Fe(II)/Fe(III)-Catalyzed Intramolecular Didehydro-Diels-Alder Reaction of Styrene-ynes

Article abstract of DOI:10.1021/acs.joc.7b02672

The intramolecular didehydro-Diels-Alder reaction of styrene-ynes was catalyzed by Fe(II) and Fe(III) to produce various naphthalene derivatives under microwave heating conditions. Mechanistic calculations found that the Fe(II) catalyst activates the styr

Full text of DOI:10.1021/acs.joc.7b02672

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Article
Fe(II)/Fe(III)-catalyzed Intramolecular Didehydro-
Diels-Alder Reaction of Styrene-ynes
Hyeon Jin Mun, Eun Young Seong, Kwang-Hyun Ahn, and Eun Joo Kang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02672 • Publication Date (Web): 20 Dec 2017
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Fe(II)/Fe(III)-catalyzed Intramolecular Didehydro-Diels-Alder Reaction
of Styrene-ynes
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Hyeon Jin Mun, Eun Young Seong, Kwang-Hyun Ahn*, and Eun Joo Kang*
Department of Applied Chemistry, Kyung Hee University, Yongin 17104, Korea
*E-mail: khahn@khu.ac.kr, ejkang24@khu.ac.kr
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ABSTRACT: The intramolecular didehydro-Diels-Alder reaction of styrene-ynes was
catalyzed by Fe(II) and Fe(III) to produce various naphthalene derivatives under microwave
heating conditions. Mechanistic calculations found that the Fe(II) catalyst activates the
styrenyl diene in an inverse-electron-demand Diels-Alder reaction, and the consecutive
dehydrogenation reaction can be promoted by either Fe(II)-catalyzed direct dehydrogenation
or an Fe(III)-catalyzed rearomatization/dehydrogenation pathway.
INTRODUCTION
The Diels−Alder reaction is one of the most useful cycloaddition reactions to construct six-
membered ring compounds.1 The Diels−Alder reaction normally combines the 4π-component of a
conjugated diene with the 2π-component of a dienophile to synthesize cyclohexenes. However the
diverse variants in the oxidation levels of the reactant pairs and products have been investigated for
venerable [4+2] cycloadditions, which effectively accompanied with the consecutive transformations
such as dehydrogenation, hydrogen atom shift and further C-X bond formation of highly reactive
cycloadducts. Among those strategies, having one of the C-C double bonds participating in the Diels-
Alder reaction replaced by a triple bond, the reaction of the diene with a dienophilic alkyne can afford
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cyclohexadiene, which process has been called the didehydro-Diels-Alder reaction. Another
involvement of alkyne; the combination of 1,3-enyne as the 4π-component with alkyne results cyclic
allene adduct, which rapidly rearranges via a [1,5] hydrogen shift to benzene in tetradehydro-Diels-
Alder reaction.2 The cycloaddition between 1,3-diyne and diynophilic alkyne generates a highly
oxidized and constrained benzyne via hexadehydro-Diels-Alder reaction, and this versatile
intermediate participates in the trapping sequence to develop the structural complexity.2d-f
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In particular, the didehydro-Diels-Alder reaction of styrenes with alkynes is an efficient strategy to
promote further dehydrogenation (aromatization) resulting a naphthalene core without additional
oxidants.3 However, utilizing styrene as the 4π-component has been considered challenging, due to
the unfavored dearomatization during the reaction and the competing polymerization and [2+2]
cycloaddition reactions.3a,4 These problems necessitate the use of harsh reaction conditions or highly
reactive dienophiles, and under these conditions the cycloadducts are sometimes more reactive as
dienes than their styrene precursors leading to further Diels-Alder reactions. Intramolecular
cycloaddition system of styrene-ynes and various strategies for increasing the reactivities of the
styrene or alkyne have been developed for the efficient and effective synthesis of polycyclic aromatic
compounds.5 Most strategies involve the preparation of electron-deficient alkyne dienophiles that
have an electron-withdrawing group on the alkyne terminus or within the tether,6 or utilize a Lewis
acid (ZnCl2) to coordinate with the carbonyl oxygen of the alkynone decreasing the energy of the
LUMO of the dienophile, accelerating the intermolecular Diels−Alder reaction.7 Alternatively,
HOMO activation of the diene by the in-situ generation of a formal trienamine species was reported
by Chen in the asymmetric dearomatic Diels−Alder reaction.8 In the inverse-electron-demand
Diels−Alder (iEDDA) reaction, 1,3-heterodienes are triggered to undergo cycloaddition by Lewis acid
(CuBr2, Cu2O) coordination increasing the electron-deficiency.9 These available methods, however,
need for an additional functional group to accelerate reactivities of the Diels-Alder and consecutive
reaction, and more versatile approach was considered necessary. Inspired by our recent studies on Fe-
catalyzed C-C multiple bond (allene and diene) activation,10 we envisaged that the relatively
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unactivated styrene-ynes could participate in didehydro-Diels-Alder reaction. Thus, polycyclic
aromatic frameworks could be prepared using the π activation ability of the green and non-toxic iron
catalysts. A thorough understanding of the mechanism as well as the role of the Fe catalyst as
determined by theoretical studies is provided herein.
