocycles of N-
Benzoyliminoquinolinium Ylides with Acrylates (Table 2). To an oven-dried screw cap reaction
vial charged with a spin vane magnetic stir-bar, N-benzoyliminoquinoline ylides (0.3 mmol) and
acrylate (2 equiv.) were added in DCE (1.5 ml) and stirred for 15 h at 110
reaction mixture was extracted with ethyl acetate. Ethyl acetate layer was dried over anhydrous
Na SO and evaporated under reduced pressure. The residue was purified by flash chromatography
̊C . After completion,
2
4
using silica gel (230-400 mesh size) and n-hexane: EtOAc as eluent.
General Procedure for Diastereoselective Synthesis of cis-N,N´-Heterocycles of N-
Benzoyliminoquinolinium Ylides with Acrylates (Table 3). To an oven-dried screw cap reaction
vial charged with a spin vane magnetic stir-bar, N-benzoyliminoquinoline ylides (0.3 mmol) and
acrylate (2 equiv.) were added in EtOH (1.5 ml) and stir for 48 h, at room temperature. After
completion, the reaction mixture was extracted with ethyl acetate. Ethyl acetate layer was dried
over anhydrous Na
2
SO and evaporated under reduced pressure. The residue was purified by flash
4
chromatography using silica gel (230-400 mesh size) and n-hexane: EtOAc as eluent.
Characterization Data. Methyl 1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-
carboxylate (Table 2, entry 4a): Yellow oily, yield = 79 mg (79%), dr = 1:7 (cis/trans), isolated
1
from flash chromatography (20% EtOAc/n-hexane); H NMR (600 MHz, CDCl
3
) δ 7.80 (d, J =
7.8 Hz, 2H), 7.40 (d, J = 6.6 Hz, 1H), 7.32 (s, br, 2H), 7.17 – 7.14 (m, 1H), 7.02 – 6.99 (m, 2H),
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6
.92 – 6.89 (m, 1H), 6.44 (d, J = 9.6 Hz, 1H), 5.99 (dd, J = 9.6, 5.4 Hz, 1H), 4.66 (s, br, 1H), 4.06
1
3
(s, br, 1H), 3.74 (s, 3H), 3.52 (s, br, 1H), 3.34 – 3.29 (m, 1H); C NMR (150 MHz, CDCl
3
) δ
171.6, 171.2, 142.6, 133.6, 131.2, 129.8, 128.0, 127.5, 126.4, 122.5, 113.9, 62.5, 52.5, 50.8, 45.8;
-1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
IR (ZnSe): νmax (cm ) 3060, 2963, 2924, 2850, 1730, 1643, 1599, 1574, 1483, 1448, 1355, 1239,
+
1
166, 1029, 757, 705, 694, 662; HRMS (ESI-TOF): m/z calcd for C20
H
19
N O
2 3
[M+H] 335.1390,
found 335.1380.
Methyl 1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-carboxylate (Table 3,
entry 3a): brown solid, yield = 63 mg (63%), dr = 2.9:1 (cis/trans), mp 95°C, isolated from flash
1
chromatography (25% EtOAc/n-hexane); H NMR (300 MHz, CDCl
3
) δ 7.79 (d, J = 7.2 Hz, 2H),
7.43 (t, J = 7.2 Hz, 1H), 7.35 – 7.30 (m, 2H), 7.22 – 7.17 (m, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.89 –
.84 (m, 1H), 6.86 (t, J = 7.3 Hz, 1H), 6.46 (d, J = 9.9 Hz, 1H), 5.80 (dd, J = 9.9, 5.1 Hz, 1H), 4.72
6
13
(s, br, 1H), 4.25 (s, br, 1H), 3.65 (s, br, 1H), 3.45 (s, 3H), 3.41 (dd, J = 8.7, 5.7 Hz, 1H); C NMR
(75 MHz, CDCl ) δ 172.1, 172.0, 142.8, 133.6, 131.4, 130.0, 128.6, 128.1, 127.5, 127.2, 122.2,
3
-1
1
1
21.9, 120.1, 112.9, 62.2, 52.0, 51.7, 45.8; IR (ZnSe): νmax (cm ) 2954, 2852, 2318, 1741, 1649,
483, 1444, 1350, 1197, 1172, 906, 754, 713, 694, 526; HRMS (ESI-TOF): m/z calcd for
+
C
20
H
19
N
2
O
3
[M+H] 335.1390, found 335.1400.
