Stereoselective annulation between an allene, an alkene, and two nitrosoarenes to access bis(isoxazoliodine) derivatives

Article abstract of DOI:10.1039/c7ob02087b

This work reports metal-free annulations between one allene, two nitrosoarenes and one electron-deficient alkene to afford bis(isoxazolidine) derivatives stereoselectively. This process involves an initial formation of isoxazolidin-4-imine oxides, followe

Full text of DOI:10.1039/c7ob02087b

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ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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DOI: 10.1039/C7OB02087B
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ARTICLE
Stereoselective annulation between an allene, an alkene, and two
nitrosoarenes to access bis(isoxazoliodine) derivatives
Pankaj Sharma,a† Prakash D. Jadhav,a† Manisha Skaria,a and Rai-Shung Liua,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Abstract: This work reports metal-free annulations between one allene, two nitrosoarenes and one electron-deficient
alkene to afford bis(isoxazolidine) derivatives stereoselectively. This process involves an initial formation of isoxazolidin-4-
imine oxides, followed by their dipolar [3+2]-cycloaddition with electron-deficient alkenes. To highlight the utility, the
annulations of 5-alleneyl-1-enes with nitrosoarenes were also feasible to afford desired bis(isoxazolidine) products with
excellent stereocontrol. Resulting bis(isoxazolidine) products produced from two systems were reduced with Zn/MeOH to
induce reductive N-O cleavages, yielding branched polyaminols stereoselectively.
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Introduction
Radical annulations via diradical intermediates are well
documented in the literatures, but their utilities are poorly
explored.1 Diradical annulations typically employ hazardous
diazo2-3 and special precursors,4 thus lacking general utility.
Although commonly used π-bond motifs generate diradicals
thermally, as exemplified with Bergman (eq 1) and Myers-Saito
reactions, their utility is restricted to intramolecular
aromatizations.5 The formation of reactive 1,n-diradicals from
readily available alkenes, alkynes, and allenes to enable
diverse annulations is highly desirable in synthetic chemistry.
Nitrosoarenes are powerful reagents for the N,O-
functionalizations of dienes, and alkynes via Lewis acid-
catalyzed annulatios.6-7 Theoretical calculations by Houk8,9
suggest that the reactions of nitrosoarenes with alkenes or
alkynes likely generate 1,4-diradicals
, which cannot be
synthetically utilized because of their transient nature. In the
context of arylallenes, we recently reported10 their reactions
with nitrosoarenes to generate 1,4-diradical species
were detectable by EPR (eq 2). Such 1,4-diradicals
trapped by ground-state O2 to yield 1,2-dioxolanes
oC (eq 2); otherwise, diradicals
to yield isoxazolidin-4-imine oxides
I that
can be
I
3
below 0
accept a second nitrosoarene
(eq 3).
generates isoxazolidin-4-imine oxides
their dipolar [3+2]-cycloadditions with electron-deficient
alkenes. Importantly, the reductive N-O cleavage of resulting
4 initially, followed by
I
4
To expand the utility of such 1,4-diradicals, this work10
reports one-pot annulations between one allene, two
nitrosoarenes and one olefin, yielding bis(isoxazolidine)
bis(isoxazolidine) species
4 provides branched polyaminols
with high stereocontrol. Notably, readily available 5-allenyl-1-
enes were treated with nitrosoarenes under ambient
species 5 with high stereoselectivity. This reaction sequence
conditions
to
yield
bis(isoxazolidine)
derivatives
stereoselectively, further highlighting the synthetic utility.
Many bioactive molecules comprise not only one nitroxy
ring, but also amino and alcohol functionalities; selected
examples I-
VI are depicted in Figure 1.11 A rapid synthesis of
these highly N,O-functionalized molecules is synthetically
challenging. We envisage that one-pot stereoselective
construction of a bicyclic ring bearing two N-O moieties is a
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group decreases their cycloaddition reactivity. TVhieewmArtoiclleecOunllianer
DOI: 10.1039/C7OB02087B
structure of compound 5a was confirmed with X-ray
diffraction.12 An analysis of this X- ray structure revealed a
preferable exo-3,5-cycloaddition of the alkene with E-
configured 4a; the nitrone oxygen is linked at the
C-CO2Et
carbon. This 3,5-regioselectivity (eq 5) typically occurs with
unsubstituted enol ethers13 and substituted electron-deficient
alkenes such as ethyl E-but-2-enolate.14 Unsubstituted 2-en-1-
ones and 2-en-1-als preferable afford 3,4-regioisomers
instead. Our 3,5-regioselectivity is rationalized with a steric
effect such that a large isoxazolidine ring is preferably attacked
with an alkene end to result in a 3,5-regioselectivity. The
overlap between nitrone and alkene is controlled by a less
hindered exo-face with the alkene lying away the phenyl
Figure 1. Representatives of several bioactive molecules
group, as depicted in TS-1 or TS-1’
. The feasible Z-E
viable route. In this work, a successive N-O cleavage of two
isomerization of isoxazolidin-4-imine oxide 4a indicates the
contribution of an alternative resonance form, as in state TS-
nitroxy rings of resulting bis(isoxazolidine) products
polyaminols is also described.
5 to afford
1
’, in which the negative carbon terminus is stabilized with the
adjacent oxygen and nitrogen atoms. Our next aim was to
achieve a one-pot operation involving an initial treatment of
allene 1g with nitrosobenzene 2a (4 equiv) in cold THF (0 C, 3
Results and Discussion
o
Unlike 1,2-dioxolanes
isoxazolidin-4-imine oxides
[3+2]-cycloadditions with
3
,
the nitrone functionality of
can undergo intermolecular
electron-deficient alkenes
h) to complete the consumption of allene 1a; to this resulting
4
Table 1. One-pot synthesis of bicyclic isoxazolidines.
stereoselectively. Compound 4a was prepared in two isomeric
ratios, E/Z = 1/1 and E/Z = 15/1, respectively at 25 C and 0 oC,
o
according to eq 3. To exploit the alkene cycloaddition, an E/Z
=1:1 mixture of compound 4a was treated with ethyl acrylate
to afford bis(isoxazolidine) compound 5a as a single
diastereoisomer (dr > 20:1, 12 h, eq 5). This diastereoisomer
was obtained efficiently also from the E-form of initial 4a, but
in a comparatively shorter reaction time (6 h). Accordingly, the
E-isomer of nitrone 4a is much more active than its Z-
analogue, whereas the less reactive Z-form isomerized
completely to its E-isomer during this cycloaddition. For the Z-
isomer, a steric interaction between the acrylate and phenyl
a
[1
] = 0.16 M; bIn entry 1, this ratio was obtained on heating the crude
products with DBU (20 mol%) in hot THF (60 oC, 5 h); the dr ratio of this
crude product is 44:44;6:6; cProduct yields are reported after purification
from a silica column.
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solution was added ethyl acrylate (4 equiv) to complete an
alkene/nitrone cycloaddition (eq. 6).