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RESULTS AND DISCUSSION
Initial experiments were directed towards the didehydro-Diels-Alder reaction of styrene-yne
substrate 1. Upon irradiating under microwave reactor (150 W) and maintain the reaction temperature
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at 150 C for 5 h, the product mixture of dihydronaphthalene 2a and the desired naphthalene 2b was
observed in 29% yield (Table 1, entry 1). Using iron(II) catalysts such as FeCl2 and Fe(acac)2, higher
yields were obtained with decreased selectivity between the two products 2a and 2b (Table 1, entries
2-4). Encouraged by the increased reactivity afforded by the Fe(II) catalysts, we turned to the
optimization of the solvent and the use of an Fe(III) catalyst. Chlorobenzene (PhCl) provided the best
yield (Table 1, entries 4-7), but various Fe(III) catalysts showed no dramatic influence on the yield or
product distribution (Table 1, entries 8-10).11 In an attempt to promote full conversion to 2b, and to
check the role of the Fe(II) and Fe(III) catalysts, the product mixture of 2a and 2b was subjected to
further reaction (Table 2). Subjecting the product mixture (2a:2b; around 50:50) to either 50 mol % of
Fe(acac)2 or 20 mol % of FeCl3 showed that the Fe(III) catalyst effectively promoted the
dehydrogenation reaction of 2a affording an 8:92 ratio of 2a:2b (Table 2, entries 1-2). When utilizing
isoprene or diphenyl ethylene as the hydrogen acceptor with Fe complex, a slightly higher ratio of 2b
was observed, which is difficult to conclude that the hydrogen acceptor has affected (Table 2, entries
3-5).12 As in the Brummond’s report on the intramolecular didehydro-Diels-Alder reaction of styrene-
ynes containing heteroatom tethers,6a the dihydronaphthalene could not be oxidized to the
corresponding naphthalene by dichlorodicyanobenzoquinone (DDQ), or O2, moreover, several
reactions with DDQ under vigorous conditions or longer reaction time gave the decomposition of the
naphthalene product (Table 2, entries 6-9).5c,13 The use of hypervalent iodine(III) reagent,
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PhI(OTs)OH (hydroxyl(tosyloxy)iodobenzene, HTIB, Koser reagent) didn’t give an acceptable result,
even with the sequential treatment of oxidant at the end of the Diels-Alder reaction (Table 2, entry
10).13f
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Consequently, further optimization of the reaction conditions focused on using a dual catalytic
system of Fe(II) and Fe(III) to efficiently promote this didehydro-Diels-Alder reaction. Investigation
of several Fe(III) catalysts, catalyst loading, and heating methods (Table 1, entries 11-17) revealed
that 10 mol % of each Fe(acac)2 and FeCl3 under microwave irradiation afforded the highest
efficiency and selectivity for naphthalene 2b synthesis (Table 1, entry 12).
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Table 1. Optimization of didehydro-Diels-Alder reaction conditions
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Table 2. Dehydrogenation experiments
The styrene-yne substrates were reacted under optimized conditions, and the results are
summarized in Table 3. Substrates containing electron-donating groups (CH3 and OCH3) on the
alkynyl benzene ring produced the desired products 2-5 in good yield. In contrast, the yields of
products 6 containing a bromo substituent, and 7 containing a pyridine, were considerably lower,
which is thought to be the reduced reactivity of electron-deficient alkyne moiety. Heteroaromatic and
fused aromatic ring-containing products 8-9 were obtained in good yield. Additionally, p-methyl and
o-methoxy substituents on styrenyl benzene rings have been introduced, resulting their respective
products. Compound 11b was exclusively produced without the corresponding dihydronaphthalene,
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and the corresponding dihydronaphthalene product were not detectable by H-NMR analysis of the
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crude reaction mixture. This result observed in the case of 11b was understood by the slightly more
congested structure due to ortho-methoxy substituents, resulting to promote the consecutive
dehydrogenation process. In contrast with the reaction forming product 6, the bromo substituted
styrenyl benzene ring did not affect the formation of 12, which suggests that the LUMO of the styrene
interacts with the HOMO of the alkyne in an iEDDA reaction.2d,9a,14 Furthermore, the Br atom was
maintained, providing a handle for further manipulation to produce a range of useful compounds. The
pyridine moiety seemed to deactivate the Fe catalysts through coordination, however thiophene and
naphthalene substituents afforded benzothiophene 13 and phenanthrene compounds 15-16 in great
yields and regioselectivities. Reaction of m-methyl substituted styrene-yne gave a 1.9:1 mixture of the
8-methyl and 6-methylnaphthalenes, 17b and 17b′ in 67% yield. Structural changes in the tether were
also examined; the precursor having an ether tether produced only one product 18b in 60% yield, and
the precursor with an all-carbon tether possessing a diester moiety afforded 19b in 24% yield with the
recovery of starting material. The preferred formation of the naphthalene products (18b and 19b) may
be explained by the tendency to gradually decrease the H-H distance in the boat conformation of
didehydro-Diels-Alder cycloadduct, depending on the element of tether.6c
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Table 3. Substrate scope of the didehydro-Diels-Alder reaction
Next, other functional groups on the terminus of the alkyne were investigated in this intramolecular
didehydro-Diels-Alder reaction (Scheme 1). Substitution of the alkyne with TMS provided
naphthalene 21b in 56% yield after a prolonged reaction time, and the CH3 and H substituents in 22
and 24 impeded the reaction considerably. Matsubara has also reported the dehydrogenation reaction
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when a silyl group is utilized as the bulky trimethylsilyl group can induce steric repulsion bringing
the two hydrogen atoms into spatial proximity.5g Other non-styrene diene substrates were also
expected to be converted to cyclohexadienes or benzene derivatives through this intramolecular
didehydro-Diels-Alder reaction. The methylated internal diene 26 bearing an aryl alkyne moiety
afforded benzene product 27b in 38% yield, while diene 28 containing a silyl alkyne moiety resulted
in a product mixture of cyclohexadiene 29a and benzene derivative 29b.