Ethyl 1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-carboxylate (Table 2,
entry 4b): Light yellow solid, yield = 82 mg (79%), dr = 1:6.6 (cis/trans), mp 106°C, isolated from
1
flash chromatography (20% EtOAc/n-hexane); H NMR (600 MHz, CDCl
3
) δ 7.81 (d, J = 7.8 Hz,
2H), 7.40 (d, J = 6.6 Hz, 1H), 7.32 (s, br, 2H), 7.17 – 7.14 (m, 1H), 7.02 – 7.00 (m, 2H), 6.91 (t, J
7.2 Hz, 1H), 6.44 (d, J = 10.2 Hz, 1H), 6.01 – 5.99 (m, 1H), 4.65 (s, br, 1H), 4.22 – 4.19 (m,
=
13
2
H), 4.07 (s, br, 1H), 3.53 (s, br, 1H), 3.30 – 3.28 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H); C NMR (150
MHz, CDCl
3
) δ 171.19, 171.16, 142.7, 133.7 131.2, 129.8, 128.6, 128.0, 127.5, 126.4, 122.7,
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2
2
2
2
2
2
3
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13
1
22.6, 113.9, 62.6, 61.5, 51.0, 46.0, 14.3; DEPT C NMR (151 MHz, CDCl
3
) δ 131.2 (CH), 129.8
(
CH), 128.6 (CH), 128.0 (CH), 127.5 (CH), 126.4 (CH), 122.6 (CH), 113.9 (CH), 62.6 (CH), 61.5
-1
(CH2), 51.0 (CH), 45.9 (CH2), 14.3(CH3); IR (ZnSe): νmax (cm ) 2920, 2850, 1720, 1639, 1446,
O
[M+H]+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
373, 1298, 1247, 1031, 763, 717, 696, 663; HRMS (ESI-TOF): m/z calcd for C21
49.1547, found 349.1530.
H
21
N
2
3
Ethyl 1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-carboxylate (Table 3,
entry 3b): yellow solid, yield = 64 mg (61%), dr = 2.9:1 (cis/trans), mp 126-128 °C, isolated from
1
flash chromatography (25% EtOAc/n-hexane); H NMR (600 MHz, CDCl
3
) δ 7.81 – 7.79 (m, 2H),
7
.42 (t, J = 7.2 Hz, 1H), 7.34 – 7.31 (m, 2H), 7.19 – 7.16 (m, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.91
(dd, J = 7.2, 1.2 Hz, 1H), 6.86 – 6.84 (m, 1H), 6.44 (d, J = 10.2 Hz, 1H), 5.81 (dd, J = 10.2, 5.4
Hz, 1H), 4.70 (s, br, 1H), 4.27 (s, br, 1H), 3.99 – 3.94 (m, 1H), 3.86 – 3.81 (m, 1H), 3.66 (s, br,
1
3
1
H), 3.39 (td, J = 8.4, 5.4 Hz, 1H), 0.98 (t, J = 7.2 Hz, 3H); C NMR (150 MHz, CDCl
3
) δ 172.0,
171.4, 142.9, 133.6, 131.3, 130.0, 128.6, 128.1, 127.5, 127.1, 122.3, 121.8, 120.1, 112.9, 62.3,
-1
6
1
1.1, 51.7, 45.7, 13.9; IR (ZnSe): νmax (cm ) 2988, 2923, 2907, 1723, 1646, 1599, 1574, 1485,
447, 1366, 1345, 1279, 1190, 1179, 1135, 1063, 1001, 800, 754, 713, 691, 526; HRMS (ESI-
+
TOF): m/z calcd for C21
H
21
N
2
O
3
[M+H] 349.1547, found 349.1559.
Butyl 1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-carboxylate (Table 2,
entry 4c): brown oily, yield = 86 mg (76%), dr = 1:5.4 (cis/trans), isolated from flash
1
chromatography (15% EtOAc/n-hexane); H NMR (600 MHz, CDCl
3
) δ 7.80 (d, J = 7.8 Hz, 2H),
7.41 (dd, J = 13.8, 7.2 Hz, 1H), 7.32 (s, br, 2H), 7.15 (td, J = 7.8, 1.2 Hz, 1H), 7.01 – 6.99 (m, 2H),
6
.91 – 6.88 (m, 1H), 6.44 (d, J = 9.6 Hz, 1H), 5.99 (dd, J = 9.6, 5.4 Hz, 1H), 4.65 (s, br, 1H), 4.16
4.14 (m, 2H), 4.06 (s, br, 1H), 3.52 – 3.51 (s, br, 1H), 3.33 – 3.29 (m, 1H), 1.65 – 1.60 (m, 2H),
–
1
3
1.41 – 1.39 (m, 2H), 0.95 – 0.92 (m, 3H); C NMR (150 MHz, CDCl ) δ 171.23, 171.15, 142.7,
3
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33.7, 131.2, 129.8, 128.5, 128.0, 127.5, 126.4, 122.6, 122.5, 113.9, 65.4, 62.6, 51.2, 46.1, 30.7,
9.2, 13.7.
-1
IR (ZnSe): νmax (cm ) 3057, 2958, 2931, 2872, 1728, 1645, 1598, 1483, 1448, 1350, 1307, 1236,
+
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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2
2
2
2
3
3
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3
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4
4
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5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
178, 1165, 758, 694, 661; HRMS (ESI-TOF): m/z calcd for C23
77.1865.