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DOI: 10.1039/C7OB02087B
We investigated the scope of these new cascade
[3+2]/[3+2]-annulations using nitrosobenzene, various allenes
and electron-deficient olefins such as enones and acrylates;
the results are summarized in Table 1. Styrenes failed with
these reactions. Herein, resulting products 5b
stereochemical course like that of parent species 5a. Among
compounds 5a and 5b 5f, their major or single diastereomeric
products have similar H NMR patterns, indicative of the same
stereochemistry. This hypothesis is confirmed by X-ray
diffraction12 of alcohol 5c’ derived from compound 5c. For
-5j followed a
-stereomer (eq 9). The stereochemical course of these N-O
annulations, as depicted in TS-2, is exactly the same as those
-
1
(TS-1) in their intermolecular fashions. The molecular
structures of this annulation product 8a was elucidated by X-
ray diffraction.12
phenylallene 1a, their N-O annulation products
to purify, but were trapped with unsaturated esters and
ketones to afford bis(isoxazolidine) species 5b 5d in
4 were difficult
The scope of this intramolecular four-component
annulation was compatible with various nitrosoarenes (2b-2f)
to yield desired bis(isoxazolidine) species 8b-8f as single
diastereomers; the results are summarized in Table 2. Herein,
products 8a-8e were obtained in 52-68% yields because their
frameworks are very strained with three five-membered rings
-
satisfactory diastereoselectivity (dr = 4.2:1 and 6.1:1). In entry
1, crude product 5b was obtained in four diastereomers with a
ratio 44:44:6:6; these isomeric mixtures were subsequently
converted to two diastereomers in a ratio 4.2:1 through a
DBU-catalyzed epimerization. For 3-phenyl, methyl and n-
fused together. For nitrosobenzenes 2b–2d bearing electron-
withdrawing (-Cl, -Br) and electron donating (-CH3) groups at
butyl-substituted
phenylallenes,
their
resulting
bis(isoxazolidine) compounds 5h
-
5k were obtained with
Table 2. Annulations with various nitrosoarenes
.
satisfactory yields and high diastereoselectivities in most
instances (entries 7-9).
a
b
[
7a] = 0.10 M, [2] = 4 equiv; Product yields are reported after purification
from a silica column.
For bis(isoxazolidine) 6a, one of the two the isoxazolidine
rings was selectively cleaved with H2. An initial treatment of
this species with LiAlH4 (3 equiv) afforded crude alcohol 6a
that was further reduced with Pd/C/H2 (1 bar) in MeOH (23 oC)
to yield monocyclic isoxazolidine 6a-H as a single diastereomer
(dr > 20:1, eq 7). In this transformation, the alcohol of 6a is
coordinated on the Pd surface to facilitate a reductive cleavage
of its proximate isoxazolidine ring. To achieve a cleavage of
two N-O rings, we treated compounds 5a and 5i with Pd/C/H2
(1 bar)15 in MeOH under reflux (5 h) to produce the
corresponding lactams 5a-H and 5i-H efficiently; the molecular
structure of compound 5a-H was characterized with x-ray
diffraction (eq 8).12
the para-phenyl positions, their reactions with 1-allenyl-5-ene
7a yielded desired products 8b–8d in 61–68 % yields (entries
1–3). Under similar conditions, ortho and meta-substituted
chlorophenyl nitroso species 2e and 2f yielded desired
bisisoxazolidines 8e and 8f in 52 % yields (entries 4-5).
We expanded the scope of this cascade annulation with
various 1-allenyl-5-enes under optimum conditions. Table 3
(entry 1) shows the suitability of this annulation reaction for
substrates 7b bearing a trans-propenyl (R4 = Me, R3 = H),
yielding desired 8g in 67 % yield; the two trans-CH-CHMe
protons of compound 8g are indicated from the 1H NOE
experiments. Such a stereochemistry is consistent with typical
alkene/nitrone cycloadditions through a concerted pathway.17
The reaction scope was extendible to additional substrates 7c
and 7d bearing different alkyl and aryl substituents (R1= Me,
R3= R4= Me; R1= Ph, R2= H, R3= R4= Me), yielding desired
The utility of these cascade annulations is significantly
expanded by their applicability to readily available 1-allenyl-5-
ene 7a,16 which reacted well with nitrosobenzene (4 equiv) in
THF (25 oC, 1 h) to afford azacyclic product 8a as a single dia-
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products 8h and 8i in 60–70 % yields (entries 2 and 3); herein, observed one diastereomeric product for compound 9b
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DOI: 10.1039/C7OB02087B
compound 8i was present as a mixture of two diastereomers bearing a 4-ClC6H4NH group.
(dr = 4:3). The sterically hindered substrate 7e (R1=R2=R3=R4=
CH3) was also compatible to this annulation reaction; thus
Conclusions
giving the desired azacyclic product 8j in good yield (60 %,
Stereoselective annulations between one allene, two
entry 4). For substrate bearing long chain alkyl group 7f (R1= n-
nitrosoarenes and one electron-deficient alkene have been
Butyl, R2=H, R3=R4= CH3); their corresponding product 8k was
developed to yield bis(isoxazolidine) derivatives with high
obtained in 51 % yield (entry 5). To enhance the further
stereoselectivities. This reaction sequence involves an initial
reaction scope, we synthesized additional
formation of isoxazolidin-4-imine oxides, followed by their
dipolar [3+2]-cycloaddition with electron-deficient alkenes.
Table 3. Annulations with various 5-allenyl-1-enes.
Herein, exo-3,5-cycloadditions between isoxazolidin-4-imine
oxides
4 and alkenes control the reaction stereoselectivity. To
highlight the utility, the annulations of 5-alleneyl-1-enes with
two nitrosoarenes were also tested, and bis(isoxazolidine)
products were produced with excellent stereocontrol.
Resulting bis(isoxazolidine) species derived from two distinct
systems were reduced with Zn/MeOH to induce reductive N-O
cleavages, yielding branched polyaminols stereoselectively.
Experimental section
General Remarks
Unless otherwise noted, all reactions were carried out under a
N2 atmosphere in reaction tube. Tetrahydrofuran was dried
with sodium and benzophenone and distilled before use.
Reagents were purchased from commercial sources and used
without purification, unless otherwise stated. Reactions were
magnetically stirred and monitored by thin layer
chromatography carried out on 0.25 mm E. Merck silica gel
plate (60f- 254) using UV light as visualizing agents and/or
potassium permanganate (KMnO4). 1H NMR and 13C NMR
spectra were recorded on a Bruker 400 MHz, Varian 400 MHz,
Varian 500 MHz, Varian 600 and Varian 700 MHz
spectrometers using chloroform-d (CDCl3) as the internal
standard.
a
[7] = 0.10 M, [2
] = 4 equiv; bProduct yields are reported after purification
from a silica column.
substrate 7g (R= Me); thus giving the desired product in 55%
yield (entry 6).
Shown in eqs 10-11 are the reductive N-O cleavage of
resulting bis(isoxazolidine) species 8a and 8b via treatment
with Zn (20 equiv) in AcOH/MeOH/H2O at room
temperatures,18 yielding highly functionalized aminoalcohols
8a-H and 8b-H in 85% and 87% yields respectively. Two
diastereomers were obtained for compounds 8a-H because of
an epimerization at the tertiary carbon center. We only
Standard procedure for synthesis of 5a:
A 10-mL flask was charged with nitrosobenzene 2a (0.446 g,
4.17 mmol) under N2, and added with dry THF (3 mL); the
resulting solution was cooled to 0 oC. To this solution was
added a dry THF solution (3.5 mL) of compound 1g (0.2 g, 1.04
mmol) before it was stirred for 3 h. To this solution was added
ethyl acrylate (0.417 g, 4.17 mmol, 4 equiv); the resulting
o
mixture was stirred for 12 h at 0 C. The solution was then
concentrated under reduced pressure, and purified on a silica
column (10% ethylacetate/hexane, Rf
= 0.7 in 20%
ethylacetate/hexane) to afford compound 5a (0.44g, 0.885
mmol, 85%) as white solid.