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Scheme 1. Additional substrates of the didehydro-Diels-Alder reaction
To demonstrate the mechanism of this Fe-catalyzed didehydro-Diels-Alder reaction,15 DFT
calculations were carried out to analyze the energy levels and molecular structures of the theoretical
reactions. Figure 1 presents the structures and energy profiles of the Diels-Alder reaction pathways in
the presence or absence of an iron(II) catalyst.16 The coordination of the FeCl2 catalyst forming the
pre-reaction complex A-FeCl2 can decrease the energy level of reactant (A) by a considerable amount
(-30.15 kcal/mol). Furthermore, the free energy barrier in the presence of FeCl2 was 14.06 kcal/mol,
which is 15.07 kcal/mol lower than the TS without catalyst. It can be concluded that the Fe(II)
catalyst accelerates the reaction via the formation of the thermodynamically more stable and
preorganized complex (A-FeCl2), and the activation of the styrene towards dearomatization by
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partially localizing the arene π system.17
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Figure 1. Energy profile for the two Diels-Alder reaction pathways
The detailed data of pre-reaction complexes A-FeCl2 and A-FeCl3 is shown in Figure 2, and the
different effect of Fe(II) or Fe(III) complex is shown to be characteristic. First of all, it is worth noting
that iron is shown to interact with the styrene moiety and not with the alkyne or arene, supporting the
proposed iEDDA reaction pathway. The structure of A-FeCl2 complex exhibits the shorter Fe…C(16)
or Fe…C(18) distances (2.157 Å and 2.070 Å respectively) than those of A-FeCl3 complex (2.466 Å
and 2.427 Å respectively). Unlike the bent-shaped FeCl2, a nearly planar structure of FeCl3 hinders
the Fe(III) center from approaching the styrenyl unit, thus making the relative minimum high (-30.15
vs -9.07 kcal/mol).
Similar to Brummond’s result,6c which supported that the naphthalene product was formed through
the loss of hydrogen gas from the initially formed cycloadduct, the cyclohexadiene intermediate B in
our DFT calculations exists in a boat-like structure showing a H(17)…H(26) distance of 3.204 Å.
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Upon a close interaction with Fe complexes, the corresponding distance was significantly reduced to
2.536 Å in the B-FeCl2 complex and 2.779 Å in the B-FeCl3 complex (Figure 2). Here again, two iron
catalysts showed the clear differences of Fe…C(18) or Fe…C(20) distance; the distances in B-FeCl2
complex was 1.4~1.6 Å shorter than those in B-FeCl3 complex and this seems to be a factor that
makes the whole structure more congested to render the direct dehydrogenation by loss of H2. In
Figure 2e, on the other hand, the structure of B-FeCl3 complex exhibits the shorter H(26)…Cl distance
(2.225 Å) and the longer C(22)-H(26) distance (1.146 Å), which verifies that FeCl3 might be involved
in the proton transfer of H(26) through a weakening of the C(22)-H(26) bond to promote the
aromatization toward dihydronaphthalene 2a or intermediate C in Figure 3. The result of deuterium
labeling experiment also supported the deuterium transfer of D(26) toward dihydronaphthalene d-2a
(84% D-incorporated) during the aromatization process (Scheme 2).
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Figure 2. DFT calculation result of related Fe complexes of A and B
Scheme 2. Deuterium labeling experiment
The following mechanism is proposed according to the reaction results and mechanistic studies.
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First, the rate acceleration of the Diels-Alder reaction arises by the lowering of the styrene LUMO
energy level in Fe-coordinated complex I, even though this process is accompanied by the disruption
of aromaticity. The resulting [4+2] cycloadduct B can proceed toward the two feasible pathways; (1)
the Fe(II) catalyst might induce a direct dehydrogenation of the two hydrogen atoms in spatial
proximity, resulting in the naphthalene derivative D, and (2) aromatization by the proton-transfer of
H(26) is promoted by the Fe(III) catalyst and consecutive dehydrogenation affords naphthalene
derivative D.