H
25
N
2
O
3
[M+H] 377.1865, found
Butyl 1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-carboxylate (Table 3,
entry 3c): light yellow solid, yield = 65 mg (58%), dr = 2.54:1 (cis/trans). mp 96 °C, isolated from
1
flash chromatography (20% EtOAc/n-hexane); H NMR (600 MHz, CDCl
3
) δ 7.80 (dd, J = 8.4,
1
.2 Hz, 2H), 7.43 – 7.41 (m, 1H), 7.34 – 7.31 (m, 2H), 7.18 – 7.16 (m, 1H), 7.04 (d, J = 7.8 Hz,
1H), 6.92 – 6.91 (m, 1H), 6.86 – 6.84 (m, 1H), 6.44 (d, J = 10.2 Hz, 1H), 5.82 – 5.79 (m, 1H),
.70 (s, br, 1H), 4.27 (s, 1H), 3.93 – 3.89 (m, 1H), 3.78 – 3.74 (m, 1H), 3.66 (s, br, 1H), 3.41 (td,
4
1
3
J = 9.0, 5.4 Hz, 1H), 1.34 – 1.29 (m, 2H), 1.20 (dt, J = 14.4, 7.2 Hz, 2H), 0.86 – 0.83 (m, 3H); C
NMR (75 MHz, CDCl ) δ 172.1, 171.5, 142.9, 133.6, 131.4, 130.0, 128.6, 128.1, 127.5, 127.2,
3
-1
1
3
6
22.2, 121.9, 120.2, 116.2, 112.9, 65.1, 62.2, 51.9, 45.8, 30.3, 19.2, 13.8; IR (ZnSe): νmax (cm )
312, 3060, 2966, 2924, 1643, 1547, 1484, 1451, 1360, 1261, 1222, 1003, 910, 779, 705, 728,
+
94, 661; HRMS (ESI-TOF): m/z calcd for C23
H
25
N
2
O
3
[M+H] 377.1860, found 377.1851.
tert-Butyl 1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-carboxylate (Table 2,
entry 4d): Yellow oily, yield = 77 mg (68%), dr = 1:4 (cis/trans), isolated from flash
1
chromatography (20% EtOAc/n-hexane); H NMR (600 MHz, CDCl
3
) δ 7.81 (d, J = 7.8 Hz, 2H),
7.40 (s(br), 1H), 7.32 (s, br, 2H), 7.14 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 7.2 Hz, 2H), 6.90 – 6.88 (m,
1
3
H), 6.43 (d, J = 10.2 Hz, 1H), 5.99 (dd, J = 10.2, 5.4 Hz, 1H), 4.58 (s, br, 1H), 4.03 (s, br, 1H),
13
.52 – 3.48 (m, 1H), 3.26 – 3.23 (m, 1H), 1.47 (s, 9H); C NMR (150 MHz, CDCl ) δ 171.1,
3
170.3, 142.8, 133.8, 131.1, 129.7, 128.6, 128.0, 127.4, 126.2, 122.9, 122.7, 122.4, 113.9, 82.1,
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6
1
2.6, 52.0, 46.2, 28.2; IR (ZnSe): νmax (cm ) 3066, 3005, 1721, 1654, 1599, 1481, 1454, 1367,
354, 1242, 1145, 1001, 882, 771, 694, 660; HRMS (ESI-TOF): m/z calcd for C23
H
25
N
2
O
[M+H]+
3
377.1860, found 377.1845.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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0
tert-Butyl 1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-carboxylate (Table 3,
entry 3d): yellow solid, yield = 36 mg (32%), dr = 2.4:1 (cis/trans), mp 110 °C, isolated from flash
1
chromatography (25% EtOAc/n-hexane); H NMR (300 MHz, CDCl
3
) δ 7.80 – 7.77 (m, 2H), 7.44
–
7.39 (m, 1H), 7.34 – 7.30 (m, 2H), 7.18 – 7.13 (m, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 7.2
Hz, 1H), 6.87 – 6.82 (m, 1H), 6.44 (d, J = 9.9 Hz, 1H), 5.84 (dd, J = 9.6, 5.1 Hz, 1H), 4.64 (s, br,
13
1
H), 4.25 (s, br, 1H), 3.61 (s, br, 1H), 3.32 – 3.24 (m, 1H), 1.18 (s, 9H); C NMR (75 MHz,
CDCl
3
) δ 170.4, 170.1, 143.1, 133.8, 131.3, 130.0, 128.5, 128.1, 127.6, 127.2, 122.4, 121.7, 120.3,
-1
1
1
12.8, 81.6, 62.3, 52.4, 46.6, 27.7; IR (ZnSe): νmax (cm ) 3070, 2978, 2930, 1722, 1650, 1600,
484, 1449, 1367, 1243, 1148, 1100, 840, 752, 709, 649; HRMS (ESI-TOF): m/z calcd for
+
C
23
H
25
N
2
O
3
[M+H] 377.1860, found 377.1852.
Benzyl 1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-carboxylate (Table 2,
entry 4e): yellow oily, yield = 87 mg (71%), dr = 1:5 (cis/trans), isolated from flash
1
chromatography (15% EtOAc/n-hexane); H NMR (600 MHz, CDCl
3
) δ 7.81 (d, J = 7.2 Hz, 2H),
7
.42 – 7.33 (m, 8H), 7.17 (t, J = 7.8 Hz, 1H), 7.04 – 7.00 (m, 2H), 6.93 – 6.90 (m, 1H), 6.43 (d, J
=
9.6 Hz, 1H), 5.97 – 5.94 (m, 1H), 5.23 – 5.16 (m, 2H), 4.72 (s, br, 1H), 4.08 (d, J = 28.9 Hz,
1
3
1H), 3.54 (s, br, 1H), 3.37 (td, J = 10.2, 6.6 Hz, 1H); C NMR (150 MHz, CDCl
3
) δ 171.2, 171.0,
42.6, 135.4, 133.6, 131.2, 129.8, 128.7, 128.6, 128.5, 128.3, 128.0, 127.5, 126.4, 122.6, 122.5,
13.9, 67.2, 62.7, 51.0, 45.7.