Standard procedure for synthesis of 6a-H:
To a suspension of LiAlH4 (0.023g, 0.592 mmol), in dry THF (10
mL) was added a solution of ethyl (3S,5R,6S,9S)-1,6,8,9-
tetraphenyl-2,7-dioxa-1,8-diazaspiro-[4.4]nonane-3-arboxylate
o
5a (100 mg, 0.197 mmol) in THF (2 mL) at 0 C. After stirring at
room temperature for 3 h, the reaction was quenched by the
ο
careful addition of water at 0 C, then filtered through a celite
bed, dried over anhydrous MgSO4, and concentrated to afford
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crude ((3S,5R,6S,9S)-1,6,8,9-tetraphenyl-
diazaspiro[4.4]nonan-3-yl)methanol 6a as colorless liquid. To a Hz, 2H), 4.86 (t, J =8.0 Hz, 1H), 4.76 (s, 1H), 4.33 (d, J =9.6 Hz,
methanol (3 mL) solution of 6a was added to a suspension of 1H), 4.10 (d, J =9.6 Hz, 1H) other protons are merged; 13C NMR
10% Pd/C (20.0 mg) in methanol (10 mL); the mixture was (100 MHz, CDCl3); δ 128.1, 121.3, 116.1 other carbons are
stirred under H2 (1 atm) at room temperature for 5 h. After a merged or not clearly visible; ESI- MS calc for C30H26N2O3Na
complete consumption of 6a, the solution was filtered through (M+Na): 485.1841, found: 485.1836.
ARTICLE
2,7-dioxa-1,8- NMR (400 MHz, CDCl3); δ 6.88 (t, J =7.2 Hz, 2H), 6.74 (d, J =8.0
View Article Online
DOI: 10.1039/C7OB02087B
a celite bed, concentrated, and the residues were purified by a
Spectral Data of Compound 5c’: 1H NMR (500 MHz, CDCl3); δ
flash silica column using 20% ethyl acetate/hexane as eluents,
7.41-7.36 (m, 7H), 7.28-7.22 (m, 8H), 7.19-7.04 (m, 7H), 6.97-
to give 6a-H (0.072 g, 0.142 mmol, 78%) as pale yellow liquid.
6.92 (m, 3H), 5.42 (s, 1H), 4.36 (t, J =7.5 Hz, 1H), 4.21 (d, J
Standard procedure for synthesis of 8a:
=10.5 Hz, 1H), 3.40 (d, J =10.5 Hz, 1H), 3.28 (bs, 1H), 2.44 (dd, J
=13.0, 8.0 Hz, 1H), 2.10 (dd, J =13.0, 7.0 Hz, 1H); 13C NMR (125
MHz, CDCl3); δ 150.0, 145.8, 145.5, 143.4, 136.2, 128.8, 128.8,
128.3, 128.3, 128.1, 128.1, 127.4, 127.1, 126.9, 126.8, 125.3,
124.0, 122.1, 119.6, 115.2, 82.4, 80.6, 78.6, 78.1, 62.5, 40.6;
ESI-MS calcd for C36H33N2O3 [M+H]: 541.2491, found:
541.2481.
To a dry THF solution (1 mL) of 1-(buta-1,2-dien-1-yl)-2-
vinylbenzene 7a (0.1 g, 0.588 mmol) was added a dry THF
solution (2 mL) of nitrosobenzene (0.25 g, 2.35 mmol, 4.0
equiv); the mixture was stirred at room temperature for 1 h,
and evaporated under reduced pressure. The crude mixture
was purified on a silica gel column (5% ethylacetate/hexane, Rf
= 0.8) to afford compound 8a (0.161 g, 0.43 mmol, 68%
light brown solid.
)
as Spectral Data of Compound 5d: 1H NMR (600 MHz, CDCl3); dr
= 9.8:1; Major isomer; δ 7.31-7.22 (m, 7H), 7.17-7.15 (m, 2H),
7.13-7.10 (m, 2H), 7.01-6.96 (m, 3H), 5.35 (s, 1H), 4.20 (d, J
=10.6 Hz, 1H), 3.97-3.95 (m, 1H), 3.45 (d, J =10.6 Hz, 1H), 2.53-
2.49 (m, 1H), 2.43-2.40 (m, 1H), 2.33 (s, 3H), 2.26 (s, 3H); 13C
NMR (150 MHz, CDCl3); δ 209.2, 149.9, 145.6, 138.1, 133.6,
129.1, 128.8, 127.1, 124.9, 122.2, 120.7, 115.3, 81.9, 80.4,
80.1, 63.0, 40.9, 26.1, 21.2 one carbon merge with others;
Spectral Data of Compound 5a: 1H NMR (400 MHz, CDCl3); δ
7.59 (d, J =7.6 Hz, 2H), 7.27 (t, J =6.8 Hz, 2H), 7.22 (d, J =6.8 Hz,
1H), 7.18-7.11 (m, 5H), 7.07-7.04 (m, 3H), 6.95 (d, J =8.4 Hz,
2H), 6.86 (t, J =7.2 Hz, 1H), 6.81 (d, J =8.0 Hz, 2H), 6.55 (d, J
=7.2 Hz, 2H), 5.44 (s, 1H), 4.82 (s, 1H), 4.68 (dd, J =10.0, 4.0 Hz,
1H), 4.14-4.07 (m, 2H), 2.68 (dd, J =9.5, 4.0 Hz, 1H), 2.45-2.39
(m, 1H), 1.18 (t, J =7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3); δ
170.4, 148.7, 147.2, 136.7, 136.1, 129.8, 128.6, 128.6, 128.1,
128.1, 127.8, 127.8, 127.7, 125.5, 122.5, 122.1, 116.5, 82.2,
79.3, 77.1, 76.8, 61.7, 41.1, 14.0; ESI-MS calcd for
C32H30N2NaO4 [M+Na]: 529.2103, found: 529.2105.
1
Minor isomer; H NMR (600 MHz, CDCl3); δ 6.83-6.80 (m, 2H),
6.62-6.60 (m, 3H), 4.58 (s, 1H), 4.41 (d, J =9.6 Hz, 1H) other
protons are merged; 13C NMR (150 MHz, CDCl3); 129.7, 128.5,
128.3, 127.9, 122.5, 120.5, 116.4, 79.1, 72.4, 72.1, 39.4 other
carbons merged or not visible; ESI-MS calcd for C26H27N2O3
[M+H]: 415.2022, found: 415.2016.
Spectral Data of Compound 5b: 1H NMR (600 MHz, CDCl3); dr
= 4.2:1; Major isomer; δ 7.30-7.29 (m, 3H) 7.28-7.26 (m, 3H),
7.25-7.24 (m, 2H), 7.23-7.20 (m, 4H), 7.18-7.16 (m, 3H), 5.34 (s,
1H), 4.33-4.32 (m, 1H), 4.28 (d, J =10.8 Hz, 1H), 4.21-4.18, (m,
2H), 3.41 (d, J =10.8 Hz, 1H), 2.46-2.37 (m, 2H), 1.28-1.25 (m,
3H); 13C NMR (150 MHz, CDCl3); δ 170.9, 150.0, 146.0, 136.4,
128.9, 128.8, 128.5, 128.4, 127.1, 125.7, 122.2, 122.1, 115.2,
Spectral Data of Compound 5e: 1H NMR (600 MHz, CDCl3); δ
7.33-7.25 (m, 8H), 7.22 (d, J =8.3 Hz, 2H), 7.14-7.12 (m, 1H),
7.01-6.97 (m, 3H), 5.36 (s, 1H), 4.19 (d, J =10.6 Hz, 1H), 3.99-
3.97 (m, 1H), 3.47 (d, J =10.6 Hz, 1H), 2.49-2.42 (m, 2H), 2.27
(s, 3H); 13C NMR (150 MHz, CDCl3); δ 209.0, 149.6, 145.4,
135.4, 134.1, 128.9, 128.9, 128.7, 128.5, 125.0, 122.4, 120.6,
115.4, 81.2, 80.2, 79.9, 63.0, 40.8, 26.1; ESI-MS calcd for
C25H24ClN2O3 [M+H]: 435.1475, found: 435.1477.