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Figure 3. Plausible mechanisms of the Fe-catalyzed IMDDA reaction
CONCLUSION
In this study, the combined system of Fe(II) and Fe(III) was found to catalyze the didehydro-Diels-
Alder reaction of styrenyl alkyne substrates to produce polyaromatic cycloadducts. In spite of the
challenges associated with the use of a styrene as a conjugated diene (dearomatization and further
dehydrogenation), the distinguishing feature of this catalytic system is that there is no need for any
other functional groups to modulate the electronic environment of diene-ynes. The experimental
results and mechanistic DFT calculations show the following two facts; (1) the coordination of Fe(II)
to the styrene reduces both the energy level of the substrate and the activation energy of the Diels-
Alder reaction step, and (2) the dehydrogenation process can be promoted by both Fe(II) via direct
dehydrogenation and Fe(III) via aromatization. Further efforts to expand the scope of this
Fe(II)/Fe(III)-catalyzed didehydro-Diels-Alder reaction for synthesizing complex molecules are in
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EXPERIMENTAL SECTION
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General Information. The reaction was conducted in the CEM Discover microwave reactor using
o
sealed reaction vessels. The reaction temperature (150 C) was reached by 150 W after 5 min and
maintained by the infrared temperature control. All solvents used in the preparation and fractionation
of samples were reagent grade and were not purified further. Flash chromatography was carried out
using silica gel (70-230 mesh ASTM). All other commercially available reagents were used as
received. Reactions were monitored by thin layer chromatography (TLC) using 0.25-mm E. Merck
pre-coated silica gel plates, and the spots were visualized under 254 nm UV light and/or charring after
dipping the TLC plate into anisaldehyde solution. NMR spectra were recorded in CDCl3 using JEOL
(300 MHz) spectrometers (1H frequency, 13C frequency MHz). Residual solvent signals were used for
reference (CHCl3 at δ 7.26 ppm for 1H, δ 77.0 for 13C NMR). Mass spectra were recorded using JEOL
(JMS-700, quadruple doublet based lens system, EI) or Thermo (Q Exactive, hybrid quadruple
orbitrap system, ESI) mass spectrometer.
General procedure for Fe-catalyzed didehydro-Diels-Alder reaction: A styrene-yne (0.1
mmol) was added in the chlorobenzene solution (1 mL) of Fe(acac)2 (2.5 mg, 0.01 mmol) and FeCl3
(1.6 mg, 0.01 mmol). The reaction mixture was reacted in the sealed reaction vessel under the
o
microwave reactor at 150 C and 150 W. The reaction temperature was monitored by the infrared
temperature control for 5 h. After cooled, it was purified through flash chromatography to give
products. Some solid products are purified by recrystallization with DCM and hexane to obtain a
single naphthalene product.
4-p-tolyl-2-tosyl-2,3-dihydro-1H-benzo[f]isoindole (2b). Yield after column chromatography 31
mg, 74% as a 22:78 mixture of 2a and 2b. Yield after recrystallization 22 mg, 52%; white powder;
m.p. 233-234 oC; Rf = 0.53 (Hex:EtOAc, 2:1); 1H NMR (300 MHz, CDCl3) δ = 7.80 (d, J = 8.1 Hz, 1
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H), 7.74 (d, J = 8.3 Hz, 2 H), 7.64 - 7.56 (m, 2 H), 7.47 - 7.40 (m, 1 H), 7.37 - 7.28 (m, 5 H), 7.15 (d,
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J = 8.1 Hz, 2 H), 4.79 (s, 2 H), 4.49 (s, 2 H), 2.47 (s, 3 H), 2.39 (s, 3 H) ppm; C NMR (75 MHz,
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CDCl3) δ = 143.9, 137.8, 134.68, 134.67, 134.5, 133.8, 133.74, 133.69, 132.2, 130.0, 129.6, 129.4,
128.1, 127.9, 126.14, 126.08, 126.06, 120.7, 53.7, 53.3, 21.5, 21.3 ppm; HRMS (EI) calcd for
C26H23NO2S (M+) 413.1449, found 413.1450.
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9-m-tolyl-2-tosyl-2,3,3a,4-tetrahydro-1H-benzo[f]isoindole (3a) and 4-m-tolyl-2-tosyl-2,3-
dihydro-1H-benzo[f]isoindole (3b). Yield after column chromatography 26 mg, 63% as a 13:87
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mixture of 3a and 3b; white powder; Rf = 0.57 (Hex:EtOAc, 2:1); H NMR (300 MHz, CDCl3) δ =
7.79 (d, J = 8.1 Hz, 1 H), 7.74 (d, J = 8.3 Hz, 2 H), 7.68 (d, J = 8.3 Hz, 0.3 H), 7.62 (s, 1 H), 7.56 (d,
J = 8.4 Hz, 1 H), 7.46 - 7.33 (m, 3 H), 7.29 (d, J = 8.4 Hz, 3 H), 7.18 - 7.09 (m, J = 6.4 Hz, 0.5 H),
7.08 - 7.01 (m, 2 H), 6.95 (br. s., 0.1 H), 6.74 (d, J = 7.3 Hz, 0.1 H), 4.87 - 4.71 (m, 2 H), 4.56 - 4.42
(m, 2 H), 4.28 (dd, J = 1.4, 15.9 Hz, 0.1 H), 3.97 (t, J = 8.7 Hz, 0.1 H), 3.62 (dd, J = 2.3, 15.7 Hz, 0.1
H), 3.11 (qd, J = 7.8, 15.4 Hz, 0.1 H), 2.92 - 2.81 (m, J = 6.8 Hz, 0.2 H), 2.66 - 2.58 (m, 0.1 H), 2.42
(s, 3 H), 2.38 (s, 3 H) ppm; 13C NMR (75 MHz, CDCl3) δ = 143.9, 143.8, 138.6, 137.8, 137.7, 136.7,
134.8, 134.4, 134.3, 133.8, 133.7, 133.5, 132.1, 130.2, 130.0, 129.9, 128.8, 128.7, 128.6, 128.1, 127.9,
127.8, 127.2, 126.9, 126.6, 126.2, 126.1, 125.9, 120.7, 54.4, 53.7, 53.5, 53.2, 50.7, 39.0, 32.8, 31.6,
21.55, 21.53 ppm; HRMS (EI) calcd for C26H25NO2S (3a, M+) 415.1606, found 415.1610 and
C26H23NO2S (3b, M+) 413.1449, found 413.1450.