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IR (ZnSe): νmax (cm ) 3061, 2922, 1732, 1658, 1643, 1483, 1448, 1350, 1236, 1163, 1026, 754,
+
6
94, 663, 474; HRMS (ESI-TOF): m/z calcd for C26
H
23
N
2
O
3
[M+H] 411.1703, found 411.1689.
Benzyl 1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-carboxylate (Table 3,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
entry 3e): light yellow solid, yield = 69 mg (56%), dr = 2.3:1 (cis/trans), mp 119-120°C, isolated
1
from flash chromatography (20% EtOAc/n-hexane); H NMR (300 MHz, CDCl
3
) δ 7.79 (d, J =
7
1
1
.2 Hz, 2H), 7.45 – 7.40 (m, 1H), 7.34 – 7.32 (m, 5H), 7.20 – 7.15 (m, 3H), 7.06 (d, J = 8.1 Hz,
H), 6.86 (d, J = 4.2 Hz, 2H), 6.25 (d, J = 9.9 Hz, 1H), 5.73 (dd, J = 9.9, 5.1 Hz, 1H), 5.03 (d, J =
2.0 Hz, 1H), 4.78 (d, J = 12.3 Hz, 1H), 4.68 (s, br, 1H), 4.25 (s, br, 1H), 3.69 – 3.66 (m, 1H), 3.45
1
3
(
td, J = 9.0, 5.7 Hz, 1H); C NMR (75 MHz, CDCl ) δ 172.1, 171.4, 142.7, 135.3, 133.5, 131.4,
3
130.0, 128.8, 128.6, 128.5, 128.1, 127.4, 127.3, 122.2, 121.9, 120.0, 112.9, 67.0, 62.3, 51.5, 45.8;
-1
IR (ZnSe): νmax (cm ) 3031, 1741, 1656, 1483, 1452, 1349, 1188, 1179, 734, 693; HRMS (ESI-
+
TOF): m/z calcd for C26
H
23
N
2
O
3
[M+H] 411.1703, found 411.1710.
Benzyl 1-benzoyl-3-methyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-carboxylate
(
Table 2, entry 4f): transparent crystalline , yield = 38 mg (30%), dr = 1:2 (cis/trans), mp 112-
1
1
13°C, isolated from flash chromatography (15% EtOAc/n-hexane); H NMR (600 MHz, CDCl
3
)
δ 7.71 (d, J = 7.8 Hz, 2H), 7.39 – 7.30 (m, 8H), 7.15 – 7.13 (m, 1H), 6.99 – 6.96 (m, 2H), 6.86 –
6
.84 (m, 1H), 6.56 (d, J = 10.2 Hz, 1H), 5.74 – 5.72 (m, 1H), 5.17 (s, br, 3H), 4.35 (s, br, 1H), 3.02
13
(
s, br, 1H), 1.24 (s, 3H); C NMR (150 MHz, CDCl
3
) δ 174.0, 171.6, 143.3, 135.6, 133.7, 131.2,
1
29.9, 128.8, 128.6, 128.4, 128.2, 128.1, 127.4, 122.2, 121.7, 120.6, 112.1, 67.4, 65.5, 56.2, 54.4,
20.4.
-1
IR (ZnSe): νmax (cm ) 2918, 2320, 1718, 1654, 1483, 1452, 1363, 1265, 1232, 1145, 1097, 754,
+
6
92, 653, 526; HRMS (ESI-TOF): m/z calcd for C27
H
25
N
2
O
3
[M+H] 425.1860, found 425.1857.
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tert-Butyl 1-benzoyl-3-methyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-carboxylate
(
Table 2, entry 4g): White solid, yield = 40 mg (34%), dr = 1:4 (cis/trans), mp 122-124°C, isolated
1
from flash chromatography (15% EtOAc/n-hexane); H NMR (600 MHz, CDCl
3
) δ 7.77 (d, J =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
6
1
1
6
1
.8 Hz, 2H), 7.41 (s, br, 1H), 7.33 (s, br, 2H), 7.12 (t, J = 7.8 Hz, 1H), 6.95 (d, J = 7.2 Hz, 2H),
.85 – 6.82 (m, 1H), 6.56 (d, J = 9.6 Hz, 1H), 5.76 – 5.74 (dd, J = 10.2, 5.4 Hz, 1H), 5.04 (s, br,
1
3
H), 4.32 (s, br, 1H), 2.96 (s, br, 1H), 1.47 (s, 9H), 1.18 (s, 3H); C NMR (150 MHz, CDCl ) δ
3
73.4, 171.4, 143.5, 133.9, 131.1, 129.8, 128.4, 128.0, 127.4, 122.3, 121.6, 121.6, 112.1, 82.0,
-1
5.6, 56.8, 54.6, 28.1, 20.4; IR (ZnSe): νmax (cm ) 2974, 2931, 2318, 1712, 1651, 1485, 1454,
365, 1334, 1278, 1172, 1138, 759, 653; HRMS (ESI-TOF): m/z calcd for C24
H
27
N
2
O
[M+H]+
3
391.2016, found 391.2009.