1
82.0, 80.8, 74.7, 63.2, 61.6, 41.5, 14.2; Minor isomer; H NMR
(600 MHz, CDCl3); δ 7.35-7.31 (m, 3H), 7.30-7.29 (m, 3H), 7.25-
7.24 (m, 2H), 7.16-7.13 (m, 3H), 6.67-6.65 (m, 3H), 4.64 (s, 1H), Spectral Data of Compound 5f: 1H NMR (700 MHz, CDCl3); dr =
4.33 (d, J =3.8 Hz, 1H), 4.21-4.18, (m, 2H), 4.19 (d, J =10.8 Hz, 9:1; Major isomer; δ 7.31-7.23 (m, 6H), 7.19-7.17 (m, 2H),
1H), 2.46-2.37 (m, 2H), 1.25-1.23 (m, 3H) other protons are 7.13-7.09 (m, 1H), 7.00-6.96 (m, 3H), 6.86-6.83 (m, 2H), 5.33
merged; 13C NMR (150 MHz, CDCl3); δ 149.6, 129.0, 128.6, (d, J =2.2 Hz, 1H), 4.21 (dd, J =18.5, 3.5 Hz, 1H), 3.98-3.94 (m,
128.1, 128.0, 125.4, 122.5, 121.6, 116.1, 73.7, 73.0, 72.5, 40.1 1H), 3.79 (d, J =3.7 Hz, 3H), 3.45 (dd, J =18.6, 3.2 Hz, 1H), 2.52-
other carbons are merged or not visible; EI+-MS calcd for 2.48 (m, 1H), 2.45-2.40 (m, 1H), 2.26 (d, J =3.9 Hz, 3H); 13C
C26H26N2O4[M+]: 430.1893, found: 430.1887.
NMR (175 MHz, CDCl3); δ 209.1, 159.5, 149.9, 145.7, 128.8,
128.5, 128.4, 124.9, 122.2, 120.7, 115.3, 113.8, 81.8, 80.3,
80.1, 63.0, 55.2, 40.8, 26.1 one carbon is merged; Minor
Spectral Data of Compound 5c: 1H NMR (400 MHz, CDCl3); dr =
6.1:1; Major isomer; δ 7.83 (d, J =7.6 Hz, 2H), 7.56-7.51 (m,
1H), 7.43-7.34 (m, 7H), 7.29-7.19 (m, 7H), 7.12 (t, J =7.6 Hz,
1H), 6.97 (d, J =8.4 Hz, 2H), 5.44 (s, 1 H), 4.93-4.89 (m, 1H),
4.13 (d, J =10.8 Hz, 1H), 3.41 (d, J = 10.8 Hz, 1H), 2.70-2.65 (m,
1H), 2.50-2.45 (m, 1H); 13C NMR (100 MHz, CDCl3); δ 195.2,
150.0, 146.4, 136.4, 134.8, 133.7, 129.1, 128.8, 128.6, 128.5,
127.3, 125.4, 122.1, 121.6, 115.2, 83.3, 81.4, 78.1, 62.8, 39.9
1
isomer; H NMR (700 MHz, CDCl3) δ 6.61 (d, J =14.0 Hz, 3H),
4.55 (d, J =2.4 Hz, 1H), 4.43 (dd, J =17.2, 3.4 Hz, 1H), 3.80 (d, J
=4.1 Hz, 3H), 2.37-2.32 (m, 2H), 2.25 (d, J =3.9 Hz, 3H) other
protons are merged; 13C NMR (175 MHz, CDCl3); δ 129.2,
128.6, 128.3, 122.6, 120.5, 116.6, 114.3, 82.1, 72.2, 39.5, 25.8
other carbons merged or not visible; ESI-MS calcd for
C26H26N2O3Na [M+Na]: 453.1790, found: 453.1795.
1
two aromatic carbons merges with others; Minor isomer; H
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
Spectral Data of Compound 5g: 1H NMR (400 MHz, CDCl3); δ 6.69 (t, J =7.2 Hz, 1H), 6.41 (d, J =8.0 Hz, 2H), 5.84 V(biesw,A1rtHicl)e,O5n.l2in4e
7.62 (d, J =7.62 Hz, 2H), 7.38-7.33 (m, 2H), 7.28-7.26 (m, 2H), (d, J =4.6 Hz, 1H), 4.75 (d, J =2.4 Hz, 1H), D3O.3I4: 1(0b.1s0,319H/C)7,O2B.90220(8b7sB,
7.20-7.12 (m, 7H), 7.09 (d, J =8.4 Hz, 2H), 7.04-7.01 (m, 2H), 1H), 2.38 (t, J =8.8 Hz, 1H), 2.04-1.98 (m, 2H); 13C NMR (150
6.99-6.95 (m, 1H), 6.67 (d, J =8.0 Hz, 2H), 5.37 (s, 1H), 4.47 (s, MHz, CDCl3); δ 177.6, 146.2, 139.5, 138.8, 138.3, 129.7, 129.4,
1H), 4.25-4.21 (m, 1H), 2.44-2.39 (m, 1H), 2.18-2.14 (m, 1H), 129.1, 129.0, 129.0, 128.6, 128.5, 128.0, 118.7, 114.7, 83.5,
2.12 (s, 3H); 13C NMR (100 MHz, CDCl3); δ 206.2, 148.9, 147.2, 70.1, 67.1, 63.9, 39.9 two carbon merged with others; ESI-MS
136.3, 136.1, 129.8, 128.7, 128.6, 128.4, 128.4, 128.2, 128.2, calcd for C30H29N2O3 [M+H]: 465.2178, found: 465.2179.
127.8, 125.6, 123.3, 123.3, 117.9, 83.0, 82.0, 80.7, 80.6, 40.5,
Spectral Data of Compound 5i-H: 1H NMR (600 MHz, CDCl3); δ
27.5; EI-MS calcd for C31H28N2NaO3 [M+Na]: 499.1998, found:
7.48-7.43 (m, 5H), 7.39 (d, J =7.0 Hz, 2H), 7.33-7.29 (m, 3H),
499.2004.
7.18-7.16 (m, 2H), 6.80 (t, J =6.9 Hz, 1H), 6.46 (d, J =7.9 Hz, 2H),
Spectral Data of Compound 5h: 1H NMR (600 MHz, CDCl3); dr 5.37 (d, J =7.0 Hz, 1H), 4.64 (bs, 1H), 4.49-4.46 (m, 1H), 4.08 (d,
= 2.5:1; Major isomer; δ 7.73-7.71 (m, 3H), 7.62 (d, J =7.9 Hz, J =6.1 Hz, 1H), 3.6 (d, J =9.9 Hz, 1H), 3.41 (bs, 1H), 2.31-2.27
1H), 7.44-7.36 (m, 5H), 7.28-7.26 (m, 3H), 7.23-7.20 (m, 1H), (m, 1H), 2.04-2.00 (m, 1H), 1.20 (d, J =6.4 Hz, 3H); 13C NMR
7.13-7.02 (m, 15H), 6.94 (d, J =8.0 Hz, 2H), 6.86-6.84 (m, 1H), (150 MHz, CDCl3); δ 176.8, 145.1, 140.0, 138.7, 129.5, 129.4,
6.67 (d, J =7.5 Hz, 2H), 6.54 (d, J =7.6 Hz, 1H), 5.54 (s, 1H), 5.20- 129.4, 128.7, 128.4, 128.1, 119.8, 114.9, 80.8, 71.6, 68.1, 54.6,
5.18 (m, 1H), 4.61 (s, 1H), 3.00 (dd, J =13.4, 5.2 Hz, 1H), 2.47- 36.9, 15.4; ESI-MS calcd for C25H27N2O3 [M+H]: 403.2022,
2.39 (m, 1H); 13C NMR (150 MHz, CDCl3); δ 195.2, 148.6, 147.4, found: 403.2021.