4-(4-methoxyphenyl)-2-tosyl-2,3-dihydro-1H-benzo[f]isoindole (4b).18 Yield after column
chromatography 25 mg, 57% as a 11:89 mixture of 4a and 4b. Yield after recrystallization 19 mg,
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45%; light yellow powder; m.p. 225-226 C; Rf = 0.45 (Hex:EtOAc, 2:1); H NMR (300 MHz,
CDCl3) δ = 7.80 (d, J = 8.1 Hz, 1 H), 7.75 (d, J = 8.3 Hz, 2 H), 7.60 (d, J = 7.3 Hz, 2 H), 7.47 - 7.40
(m, 1 H), 7.36 (d, J = 7.2 Hz, 1 H), 7.30 (d, J = 8.1 Hz, 2 H), 7.18 (d, J = 8.6 Hz, 2 H), 7.03 (d, J =
8.6 Hz, 2 H), 4.79 (s, 2 H), 4.49 (s, 2 H), 3.91 (s, 3 H), 2.38 (s, 3 H) ppm; 13C NMR (75 MHz, CDCl3)
δ = 159.5, 143.9, 134.4, 134.3, 133.9, 133.8, 132.3, 130.7, 130.0, 129.8, 128.1, 127.8, 126.2, 126.1,
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126.0, 120.6, 114.4, 55.5, 53.7, 53.3, 21.5 ppm; HRMS (EI) calcd for C26H23NO3S (M+) 429.1399,
found 429.1399.
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9-(2-methoxyphenyl)-2-tosyl-2,3,3a,4-tetrahydro-1H-benzo[f]isoindole
methoxyphenyl)-2-tosyl-2,3-dihydro-1H-benzo[f]isoindole (5b). Yield
(5a)
and
after
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chromatography 34 mg, 78% as a 15:85 mixture of 5a and 5b; light yellow powder; Rf = 0.49
(Hex:EtOAc, 2:1); 1H NMR (300 MHz,CDCl3) δ = 7.81 - 7.71 (m, 3 H), 7.70 - 7.65 (m, 0.48 H), 7.61
(s, 1 H), 7.49 - 7.39 (m, 3 H), 7.38 (br. s., 0.32 H), 7.36 - 7.28 (m, 3 H), 7.11 - 7.03 (m, 3 H), 6.99 (d,
J = 8.1 Hz, 0.32 H), 6.96 - 6.89 (m, 0.32 H), 6.63 (d, J = 6.6 Hz, 0.17 H), 4.86 - 4.73 (m, 2 H), 4.53 -
4.39 (m, 2 H), 4.25 - 4.04 (m, 0.32 H), 3.99 (t, J = 8.5 Hz, 0.16 H), 3.78 - 3.54 (m, 3.48 H), 3.10 (tt, J
= 8.3, 16.2 Hz, 0.16 H), 2.96 - 2.80 (m, J = 12.8 Hz, 0.32 H), 2.74 - 2.57 (m, J = 2.9 Hz, 0.16 H), 2.41
(br. s., 0.48 H), 2.37 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ = 157.0, 143.84, 143.79, 143.77, 138.4,
137.5, 134.5, 134.3, 134.1, 133.8, 133.7, 133.6, 132.2, 131.6, 131.5, 131.0, 130.6, 129.92, 129.86,
129.6, 129.4, 128.1, 127.9, 127.8, 127.0, 126.9, 126.84, 126.79, 126.0, 125.9, 125.6, 124.5, 121.1,
121.0, 120.8, 111.5, 55.6, 55.5, 54.9, 53.8, 53.4, 51.0, 38.9, 38.8, 32.7, 21.5 ppm; HRMS (EI) calcd
for C26H25NO3S (5a, M+) 431.1555, found 431.1559 and C26H23NO3S (5b, M+) 429.1399, found
429.1402.
4-(4-bromophenyl)-2-tosyl-2,3-dihydro-1H-benzo[f]isoindole (6b). Yield after column
chromatography 12 mg, 26% as a 8:92 mixture of 6a and 6b. Yield after recrystallization 8 mg, 17%;
o
light yellow powder; m.p. 257-258 C; Rf = 0.59 (Hex:EtOAc, 2:1); 1H NMR (300 MHz, CDCl3) δ =
7.82 (d, J = 8.1 Hz, 1 H), 7.75 (d, J = 8.1 Hz, 2 H), 7.65 (d, J = 8.1 Hz, 3 H), 7.54 - 7.42 (m, 3 H),
7.38 (d, J = 7.3 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.15 (d, J = 8.3 Hz, 2 H), 4.80 (s, 2 H), 4.45 (s, 2
13
H), 2.40 (s, 3 H) ppm; C NMR (75 MHz, CDCl3) δ = 144.0, 136.6, 134.5, 133.71, 133.68, 133.2,
132.3, 131.8, 131.3, 130.1, 130.0, 128.2, 127.94, 127.87, 126.5, 126.3, 125.7, 125.6, 122.4, 121.3,
53.6, 53.1, 21.6 ppm; HRMS (EI) calcd for C25H20BrNO2S (M+) 477.0398, found 477.0400.