,2,3,3,3-Pentafluoropropyl 1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-
2
carboxylate (Table 2, entry 4h): yellow oily, yield = 98 mg (72%), dr = 1:4.7 (cis/trans), isolated
1
from flash chromatography (15% EtOAc/n-hexane); H NMR (600 MHz, CDCl
3
) δ 7.81 (d, J =
7
.2 Hz, 2H), 7.43 (t, J = 7.2 Hz, 1H), 7.33 (t, J = 7.2 Hz, 2H), 7.19 (td, J = 7.8, 1.2 Hz, 1H), 7.06
d, J = 7.8 Hz, 1H), 7.04 – 7.03 (m, 1H), 6.96 – 6.93 (m, 1H), 6.48 (d, J = 9.6 Hz, 1H), 5.97 (dd, J
9.6, 5.4 Hz, 1H), 4.73 – 4.66 (m, 2H), 4.60 – 4.53 (m, 1H), 4.06 (s, br, 1H), 3.57 – 3.53 (m, 1H),
(
=
1
3
3
1
1
.43 – 3.39 (m, 1H); C NMR (150 MHz, CDCl ) δ 171.3, 169.9, 142.5, 133.4, 131.4, 130.0,
3
28.6, 128.1, 127.7, 126.9, 122.8, 122.7, 121.8, 119.65–119.19 (m), 117.8 – 117.3 (m), 114.0,
13.6 (d, JCF = 38.0 Hz), 112.3 – 111.6 (m), 110.37 (m), 62.9, 59.9 – 59.5 (m), 50.8, 45.9; IR
-1
(ZnSe): νmax (cm ) 3061, 2926, 1753, 1643, 1452, 1392, 1352, 1195, 1145, 1107, 1028, 758, 704,
+
6
63; HRMS (ESI-TOF): m/z calcd for C22
,2,3,3,3-pentafluoropropyl
H
18
F
5
N O
2 3
[M+H] 453.1232, found 453.1215.
2
1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-
carboxylate (Table 3, entry 3h): white solid, yield = 72 mg (53%), dr = 2:1 (cis/trans), mp 133°C,
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isolated from flash chromatography (20% EtOAc/n-hexane); H NMR (300 MHz, CDCl
3
) δ 7.79
(
d, J = 7.5 Hz, 2H), 7.46 – 7.42 (m, 1H), 7.36 – 7.31 (m, 2H), 7.25 – 7.19 (m, 1H), 7.10 (d, J = 8.1
Hz, 1H), 6.95 – 6.87 (m, 2H), 6.48 (d, J = 9.6 Hz, 1H), 5.80 (dd, J = 9.9, 5.1 Hz, 1H), 4.76 (s, br,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
–
5
1
H), 4.52 – 4.39 (m, 1H), 4.32 – 4.26 (m, 1H), 4.23 – 4.10 (m, 1H), 3.67 – 3.61 (m, 1H), 3.56 –
1
3
.48 (m, 1H); C NMR (75 MHz, CDCl
3
) δ 172.2, 170.4, 142.5, 133.3, 131.6, 130.4, 128.6, 128.46
128.04 (m), 128.2, 128.0, 127.4, 122.3, 122.1, 119.5, 113.1, 112.73 – 111.73 (m), 62.4, 60.17 –
-1
9.44 (m), 51.4, 45.6; IR (ZnSe): νmax (cm ) 2964, 2894, 1753, 1662, 1481, 1454, 1354, 1279,
174, 1158, 1041, 973, 746, 721, 628, 527; HRMS (ESI-TOF): m/z calcd for C22
H
18
F
5
N
2
O
3
+
[
M+H] 453.1232, found 453.1232.
3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10Hheptadecafluorodecyl
1-benzoyl-1,2,3,3a-
tetrahydropyrazolo[1,5-a]quinoline-3-carboxylate (Table 3, entry 4i): yellow oily, yield = 158 mg
69%), dr = 1:5.7 (cis/trans), isolated from flash chromatography (15% EtOAc/n-hexane); 1H
NMR (300 MHz, CDCl ) δ 7.81 (d, J = 6.9 Hz, 2H), 7.47 – 7.40 (m, 1H), 7.33 (t, J = 7.5 Hz, 2H),
.21 – 7.15 (m, 1H), 7.05 – 7.00 (m, 2H), 6.95 – 6.90 (m, 1H), 6.46 (d, J = 9.9 Hz, 1H), 6.00 –
.95 (m, 1H) 4.67 (s, br, 1H), 4.51– 4.42 (m, 2H), 4.09 – 4.04 (m, 1H), 3.53 (t, J = 11.1 Hz, 1H),
(
3
7
5
3
1
1
4
1
3
.38 – 3.29 (m, 1H), 2.56 – 2.44 (m, 2H); C NMR (75 MHz, CDCl ) δ 171.3, 170.9, 142.6, 133.6,
3
31.3, 130.2, 130.0, 128.6, 128.5, 128.1, 127.6, 126.7, 122.7, 122.3, 119.63-119.15 (m), 117.65-
17.12 (m), 115.41-114.47 (m), 114.0, 111.67-111.05 (m), 110.43-109.94 (m), 62.7, 57.4, 51.1,
-
1
6.0, 30.9- 30.3(m); IR (ZnSe): νmax (cm ) 2918, 2848, 1736, 1654, 1484, 1452, 1234, 1199, 1144,
+
1158, 758, 703, 654, 528; HRMS (ESI-TOF): m/z calcd for C29
found 767.1181.