136.9, 135.6, 134.6, 133.6, 129.9, 129.4, 128.8, 128.6, 128.6,
Spectral Data of Compound 6a-H: 1H NMR (600 MHz, CDCl3); δ
128.5, 128.4, 128.2, 127.7, 125.1, 124.5, 122.0, 117.5, 83.0,
7.66 (d, J =7.5 Hz, 2H), 7.41-7.38 (m, 2H), 7.36-7.34 (m, 3H),
1
81.4, 79.7, 78.2, 40.2 one carbon merged; Minor isomer; H
7.32-7.30 (m, 3H), 7.18 (t, J =7.5 Hz, 2H), 6.99 (dd, J =8.0, 1.0
NMR (600 MHz, CDCl3); δ 5.32 (s, 1H), 4.88-4.85 (m, 1H), 4.41
Hz, 2H), 6.95 (t, J =7.7 Hz, 2H), 6.92-6.89 (m, 1H), 6.32 (d, J =8.5
(s, 1H), 2.26-2.23 (m, 1H) other protons are merged; 13C NMR
Hz, 2H), 5.51 (s, 1H), 5.24 (s, 1H), 4.02 (bs, 1H), 3.67-3.65 (m,
(150 MHz, CDCl3); δ 194.6, 149.0, 147.6, 136.5, 136.2, 135.2,
1H), 3.10-3.04 (m, 2H), 1.99-1.91 (m, 2H); 13C NMR (150 MHz,
133.8, 130.1, 129.2, 128.3, 128.1, 127.8, 126.1, 123.6, 122.8,
CDCl3); δ 149.3, 144.8, 137.1, 136.5, 129.3, 128.9, 128.8, 128.8,
118.3, 84.0, 81.2, 80.8, 78.9, 38.9 other carbons merged or not
128.6, 128.4, 128.2, 121.8, 118.8, 117.1, 116.1, 86.3, 77.6,
visible; ESI-MS calcd for C36H30N2NaO3 [M+Na]: 561.2154,
71.5, 68.8, 66.9, 31.2 one carbon merged with others; ESI-MS
found: 561.2153.
calcd for C30H31N2O3 [M+H]: 467.2335, found: 467.2334.
Spectral Data of Compound 5i: 1H NMR (600 MHz, CDCl3); δ
Spectral Data of Compound 8a: 1H NMR (600 MHz, CDCl3); δ
7.50-7.48 (m, 2H), 7.38-7.35 (m, 4H), 7.27-7.26 (m, 2H), 7.21-
7.53-7.51 (m, 2H), 7.38-7.35 (m, 1H), 7.33 (d, J =7.5 Hz, 1H),
7.20 (m, 3H), 7.14-7.11 (m, 2H), 6.91-6.90 (m, 2H), 5.48 (s, 1H),
7.30-7.27 (m, 5H), 7.24-7.22 (m, 3H), 7.13-7.10 (m, 1H), 6.94 (t,
4.43-4.40 (m, 1H), 4.25-4.19 (m, 2H), 3.60 (q, J =6.5 Hz, 1H),
J =7.3 Hz, 1H), 5.74 (s, 1H), 4.42-4.39 (m, 1H), 4.31 (t, J =4.8 Hz,
2.60-2.56 (m, 1H), 2.42 (dd, J =9.6, 7.8 Hz, 1H), 1.37 (d, J
1H), 3.93 (dd, J =8.3, 4.7 Hz, 1H), 3.46 (q, J =6.6, Hz, 1H), 1.40
=6.5Hz, 3H), 1.27 (t, J =7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3);
(d, J =3.8 Hz, 3H); 13C NMR (125 MHz, CDCl3); δ 148.2, 147.0,
δ 171.1, 148.0, 146.9, 138.1, 128.9, 128.7, 128.2, 127.9, 127.0,
142.6, 140.3, 130.0, 128.7, 128.6, 128.4, 126.5, 125.5, 124.6,
124.3, 124.1, 121.2, 119.2, 81.8, 79.4, 74.8, 69.8, 61.6, 42.0,
121.6, 121.0, 117.4, 90.0, 82.9, 71.7, 71.2, 63.2, 12.6 ; ESI-MS
14.1, 11.3; ESI-MS calcd for C27H28N2NaO4 [M+Na]: 467.1947,
calcd for C24H23 N2O2 [M+H]: 371.1759, found: 371.1755.
found: 467.1941.
Spectral Data of Compound 8b: 1H NMR (600 MHz, CDCl3); δ
Spectral Data of Compound 5j: 1H NMR (400 MHz, CDCl3); dr =
7.45 (d, J =8.5 Hz, 2H), 7.38-7.37 (m, 1H), 7.31-7.28 (m, 2H),
6.7:1; Major Isomer; δ 7.47-7.38 (m, 2H), 7.39-7.31 (m, 5H),
7.24-7.23 (m, 5H), 7.15 (d, J =8.2 H, 2H), 5.67 (s, 1H), 4.38 (t, J
7.27-7.24 (m, 1H), 7.21-7.07 (m, 6 H), 6.90-6.88 (m, 2H), 5.50
=7.2 Hz, 1H), 4.28 (s, 1H), 3.90 (d, J =3.0 Hz, 1H), 3.36 (d, J =6.6
(s, 1H), 4.64-4.57 (m, 1H), 4.23-4.18 (m, 2H), 3.63 (t, J =6.0 Hz,
Hz, 1H), 1.34 (d, J =6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3);
1H), 2.60-2.44 (m, 2H), 2.22-2.10 (m, 1H), 1.73-1.65 (m, 1H),
146.6, 145.4, 142.3, 139.9, 131.0, 130.2, 128.8, 128.6, 126.7,
1.47-1.43 (m, 1H), 1.28-1.22 (m, 7H), 0.81 (t, J =9.0 Hz, 3H); 13
NMR (100 MHz, CDCl3); δ 171.1, 148.8, 147.1, 137.4, 128.9,
128.7, 128.1, 127.9, 127.4, 124.2, 124.0, 121.4, 119.0, 81.2,
79.9, 75.0, 73.2, 61.5, 41.9, 29.6, 27.6, 22.9, 14.1, 13.9; Minor
C
126.5, 124.7, 122.4, 118.6, 89.8, 83.0, 71.7, 71.4, 63.0, 12.4
one carbon merged; ESI-MS calcd for C24H21Cl2N2O2[M+H]:
439.0980, found: 439.0981.
Isomer; 13C NMR (100 MHz, CDCl3); δ 6.54 (d, J = 8.0 Hz, 2H), Spectral Data of Compound 8c: 1H NMR (500 MHz, CDCl3); δ
5.32 (s, 1H), 0.88 (t, J =7.2 Hz, 3H) other protons are merged; 7.41-7.37 (m, 7H), 7.34-7.29 (m, 2H), 7.24-7.23 (m, 1H), 7.11-
13C NMR (100 MHz, CDCl3); δ 170.1, 147.9, 136.9, 125.6, 123.8, 7.09 (m, 2H), 5.68 (s, 1H), 4.38 (t, J =5.0 Hz, 1H), 4.29 (t, J =4.5
122.6, 116.9, 82.2, 79.6, 73.7, 41.3, 28.4, 23.0, 14.0 other Hz, 1H), 3.90 (dd, J =8.0, 4.5 Hz, 1H), 3.37 (q, J = 6.5 Hz, 1H),
carbon are merged or not clearly visible; EI+MS calcd for 1.35 (d, J =5.0 Hz, 3H); 13C NMR (125 MHz, CDCl3); 147.2,
C30H34N2O4 [M+]: 486.2519, found: 486.2517.