9-(thiophen-2-yl)-2-tosyl-2,3,3a,4-tetrahydro-1H-benzo[f]isoindole (7a) and 4-(thiophen-2-yl)-
2-tosyl-2,3-dihydro-1H-benzo[f]isoindole (7b). Yield after column chromatography 8 mg, 20% as a
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13:87 mixture of 7a and 7b; brown solid; Rf = 0.40 (Hex:EtOAc, 2:1); 1H NMR (300 MHz, CDCl3) δ
= 7.83 - 7.74 (m, 4 H), 7.71 (d, J = 8.1 Hz, 0.48 H), 7.65 (s, 1 H), 7.53 - 7.39 (m, 3 H), 7.39 - 7.36 (m,
0.48 H), 7.31 (d, J = 7.9 Hz, 2 H), 7.23 - 7.19 (m, 1 H), 7.13 (s, 0.32 H), 7.05 - 7.01 (m, 1 H), 6.93 (d,
J = 3.7 Hz, 0.16 H), 4.80 (s, 2 H), 4.62 (s, 2 H), 4.39 (d, J = 16.5 Hz, 0.16 H), 3.98 (t, J = 8.9 Hz, 0.16
H), 3.80 (d, J = 14.7 Hz, 0.16 H), 3.19 - 3.02 (m, J = 9.4 Hz, 0.16 H), 2.91 - 2.81 (m, J = 9.4 Hz, 0.32
H), 2.65 - 2.57 (m, 0.16 H), 2.42 (s, 0.48 H), 2.39 (s, 3 H) ppm; 13C NMR (75 MHz, CDCl3) δ =
156.7, 150.4, 144.0, 136.8, 134.7, 134.4, 133.8, 133.6, 132.8, 131.3, 130.0, 128.4, 128.3, 127.9, 126.6,
126.2, 125.4, 125.3, 122.8, 121.9, 53.4, 53.1, 21.5 ppm; HRMS (EI) calcd for C23H21NO2S2 (7a, M+)
407.1014, found 407.1015 and C23H19NO2S2 (7b, M+) 405.0857, found 405.0856.
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4-(pyridin-2-yl)-2-tosyl-2,3-dihydro-1H-benzo[f]isoindole
8b.
Yield
after
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chromatography 25 mg, 63% as a 17:83 mixture of 8a and 8b. Yield after recrystallization 18 mg,
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44%; brown solid; m.p. 215-217 C; Rf = 0.49 (Hex:EtOAc, 2:1); H NMR (300 MHz, CDCl3) δ =
8.79 (d, J = 4.0 Hz, 1 H), 7.90 - 7.79 (m, 2 H), 7.75 (d, J = 8.1 Hz, 2 H), 7.71 - 7.61 (m, 2 H), 7.48 -
7.36 (m, 4 H), 7.30 (d, J = 8.1 Hz, 2 H), 4.77 (s, 2 H), 4.60 (s, 2 H), 2.38 (s, 3 H) ppm; 13C NMR (75
MHz, CDCl3) δ = 144.00, 143.97, 139.6, 138.4, 137.5, 135.7, 134.4, 134.2, 133.7, 133.6, 133.0,
130.05, 130.01, 128.3, 128.1, 128.0, 127.9, 127.8, 127.64, 127.59, 127.3, 127.1, 126.8, 126.6, 126.3,
126.0, 125.82, 125.79, 121.9, 54.2, 53.7, 53.6, 51.2, 39.3, 32.5, 21.6, 21.5 ppm; HRMS (EI) calcd for
C24H20N2O2S (M+) 400.1245, found 400.1245.
9-(naphthalen-1-yl)-2-tosyl-2,3,3a,4-tetrahydro-1H-benzo[f]isoindole (9a) and 4-(naphthalen-
1-yl)-2-tosyl-2,3-dihydro-1H-benzo[f]isoindole (9b). Yield after column chromatography 31 mg,
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69% as a 10:90 mixture of 9a and 9b; light brown solid; Rf = 0.51 (Hex:EtOAc, 2:1); H NMR (300
MHz, CDCl3) δ = 7.98 (dd, J = 4.6, 8.3 Hz, 2 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.73 (s, 1 H), 7.67 (d, J =
8.3 Hz, 2 H), 7.60 (dd, J = 7.0, 8.3 Hz, 1 H), 7.50 (ddd, J = 1.1, 6.9, 8.2 Hz, 1 H), 7.43 (ddd, J = 2.8,
5.3, 8.1 Hz, 1 H), 7.33 (dd, J = 1.1, 7.0 Hz, 1 H), 7.28 (t, J = 3.3 Hz, 3 H), 7.24 (d, J = 1.1 Hz, 2 H),
7.10 (d, J = 8.4 Hz, 1 H), 6.98 - 6.87 (m, 0.1 H), 6.47 (d, J = 2.4 Hz, 0.1 H), 4.91 - 4.78 (m, 2 H), 4.45
- 4.35 (m, 1 H), 4.26 - 4.17 (m, 1 H), 4.06 (qd, J = 4.0, 9.5 Hz, 0.1 H), 3.85 - 3.76 (m, J = 1.7 Hz, 0.1
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H), 3.51 - 3.40 (m, J = 2.8 Hz, 0.1 H), 3.28 - 3.14 (m, 0.1 H), 3.05 - 2.87 (m, J = 5.0, 5.0 Hz, 0.2 H),
2.84 - 2.72 (m, J = 15.6 Hz, 0.1 H), 2.43 (s, 0.3 H), 2.38 (s, 3 H) ppm; 13C NMR (75 MHz, CDCl3) δ
= 143.9, 135.2, 134.8, 134.6, 134.1, 133.8, 133.6, 132.8, 132.7, 131.9, 129.99, 129.96, 128.8, 128.7,
128.62, 128.59, 128.1, 128.02, 127.98, 127.9, 127.8, 127.5, 127.3, 127.2, 126.7, 126.4, 126.32,
126.27, 126.2, 126.14, 126.10, 126.0, 125.9, 125.8, 125.7, 121.2, 54.8, 53.8, 53.1, 50.7, 50.6, 39.1,
38.9, 32.9, 32.7, 21.5 ppm; HRMS (EI) calcd for C29H25NO2S (9a, M+) 451.1606, found 451.1604
and C29H23NO2S (9b, M+) 449.1449, found 449.1451.