H
20
F
17
N O
2 3
[M+H] 767.1197,
3
,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecyl
1-benzoyl-1,2,3,3a-
tetrahydropyrazolo[1,5-a]quinoline-3-carboxylate (Table 3, entry 3i): white solid, yield = 129 mg
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2
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5
5
5
5
5
6
(
56%), dr = 2.5:1 (cis/trans), mp 121 °C, isolated from flash chromatography (20% EtOAc/n-
1
hexane); H NMR (300 MHz, CDCl
3
) δ 7.82 (d, J = 7.5 Hz, 2H), 7.47 – 7.42 (m, 1H), 7.35 (t, J =
7.5 Hz, 2H), 7.21 (td, J = 7.2, 1.8 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 6.96 – 6.93 (m, 1H), 6.92 –
.86 (m, 1H), 6.48 (d, J = 9.9 Hz, 1H), 5.83 (dd, J = 9.9, 5.1 Hz, 1H), 4.71 (s, br, 1H), 4.33 – 4.28
m, 1H), 4.25 – 4.17 (m, 1H), 4.06 – 3.98 (m, 1H), 3.71 – 3.65 (m, 1H), 3.49 – 3.42 (m, 1H), 2.15
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
(
1
3
–
1
1
1.98 (m, 2H); C NMR (75 MHz, CDCl ) δ 172.1, 171.1, 143.0, 133.6, 131.4, 130.2, 128.6,
3
28.1, 127.7, 127.1, 122.1, 121.9, 121.2 – 120.6 (m), 120.1, 119.2 – 119.0 (m), 117.8 – 117.4 (m),
16.2 – 115.8 (m), 115.3 – 114.9 (m), 114.5 – 114.3 (m), 114.1 – 113.9 (m), 113.0, 111.3 – 110.5
-1
(m), 62.3, 57.0, 51.8, 45.8, 30.3 – 29.8(m,); IR (ZnSe): νmax (cm ) 3064, 2326, 1732, 1662, 1600,
1483, 1454, 1197, 1184, 1166, 1143, 1112, 1010, 977, 752, 659, 650, 530; HRMS (ESI-TOF): m/z
+
calcd for C29
H
20
F
17
N
2
O
3
[M+H] 767.1197, found 767.1176.
Anthracen-9-ylmethyl
1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-
carboxylate (Table 2, entry 4j): White solid, yield = 90 mg (59%), dr = 1:3 (cis/trans). mp 149-
1
1
51 °C, isolated from flash chromatography (15% EtOAc/n-hexane); H NMR (600 MHz, CDCl
3
)
δ 8.53 (s, 1H), 8.31 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 7.2 Hz, 2H), 7.61 –
7
1
2
1
.58 (m, 2H), 7.52 – 7.50 (m, 2H), 7.40 – 7.39 (m, 1H), 7.31 – 7.29 (m, 2H), 7.11 (t, J = 7.8 Hz,
H), 6.96 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 7.2 Hz, 1H), 6.87 – 6.84 (m, 1H), 6.28 (d, J = 9.6 Hz,
H), 6.20 (d, J = 12.6 Hz, 1H), 5.76 – 5.74 (m, 1H) 4.70 (s, br, 1H), 4.03 (s, br, 1H), 3.48 (s, br,
1
3
H), 3.34 – 3.29 (m, 1H); C NMR (150 MHz, CDCl ) δ 171.5, 171.2, 142.6, 133.7, 131.5, 131.2,
3
131.1, 129.8, 129.6, 129.3, 128.6, 128.0, 127.4, 127.0, 126.4, 125.7, 125.3, 123.8, 122.53, 122.48,
-1
1
1
13.9, 62.8, 60.0, 51.1, 46.0; IR (ZnSe): νmax (cm ) 3059, 2318, 1726, 1649, 1483, 1446, 1354,
234, 1166, 1132, 887, 732, 719, 694; HRMS (ESI-TOF): m/z calcd for C34
H
27
N
2
O
[M+H]+
3
511.2016, found 511.2020.