145.9, 142.3, 139.8, 131.8, 131.5, 130.2, 128.6, 126.5, 124.7,
122.6, 118.9, 118.7, 114.1, 89.8, 82.9, 71.7, 71.3, 63.0, 12.4.;
ESI-MS calcd for C24H21Br2N2O2[M+H]: 526.9970, found:
526.9962.
Spectral Data of Compound 5a-H: 1H NMR (600 MHz, CDCl3); δ
7.75 (d, J =7.1 Hz, 2H), 7.54-7.52 (m, 2H), 7.48-7.45 (m, 1H),
7.39 (d, J =6.3 Hz, 2H), 7.33-7.24 (m, 8H), 7.04 (t, J =7.9 Hz, 2H),
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
Spectral Data of Compound 8d: 1H NMR (500 MHz, CDCl3): δ 78.7, 70.1, 25.8, 22.7; 1H NMR (600 MHz, CVDieCwl3A)r;ticlMe Oinnlioner
DOI: 10.1039/C7OB02087B
7.43 (d, J =8.5 Hz, 2H), 7.36 (t, J =7.0 Hz, 1H), 7.31-7.22 (m, 3H), isomer; δ 7.52-7.51 (m, 1H), 7.43-7.40 (m, 3H), 7.38-7.36 (m,
7.14-7.07 (m, 6H), 5.68 (s, 1H), 4.37 (t, J =7.0 Hz, 1H), 4.27 (t, J 1H), 7.35-7.32 (m, 3H), 7.28-7.23 (m, 5H), 7.20-7.18 (m, 1H),
=4.0 Hz, 1H), 3.93 (dd, J =8.0, 4.0 Hz, 1H), 3.41 (q, J = 6.5 Hz, 7.07-7.04 (m, 1H), 6.94-6.93 (m, 1H), 6.85-6.84 (m, 1H), 6.65-
1H), 2.28 (s, 3H), 2.29 (s, 3H), 1.35 (d, J =6.5 Hz, 3H); 13C NMR 6.62 (m, 1H), 5.63 (s, 1H), 5.12 (s, 1H), 4.13(s, 1H), 1.53 (s, 3H),
(125 MHz, CDCl3); 145.7, 144.8, 142.9, 140.5, 135.4, 131.1, 0.81 (s, 3H) other peaks merge with others; 13C NMR (150
129.9, 129.3, 129.1, 128.3, 126.4, 124.6, 121.3, 117.8, 89.9, MHz, CDCl3); δ 149.4, 147.1, 143.6, 133.0, 129.6, 129.2, 128.7,
82.9, 71.6, 71.2, 63.1, 20.9, 20.6, 12.4; ESI-MS calcd for 128.5, 126.2, 124.8, 119.8, 115.0, 92.0, 82.4, 73.1, 68.4, 26.1,
C26H27N2O2[M+H]: 399.2073, found: 399.2076.
23.2 Other peaks merged; ESI-MS calcd for C31H28N2O2 [M+]:
460.2151, found: 460.2148.
Spectral Data of Compound 8e: 1H NMR (500 MHz, CDCl3); δ
7.52 (t, J =2.0 Hz, 1H), 7.42-7.29 (m, 4H), 7.26-7.24 (m, 2H), Spectral Data of Compound 8j: 1H NMR (500 MHz, CDCl3); δ
7.24-7.19 (m, 3H), 7.11-7.08 (m, 2H), 6.90 (dd, J =8.0, 1.5 Hz, 7.34-7.24 (m, 5H), 7.23-7.14 (m, 3H), 7.02-6.98 (m, 3H), 6.84 (t,
1H), 5.72 (s, 1H), 4.39 (t, J =7.5 Hz, 1H), 4.31 (t, J =4.5 Hz, 1H), J =8.4 Hz, 2H), 6.62 (t, J =6.0 Hz, 1H), 5.48 (s, 1H), 3.99 (s, 1H),
3.90 (dd, J =8.0, 4.5 Hz, 1H), 3.43 (q, J =6.5 Hz, 1H), 1.38 (d, J 1.63 (s, 3H), 1.55 (s, 3H), 1.32 (s, 3H), 0.82 (s, 3H); 13C NMR
=6.5 Hz, 3H); 13C NMR (150 MHz, CDCl3); 149.3, 147.9, 142.3, (125 MHz, CDCl3); 149.4, 147.4, 143.1, 140.7, 128.7, 128.1,
139.8, 134.6, 134.5, 130.3, 129.7, 129.6, 128.7, 126.6, 125.6, 125.7, 123.5, 121.4, 119.4, 115.0, 114.7, 94.9, 83.5, 83.0, 72.5,
124.7, 121.4, 120.9, 119.3, 116.9, 115.3, 89.8, 83.1, 71.8, 71.2, 67.4, 26.4, 24.3, 22.9, 21.6 other carbons are merged; EI+-MS
63.1, 12.5; ESI-MS calcd for C24H21Cl2N2O2[M+H]: 439.0980, calcd for C27H28N2O2[M+]: 412.2151, found: 412.2154.
found: 439.0975.
Spectral Data of Compound 8k: 1H NMR (400 MHz, CDCl3); δ
Spectral Data of Compound 8f: 1H NMR (400 MHz, CDCl3); δ 7.45 (dd, J =8.0, 1.0 Hz, 2H), 7.35 (dd, J =8.0, 2.8 Hz, 1H), 7.29-
7.39-7.36 (m, 3H), 7.32-7.27 (m, 4H), 7.24-7.22 (m, 1H), 7.17- 7.25 (m, 4H), 7.24-7.23 (m, 1H), 7.19 (d, J =7.1 Hz, 2H), 7.16-
7.11 (m, 1H), 7.09-6.96 (m, 3H), 5.49 (s, 1H), 4.59 (dd, J =8.0, 7.13 (m, 2H), 7.06-7.02 (m, 1H), 6.84-6.80 (m, 1H), 5.96 (s, 1H),
3.9 Hz, 1H), 4.50 (t, J =8.0 Hz, 1H), 4.27 (q, J =6.8 Hz, 1H), 4.09 4.07 (s, 1H), 3.25 (dd, J =7.3, 3.8 Hz, 1H), 2.07-2.02 (m, 1H),
(dd, J =8.0, 4.0 Hz, 1H) 1.18 (d, J =6.8 Hz, 3H); 13C NMR (150 1.64-1.63 (m, 1H), 1.60-1.52 (m, 5H), 1.29-1.20 (m, 2H), 0.80 (t,
MHz, CDCl3): δ 144.7, 144.4, 143.4, 140.7, 132.6, 130.8, 130.2, J =8.0 Hz, 3H), 0.71 (s, 3H); 13C NMR (100 MHz, CDCl3); 149.3,
129.8, 128.3, 127.5, 127.2, 126.5, 126.1, 125.5, 125.3, 124.1, 147.9, 142.0, 139.1, 129.4, 128.8, 128.5, 128.1, 126.5, 125.2,
121.6, 90.5, 84.2, 72.6, 67.8, 62.8, 11.6 one carbon merged; 124.3, 121.0, 119.3, 114.7, 91.7, 83.0, 82.6, 75.5, 71.0, 29.1,
ESI-MS calcd for C24H21Cl2N2O2[M+H]: 409.0980, found: 28.1, 26.2, 23.0, 22.9, 14.0; ESI-MS calcd for C29H33N2O2[M+H]:
439.0976.
441.2542, found: 441.2535.