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6-methyl-4-p-tolyl-2-tosyl-2,3-dihydro-1H-benzo[f]isoindole (10b). Yield after column
chromatography 30 mg, 71% as a 8:92 mixture of 10a and 10b. Yield after recrystallization 24 mg,
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57%; light yellow powder; m.p. 187-188 C; Rf = 0.63 (Hex:EtOAc, 2:1); H NMR (300 MHz,
CDCl3) δ = 7.76 - 7.67 (m, 3 H), 7.57 (s, 1 H), 7.31 (dd, J = 5.2, 8.0 Hz, 6 H), 7.14 (d, J = 8.1 Hz, 2
H), 4.77 (s, 2 H), 4.46 (s, 2 H), 2.48 (s, 3 H), 2.38 (d, J = 6.6 Hz, 6 H) ppm; 13C NMR (75 MHz,
CDCl3) δ = 143.9, 137.7, 136.0, 134.9, 134.0, 133.81, 133.79, 133.7, 133.4, 132.3, 132.0, 130.0,
129.6, 129.4, 128.4, 127.91, 127.85, 124.9, 120.4, 53.7, 53.3, 31.6, 22.7, 21.9, 21.5, 21.4, 14.1 ppm;
HRMS (EI) calcd for C27H25NO2S (M+) 427.1606, found 427.1606.
8-methoxy-4-p-tolyl-2-tosyl-2,3-dihydro-1H-benzo[f]isoindole (11b). Yield after column
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chromatography 32 mg, 72%; brown solid; m.p. 226-229 C; Rf = 0.62 (Hex:EtOAc, 2:1); H NMR
(300 MHz, CDCl3) δ = 8.08 (s, 1 H), 7.73 (d, J = 8.3 Hz, 2 H), 7.29 (d, J = 7.9 Hz, 4 H), 7.22 (d, J =
7.5 Hz, 1 H), 7.17 - 7.10 (m, 3 H), 6.79 (d, J = 7.3 Hz, 1 H), 4.79 (s, 2 H), 4.48 (s, 2 H), 3.99 (s, 3 H),
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2.46 (s, 3 H), 2.38 (s, 3 H) ppm; C NMR (75 MHz, CDCl3) δ = 155.5, 143.9, 137.7, 135.0, 134.3,
134.1, 133.8, 133.7, 133.2, 130.0, 129.6, 129.4, 127.9, 127.8, 126.0, 125.9, 118.4, 115.0, 104.0, 55.7,
54.0, 53.4, 21.5, 21.3 ppm; HRMS (EI) calcd for C27H25NO3S (M+) 443.1555, found 443.1552.
6-bromo-4-p-tolyl-2-tosyl-2,3-dihydro-1H-benzo[f]isoindole (12b). Yield after column
chromatography 38 mg, 77% as a 10:90 mixture of 12a and 12b. Yield after recrystallization 30 mg,
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62%; white solid; m.p. 218-221 C; Rf = 0.58 (Hex:EtOAc, 2:1); H NMR (300 MHz, CDCl3) δ =
7.76 - 7.71 (m, 3 H), 7.67 (d, J = 8.8 Hz, 1 H), 7.59 (s, 1 H), 7.51 (dd, J = 1.8, 8.8 Hz, 1 H), 7.32 (t, J
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= 6.7 Hz, 4 H), 7.12 (d, J = 7.9 Hz, 2 H), 4.76 (s, 2 H), 4.47 (s, 2 H), 2.48 (s, 3 H), 2.39 (s, 3 H) ppm;
13C NMR (75 MHz, CDCl3) δ = 144.0, 138.2, 135.0, 134.9, 134.0, 133.9, 133.7, 133.6, 133.3, 132.2,
130.0, 129.9, 129.7, 129.5, 129.3, 128.2, 127.8, 120.6, 120.5, 53.6, 53.2, 21.5, 21.4 ppm; HRMS (EI)
calcd for C26H22BrNO2S (M+) 491.0555, found 491.0551.