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Anthracen-9-ylmethyl
1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-
carboxylate (Table 3, entry 3j): pale yellow solid, yield = 98 mg (64%), dr = 3.5:1 (cis/trans), mp
1
65-68°C, isolated from flash chromatography (20% EtOAc/n-hexane); H NMR (300 MHz,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CDCl ) δ 8.52 (s, 1H), 8.19 (d, J = 8.4 Hz, 2H), 8.06 – 8.03 (m, 2H), 7.73 (d, J = 7.8 Hz, 2H), 7.57
3
–
1
1
–
1
7.49 (m, 4H), 7.41 – 7.36 (m, 1H), 7.30 – 7.26 (m, 2H), 7.07 – 7.02 (m, 1H), 6.96 (d, J = 7.8 Hz,
H), 6.66 – 6.61 (m, 1H), 6.36 (d, J = 6.9 Hz, 1H), 6.22 (d, J = 12.6 Hz, 1H), 5.81 (d, J = 12.3 Hz,
H), 5.74 (d, J = 9.9 Hz, 1H), 5.39 (dd, J = 9.9, 5.1 Hz, 1H), 4.71 (s, br, 1H), 4.12 (s, br, 1H), 3.69
13
3.67 (m, 1H), 3.46 – 3.36 (m, 1H); C NMR (75 MHz, CDCl
3
) δ 172.0, 171.7, 142.5, 133.5,
31.5, 131.3, 131.2, 129.7, 129.4, 129.1, 128.5, 128.0, 127.4, 126.9, 126.7, 126.1, 125.3, 124.2,
-1
122.0, 121.7, 119.6, 112.6, 62.3, 59.2, 51.5, 45.8; IR (ZnSe): νmax (cm ) 3057, 2958, 2852, 2326,
1
730, 1658, 1448, 1313, 1238, 1159, 889, 732, 698, 418; HRMS (ESI-TOF): m/z calcd for
+
C
34
H
27
N
2
O
3
[M+H] 511.2016, found 511.2012.
1-Benzoyl-N-(tert-butyl)-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-carboxamide
(
Table 2, entry 4k): White solid, yield = 74 mg (66%), dr = 1:4.8 (cis/trans), mp 169-172 °C,
1
isolated from flash chromatography (25% EtOAc/n-hexane); H NMR (600 MHz, CDCl
3
) δ 7.78
(
d, J = 7.2 Hz, 2H), 7.39 (s, br, 1H), 7.30 (s, br, 2H), 7.15 – 7.12 (m, 1H), 6.99 – 6.96 (m, 2H),
6
.89 – 6.87 (m, 1H), 6.44 (d, J = 9.6 Hz, 1H), 5.94 (dd, J = 10.2, 5.4 Hz, 1H), 5.49 (s, br, 1H,
NH), 4.51 (s, br, 1H), 4.06 – 4.03 (m, 1H), 3.44 (s, br, 1H), 2.94 (td, J = 9.6, 7.2 Hz, 1H), 1.35 (s,
1
3
9
H); C NMR (150 MHz, CDCl
3
) δ 171.2, 168.9, 143.2, 133.9, 131.0, 129.8, 128.4, 128.0, 127.4,
-1
126.7, 122.6, 122.4, 114.1, 63.3, 53.0, 51.9, 46.9, 28.9; IR (ZnSe): νmax (cm ) 3363, 2966, 2347,
1
664, 1629, 1529, 1454, 1379, 1361, 1263, 1107, 1006, 781, 754, 713, 665, 494; HRMS (ESI-
+
TOF): m/z calcd for C23
H
26
N
3
O
2
[M+H] 376.2020, found 376.2005.
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2
-Cyanoethyl
1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-carboxylate
(
Table 2, entry 4l): yellow oily, yield = 76 mg (68%), dr = 1:4.7 (cis/trans), isolated from flash
1
chromatography (15% EtOAc/n-hexane); H NMR (300 MHz, CDCl
3
) δ 7.80 (d, J = 7.2 Hz, 2H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
.44 – 7.39 (m, 1H), 7.35 – 7.30 (m, 2H), 7.21 – 7.15 (m, 1H), 7.03 (d, J = 7.8 Hz, 2H), 6.93 (td,
J = 7.2, 0.6 Hz, 1H), 6.47 (d, J = 9.9 Hz, 1H), 6.05 (dd, J = 9.9, 5.1 Hz, 1H), 4.69 (s, br, 1H), 4.43
4.26 (m, 2H), 4.06 (s, br, 1H), 3.56 – 3.49 (m, 1H), 3.41 – 3.32 (m, 1H), 2.76 – 2.72 (m, 2H);
–
13C NMR (75 MHz, CDCl
) δ 171.3, 170.8, 142.4, 133.4, 131.3, 129.9, 128.6, 128.1, 127.6, 126.7,
3
-1
1
2
22.74, 122.65, 122.2, 116.6, 113.9, 62.8, 59.6, 50.9, 45.9, 18.1; IR (ZnSe): νmax (cm ) 3067, 2963,
251, 1731, 1643, 1599, 1574, 1483, 1448, 1350, 1235, 1163, 1040, 1000, 777, 759, 695, 662.
+
HRMS (ESI-TOF): m/z calcd for C22
-Cyanoethyl
H
20
N
3
O
3
[M+H] 374.1499, found 374.1516.