Spectral Data of Compound 8g: 1H NMR (600 MHz, CDCl3); δ Spectral Data of Compound 8l: 1H NMR (600 MHz, CDCl3); δ
7.40 (d, J =8.3 Hz, 2H), 7.35-7.27 (m, 7H), 7.24-7.19 (m, 3H), 7.55 (dd, J =7.1, 1.0 Hz, 2H), 7.28-7.26 (m, 3H), 7.24-7.22 (m,
7.10 (t, J =7.3 Hz, 1H), 6.91 (t, J =7.3 Hz, 1H), 5.81 (s, 1H), 3.93- 3H), 7.16-7.14 (m, 2H), 7.12-7.10 (m, 1H), 7.06 (d, J =12.0 Hz,
3.91 (m, 1H), 3.81 (d, J =8.2 Hz, 1H), 3.32 (q, J =6.4 Hz, 1H), 1H), 6.85-6.82 (m, 1H), 5.88 (s, 1H), 3.91 (s, 1H), 3.19 (q, J = 6.0
1.59 (d, J =6.0 Hz, 3H), 1.40 (d, J =6.0 Hz, 3H); 13C NMR (150 Hz, 1H), 2.33 (s, 3H), 1.60 (s, 3H), 1.35 (d, J =6.0 Hz, 3H), 0.83
MHz, CDCl3); δ 148.4, 147.8, 141.0, 140.3, 129.6, 128.7, 128.6, (s, 3H); 13C NMR (150 MHz, CDCl3); δ 148.5, 147.6, 142.2,
126.9, 125.3, 124.2, 121.1, 120.8, 116.3, 92.8, 82.8, 80.1, 70.8, 138.5, 136.5, 130.4, 128.6, 128.4, 126.7, 125.7, 124.8, 121.4,
68.4, 17.0, 12.0 one carbon merged; ESI-MS calcd for 119.5, 115.2, 91.6, 82.4, 81.5, 71.2, 70.1, 26.6, 23.0, 21.3, 12.0.
C25H25N2O2[M+H]: 385.1916, found: 385.1908.
ESI-MS calcd for C27H28N2O2[M+]: 412.2151, found: 412.2156.
Spectral Data of Compound 8h: 1H NMR (600 MHz, CDCl3); δ Spectral Data of Compound 8a-H: 1H NMR (500 MHz, CDCl3);
7.57 (d, J =7.4 Hz, 2H), 7.40-7.20 (m, 10H), 7.14 (d, J =6.7 Hz, dr = 3:1; Major isomer; δ 7.40-7.28 (m, 3H), 7.22-7.20 (m, 4H),
1H), 6.87 (t, J =6.5 Hz, 1H), 5.95 (s,1H), 3.98 (s, 1H), 3.23 (d, J 7.18-7.06 (m, 3H ), 6.95-6.88 (m, 2H), 6.75 (d, J =8.0 Hz, 2H),
=4.8 Hz, 1H), 1.64 (s, 3H), 1.39 (d, J =4.6 Hz, 3H), 0.87 (s, 3H); 5.8 (s, 1H), 4.04-4.03 (m, 1H), 3.96 (t, J =3.5 Hz, 2H), 3.80 (t, J
13C NMR (150 MHz, CDCl3); δ 148.6, 147.6, 142.2, 139.4, 129.4, =5.0 Hz, 1H), 1.01 (d, J =6.0 Hz, 3H); 13C NMR (125 MHz, CDCl3);
128.7, 128.4, 126.3, 125.6, 125.0, 121.3, 119.6, 115.3, 91.4, δ 145.2, 143.2, 139.3, 129.6, 128.7, 128.2, 124.2, 123.6, 121.3,
82.5, 81.5, 77.8, 71.3, 70.5, 26.6, 23.0, 12.0; ESI-MS calcd for 119.8, 117.8, 116.0, 80.0, 73.1, 64.6, 55.9, 51.5, 15.3; Minor
C26H27N2O2[M+H]: 399.2073, found: 399.2067.
isomer; 1H NMR (500 MHz, CDCl3); δ 7.40-7.28 (m, 3H), 7.22-
7.20 (m, 4H), 7.18-7.06 (m, 3H, ), 6.82-6.77 (m, 2H), 6.45 (d, J
=7.5 Hz, 2H), 5.63 (s, 1H), 4.50 (dd, J =6.5, 1H), 4.0-3.99 (m,
2H), 3.63 (q, J =4.0 Hz, 1H), 1.05 (d, J =7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3); δ 129.5, 129.4, 128.8, 124.3, 121.9, 118.4,
117.1, 82.9, 71.2, 65.0, 51.2, 13.9 other carbons are merged or
not visible ESI-MS calcd for C24H27N2O2[M+H]: 375.2070,
found: 375.2072.
Spectral Data of Compound 8i: 1H NMR (600 MHz, CDCl3); dr =
4:3; Major isomer; δ 7.52-7.51 (m, 1H), 7.43-7.40 (m, 3H),
7.38-7.36 (m, 2H), 7.35-7.32 (m, 3H), 7.28-7.23 (m, 5H), 7.10-
7.08 (m, 2H), 7.04-7.01 (m, 1H), 6.93-6.91 (m, 1H), 6.82-6.80
(m, 1H), 6.17 (s, 1H), 4.31 (s, 1H), 4.14 (s, 1H), 1.46 (s, 3H), 0.71
(s, 3H), 13C NMR (150 MHz, CDCl3); δ 149.1, 147.5, 142.9,
138.3, 134.4, 129.4, 129.0, 128.4, 128.3, 128.0, 126.5, 124.6,
124.1, 121.8, 119.6, 119.3, 114.8, 114.6, 92.7, 85.5, 82.5, 82.1,
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J. Name., 2013, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
Page 8 of 8
ARTICLE
Journal Name
Spectral Data of Compound 8b-H: 1H NMR (600 MHz, CDCl3); δ
7.34 (d, J =7.4 Hz, 1H), 7.31-7.25 (m, 2H), 7.16-7.13 (m, 3H),
7.07 (dd, J =6.8, 2.0 Hz, 2H), 6.98 (dd, J =6.7, 2.2 Hz, 2H), 6.51
(dd, J =6.8, 2.0 Hz, 2H), 5.75 (s, 1H), 3.96-3.89 (m, 4H), 3.60 (t, J
=4.3 Hz, 1H), 1.0 (d, J =6.5 Hz, 3H); 13C NMR (150 MHz, CDCl3);
144.1, 143.7, 143.2, 139.2, 129.3, 129.2, 128.8, 128.3, 125.8,
125.0, 124.1, 123.6, 120.5, 117.3, 80.2, 73.1, 64.3, 54.0, 51.9,
16.2; ESI-MS calcd for C24H25Cl2N2[M+H]: 443.1293 found:
443.1290.
2043; (g) H. Yamamoto and N. Momiyama, CheVmiew. CAortimclemOunlnin.e,
2005, 3514–3525.
7
(a) P. Sharma and R. -S. Liu, Org. Lett. 2016,
DOI: 10.101389/,C471O2B;02(b0)87PB.
Sharma and R. -S. Liu, Chem. Eur. J. 2016, 22, 15881; (c) I.
Chatterjee, R. Fröhlich and A. Studer, Angew. Chem. Int. Ed.
2011, 50, 11257; (d) A. Mukherjee, R. B. Dateer, R.
Chaudhuri, S. Bhunia, S. N. Karad and R. -S. Liu, J. Am. Chem.
Soc. 2011, 133, 15372.
(a) A. G. Leach and K. N. Houk, Org. Biomol. Chem. 2003, 1,
1389; (b) A. G. Leach and K. N. Houk, J. Am. Chem. Soc. 2002,
124, 14820.
8
9
A. Penon, G. Palmisano, Y. -L. Zhao, K. N. Houk, J. Volkman
and K. M. Nicholas, J. Am. Chem. Soc. 2009, 131, 653-661.
10 Part of this work is recently published; see: J. Liu, M. Skaria,
Acknowledgements
The authors wish to thank the National Science Council,
P. Sharma, Y. -W. Chiang and R. -S. Liu, Chem. Sci. 2017, 8,
5482-5487.