2
1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-carboxylate
(
Table 3, entry 3l): yellow oily, yield = 73 mg (65%), dr = 3.5:1 (cis/trans), isolated from column
1
chromatography (27% EtOAc/n-hexane); H NMR (300 MHz, CDCl
3
) δ 7.79 (d, J = 7.5 Hz, 2H),
7
.45 – 7.40 (m, 1H), 7.35 – 7.30 (m, 2H), 7.23 – 7.18 (m, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.93 (d, J
=
6.0 Hz, 1H), 6.87 (t, J = 7.2 Hz, 1H), 6.50 (d, J = 9.9 Hz, 1H), 5.89 (dd, J = 9.9, 5.1 Hz, 1H),
4
1
1
4
.68 (s, br, 1H), 4.29 (s, br, 1H), 4.18 – 4.10 (m, 1H), 3.96 – 3.89 (m, 1H), 3.68 (d, J = 6.6 Hz,
1
3
H), 3.49 – 3.42 (m, 1H), 2.46 – 2.25 (m, 2H); C NMR (75 MHz, CDCl
3
) δ 172.0, 171.1, 142.8,
33.4, 131.4, 130.2, 128.5, 128.1, 127.8, 127.1, 122.1, 121.9, 120.1, 116.8, 113.0, 62.2, 59.4, 51.4,
-1
5.8, 17.9; IR (ZnSe): νmax (cm ) 2957, 2923, 2852, 2251, 1737, 1643, 1599, 1575, 1484, 1454,
[M+H]+
1448, 1352, 1258, 1165, 908, 726, 694, 647; HRMS (ESI-TOF): m/z calcd for C22
H
20
N
3
O
3
3
74.1499, found 374.1490.
-Benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinolin-3-yl)(morpholino)methanone
1
(Table 2, entry 4m): White solid, yield = 82 mg (70%), dr = 1:8.5 (cis/trans), mp 152 °C, isolated
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from flash chromatography (25% EtOAc/n-hexane); H NMR (600 MHz, CDCl
3
) δ 7.79 (d, J =
6
.6 Hz, 2H), 7.39 (s, br, 1H), 7.30 (s, br, 2H), 7.15 (t, J = 7.2 Hz, 1H), 6.99 (d, J = 6.6 Hz, 2H),
6.90 (t, J = 7.2 Hz, 1H), 6.42 (d, J = 9.6 Hz, 1H), 5.97 (dd, J = 9.0, 4.8 Hz, 1H), 4.41 (s, br, 1H),
1
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
.35 (dd, J = 9.0, 4.8 Hz, 1H), 3.66 – 3.62 (m, 6H), 3.55 (br s, 1H) 3.40 (s, br, 3H); C NMR (150
MHz, CDCl ) δ 171.1, 168.9, 143.2, 133.7, 131.1, 129.7, 128.5, 127.9, 127.4, 126.5, 123.3, 122.7,
3
-1
1
2
22.5, 113.9, 66.8, 66.7, 62.4, 47.8, 46.6, 46.2, 42.6; IR (ZnSe): νmax (cm ) 3063, 2968, 2368,
326, 1942, 1656, 1627, 1483, 1438, 1369, 1271, 1240, 1116, 1051, 885, 763, 731, 698, 657;
+
HRMS (ESI-TOF): m/z calcd for C23
H
24
N
3
O
3
[M+H] 390.1822, found 390.1819.
Cyclohexyl 1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-carboxylate (Table
2, entry 4n): yellow solid, yield = 81 mg (67%), dr = 1:5 (cis/trans), mp 101 °C, isolated from flash
1
chromatography (20% EtOAc/n-hexane); H NMR (600 MHz, CDCl
3
) δ 7.81 (d, J = 7.2 Hz, 2H),
7
.40 (d, J = 6.6 Hz, 1H), 7.32 (s, br, 2H), 7.17 – 7.14 (m, 1H), 7.01 – 6.99 (m, 1H), 6.92 – 6.89
(m, 2H), 6.44 (d, J = 9.6 Hz, 1H), 6.01 – 5.98 (m, 1H), 4.84 (s, br, 1H), 4.64 (s, br, 1H), 4.05 (s,
br, 1H), 3.53 (s, br, 1H), 3.32 – 3.28 (m, 1H), 1.83 (s, br, 2H), 1.75 – 1.61 (m, 2H), 1.58 – 1.51 (m,
13
1
H), 1.48 – 1.43 (m, 2H), 1.41 – 1.35 (m, 2H), 1.32 – 1.28 (m, 1H); C NMR (150 MHz, CDCl
3
)
δ 171.1, 170.6, 142.8, 133.8, 131.2, 129.8, 128.6, 128.0, 127.4, 126.3, 122.8, 122.5, 113.9, 73.9,
-1
6
1
2.7, 51.2, 46.0, 31.61, 31.55, 25.4, 23.65, 23.63; IR (ZnSe): νmax (cm ) 2935, 2858, 1726, 1653,
483, 1452, 1373, 1357, 1226, 1186, 1001, 759, 694, 663; HRMS (ESI-TOF): m/z calcd for
+
C
25
H
27
N
2
O
3
[M+H] 403.2016, found 403.2023.
Cyclohexyl 1-benzoyl-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-carboxylate (Table
3
, entry 3n): light yellow solid, yield = 59 mg (49%), dr = 3:1 (cis/trans), mp 121°C, isolated from
1
flash chromatography (25% EtOAc/n-hexane); H NMR (300 MHz, CDCl
3
) δ 7.79 (d, J = 7.2 Hz,
2H), 7.42 (t, J = 7.2 Hz, 1H), 7.32 (t, J = 7.2 Hz, 2H), 7.17 (t, J = 7.2 Hz, 1H), 7.04 (d, J = 7.8 Hz,
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