Taiwan, and the Ministry of Education, Taiwan for support of 11 (a) A. Rescifina, M. A. Chiacchio, A. Corsaro, E. D. Clercq, D.
Iannazzo, A. Mastino, A. Piperno, G. Romeo, R. Romeo and V.
Valveri, J. Med. Chem. 2006, 49, 709; (b) A. Pinto, P. Conti, L.
Tamborini and C. D. Micheli, Tetrahedron: Asymmetry, 2009,
this work.
20, 508; (c) W. Hartwig and L. Born, J. Org. Chem, 1987, 52
,
Notes and references
4352; (d) Y. Nishimura, E. Shitara, H. Adachi, M. Toyoshima,
M. Nakajima, Y. Okami and T. Takeuchi, J. Org. Chem. 2000,
1
For the reviews of radical annulations, see: (a) A. Studer and
D. P. Curran, Angew. Chem. Int. Ed. 2016, 55, 58; (b) H. Togo,
Advanced free radical reactions for organic synthesis,
Amsterdam: Elsevier, Boston, 1st ed., 2004; (c) T. R. Rheault
65, 2; (e) Y. Hayashi and S. Ogasawara, Org. Lett. 2016, 18
,
3426; (f) G. Righi, S. Ciambrone, C. Bonini and P. Campaner,
Bioorg. Med. Chem, 2008, 16, 902.
12 Crystallographic data of compounds 5a, 5c’, 5a-H and 8a
and M. P. Sibi, Synthesis 2003, 6, 803; (d) A. J. McCarroll and
were deposited in Cambridge Crystallographic Data Center;
5a, CCDC 1540300; 5c’, CCDC 1540298, 5a-H, CCDC 1540301
and 8a, CCDC 1541215.
J. C. Walton, J. Chem. Soc., Trans. 1 2001, 3215; (e) P. Dowd
and W. Zhang, Chem. Rev. 1993, 93, 2091.
For carbon-based 1,n-diradicals, see selected reviews: (a) H. -
Y. Lee, Acc. Chem. Res. 2015, 48, 2308; (b) M. Abe, Chem.
Rev. 2013, 113, 7011; (c) P. W. Peterson, R. K. Mohamed and
I. V. Alabugin, Eur. J. Org. Chem. 2013, 2505; (d) M. Abe, J. Ye
and M. Mishima, Chem. Soc. Rev. 2012, 41, 3808.
For diradicals from diazo reagents, see: (a) W. Adam, S.
Grabowski and H. Platsch, J. Am. Chem. Soc. 1989, 111, 751;
(b) W. Adam, K. Hannemann and R. M. Wilson, J. Am. Chem.
Soc. 1986, 108, 929; (c) W. Adam, K. Hannemann and R. M.
Wilson, J. Am. Chem. Soc. 1984, 106, 7646; (d) W. R. Roth, M.
Biermann, G. Erker, K. Jelich, W. Gerhartz and H. Görner,
Chem. Ber. 1980, 113, 586.
2
3
13 For cycloaddition of ketonitrones with alkenes, see selected
examples: (a) T. B. Nguyen, A. Matel, R. Dhal and G. Dujardin,
Org. Lett. 2008, 10, 4493; (b) T. Q. Tran, V. V. Diev, G. L.
Starova, V. V. Gurzhiy and A. P. Molchanov, Eur. J. Org.
Chem. 2012, 2054; (c) M. Burdisso, R. Gandolfi, P. Gandilfi
and P. Grünanger, Tetrahedron, 1989, 45, 5579.
14 (a) M. Berthet, T. Cheviet, G. Dujardin, I. Parrot and J.
Martinez, Chem. Rev., 2016, 116, 15235; (b) A. Badoiu, Org.
Biomol. Chem., 2012, 10, 114; (c) L. Dong, C. Geng and P.
Jiao, J. Org. Chem., 2015, 80, 10992; (d) S. A. Ali and M. Z. N.
Iman, Tetrahedron, 2007, 63, 9134.
15 S. Ghorpade and R. -S. Liu, Angew. Chem. Int. Ed. 2014, 53
,
4
5
(a) J. Drujon, R. Rahmani, V. Heran, R. Blanc, Y. Carissan, B.
Tuccio, L. Commeiras and J. Parrain, Phys. Chem. Chem. Phys.
2014, 16, 7513; (b) R. Roth, T. Ebbrecht and A. Beitat, Chem.
Berr. 1988, 121, 1357; (c) W. R. Roth, R. Longer, M.
Bartmann, B. Stevermann, G. Maier, H. P. Reisenauer, R.
12885.
16 R. Chaudhuri, H. -Y. Liao and R. -S. Liu, Chem. Eur. J. 2009,
15, 8895.
17 Reviews for nitrone/alkene cycloadditions, see: (a) K. V.
Gothelf and K. A. Jørgensen Chem. Rev. 1998, 98, 863; (b) H.
Pellissier, Tetrahedron 2007, 63, 3235; (c) L. M. Stanley and
M. P. Sibi, Chem. Rev. 2008, 108, 2887; (d) M. Kissanea and
A. R. Maguire, Chem. Soc. Rev. 2010, 39, 845; (e) T.
Hashimoto and K. Maruoka, Chem. Rev. 2015, 115, 5366; (f)
Sustmann and W. Müller, Angew. Chem. Int. Ed. 1987, 26
,
256; (d) W. R. Roth, B. P. Scholz, R. Breuckmann, K. Jelich and
H. W. Lennartz, Chem. Ber. 1982, 115, 1934; (e) W. R. Roth
and B. P. Scholz, Chem. Ber. 1982, 115, 1197.
(a) R. R. Jones and R. G. Bergman, J. Am. Chem. Soc., 1972,
94, 660; (b) R. Nagata, H. Yamanaka, E. Okazaki and I. Saito,
Tetrahedron Letters, 1989, 30, 4995; (c) A. G. Myers, E. Y.
Kuo, and N. S. Finney, J. Am. Chem. Soc. 1989, 111, 8057; (d)
A. G. Myers, and P. S. Dragovich, J. Am. Chem. Soc., 1989,
R. Huisgen, Angew. Chem. Int. Ed. Engl. 1963, 2, 565; (g) P. N.
Confalone and E. M. Huie, Org. React. 1988, 36, 1; (h) D. B.
Huple, B. D. Mokar and R. -S. Liu, Angew. Chem. Int. Ed.
2015, 54, 14924.
18 (a) R. K. Kawade and R.-S. Liu, Angew. Chem. Int. Ed. 2017,
56, 2035; (b) S. Chakrabarty, I. Chatterjee, B. Wibbeling, C. G.
Daniliuc and A. Studer, Angew. Chem. Int. Ed. 2014, 53, 5964.
111, 9130; (e) R. G. Bergman, Acc. Chem. Res., 1973,
(f) A. Basak, S. Mandal and S. S. Bag, Chem. Rev. 2003, 103
6 , 25;
,
4077; (g) C. Raviola, S. Protti, D. Ravelli and M. Fagnoni,
Chem. Soc. Rev., 2016, 45, 4364; (h) C. Wentrup, Acc. Chem.
Res. 2011, 44, 393.
(a) Y. Yamamoto and H. Yamamoto, Angew. Chem. Int. Ed.
2005, 44, 7082; (b) B. S. Bodnar and M. J. Miller, Angew.
Chem. Int. Ed. 2011, 50, 5630; (c) L. Brulíková, A. Harrison, M.
J. Miller and J. Hlaváč, Beilstein J. Org. Chem. 2016, 12, 1949;
(d) P. F. Vogt and M. J. Miller, Tetrahedron 1998, 54, 1317;
(e) J. Streith and A. Defoin, Synthesis 1994, 1994, 1107; (f) Y.
Yamamoto and H. Yamamoto, Eur. J. Org. Chem. 2006, 2031–
6
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