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4-p-tolyl-6-tosyl-6,7,7a,8-tetrahydro-5H-thieno[3,2-f]isoindole (13a) and 4-p-tolyl-6-tosyl-6,7-
dihydro-5H-thieno[3,2-f]isoindole (13b). Yield after column chromatography 24 mg, 57% as a
11:89 mixture of 13a and 13b; brown solid; Rf = 0.63 (Hex:EtOAc, 2:1); 1H NMR (300 MHz, CDCl3)
δ = 7.74 (d, J = 8.3 Hz, 2 H), 7.69 (d, J = 8.3 Hz, 0.3 H), 7.62 (s, 1 H), 7.35 - 7.27 (m, 5 H), 7.25 -
7.19 (m, 2 H), 7.17 (s, 0.1 H), 7.12 (d, J = 5.5 Hz, 1 H), 7.10 - 7.05 (m, 0.2 H), 6.96 (d, J = 5.1 Hz,
0.1 H), 6.59 (d, J = 5.1 Hz, 0.1 H), 4.75 (s, 2 H), 4.56 (s, 2 H), 4.34 (d, J = 15.6 Hz, 0.1 H), 3.94 (t, J
= 8.7 Hz, 0.1 H), 3.69 (dd, J = 2.5, 15.3 Hz, 0.1 H), 3.41 - 3.24 (m, 0.1 H), 3.01 (dd, J = 8.0, 15.3 Hz,
0.1 H), 2.89 (t, J = 9.4 Hz, 0.1 H), 2.66 - 2.57 (m, J = 16.1 Hz, 0.1 H), 2.44 (s, 3 H), 2.41 (br. s., 0.6
H), 2.39 (s, 3 H) ppm; 13C NMR (75 MHz, CDCl3) δ = 143.9, 140.3, 138.8, 137.9, 135.1, 133.8, 133.5,
132.7, 131.6, 130.0, 129.6, 128.9, 127.8, 126.6, 123.2, 115.4, 53.7, 53.0, 21.5, 21.3 ppm; HRMS (EI)
calcd for C24H23NO2S2 (13a, M+) 421.1170, found 421.1171 and C24H21NO2S2 (13b, M+) 419.1014,
found 419.1017.
7-p-tolyl-9-tosyl-9,10,10a,11-tetrahydro-8H-naphtho[2,1-f]isoindole (15a) and 7-p-tolyl-9-
tosyl-9,10-dihydro-8H-naphtho[2,1-f]isoindole (15b). Yield after column chromatography 36 mg,
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77% as a 10:90 mixture of 15a and 15b; white powder; Rf = 0.53 (Hex:EtOAc, 2:1); H NMR (300
MHz, CDCl3) δ = 8.62 (d, J = 8.1 Hz, 1 H), 8.48 (s, 1 H), 8.01 (d, J = 8.4 Hz, 0.2 H), 7.83 (d, J = 7.7
Hz, 1 H), 7.76 (d, J = 8.1 Hz, 2 H), 7.64 - 7.48 (m, 4 H), 7.42 (d, J = 7.7 Hz, 0.2 H), 7.31 (t, J = 8.0
Hz, 4 H), 7.25 - 7.19 (m, 0.8 H), 7.16 (d, J = 7.7 Hz, 2 H), 7.05 (br. s., 0.4 H), 6.97 (d, J = 8.4 Hz, 0.2
H), 4.89 (s, 2 H), 4.53 (s, 2 H), 4.38 (d, J = 15.6 Hz, 0.2 H), 4.06 (t, J = 8.5 Hz, 0.2 H), 3.75 - 3.59 (m,
0.4 H), 3.26 - 3.09 (m, J = 7.4, 7.4, 15.2 Hz, 0.2 H), 3.05 - 2.95 (m, 0.2 H), 2.72 - 2.62 (m, 0.2 H),
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2.48 (s, 3 H), 2.40 (d, J = 5.0 Hz, 1.2 H), 2.37 (s, 3 H) ppm; C NMR (75 MHz, CDCl3) δ = 143.9,
137.8, 137.6, 136.3, 135.5, 135.2, 135.0, 134.8, 134.3, 133.93, 133.91, 133.5, 133.4, 133.3, 133.1,
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132.6, 131.9, 131.3, 130.8, 130.4, 130.2, 130.01, 129.97, 129.74, 129.68, 129.6, 129.5, 129.3, 128.8,
128.7, 127.9, 127.8, 127.0, 126.9, 126.6, 126.5, 125.6, 124.6, 124.4, 123.6, 122.9, 115.7, 54.6, 54.3,
53.6, 50.8, 39.0, 27.8, 21.6, 21.5, 21.4, 21.3 ppm; HRMS (EI) calcd for C30H27NO2S (15a, M+)
465.1762, found 465.1760 and C30H25NO2S (15b, M+) 463.1606, found 463.1609.
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11-p-tolyl-9-tosyl-9,10-dihydro-8H-naphtho[1,2-f]isoindole (16b). Yield after column
chromatography 54 mg, 96% as a 18:82 mixture of 16a and 16b. Yield after recrystallization 32 mg,
o
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68%; white powder; m.p. 188-191 C; Rf = 0.63 (Hex:EtOAc, 2:1); H NMR (300 MHz, CDCl3) δ =
7.79 (dd, J = 1.3, 7.9 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 2 H), 7.69 - 7.62 (m, 4 H), 7.40 (ddd, J = 1.1, 7.0,
7.9 Hz, 1 H), 7.31 (t, J = 8.7 Hz, 4 H), 7.11 (d, J = 7.9 Hz, 3 H), 4.84 (s, 2 H), 4.41 (s, 2 H), 2.51 (s, 3
H), 2.38 (s, 3 H) ppm; 13C NMR (75 MHz, CDCl3) δ = 143.9, 139.0, 137.7, 136.6, 135.5, 134.3, 134.0,
133.9, 133.6, 130.85, 130.76, 130.0, 128.7, 128.5, 128.2, 128.1, 128.0, 127.81, 127.78, 127.4, 126.3,
126.2, 125.5, 122.0, 54.3, 54.1, 21.5, 21.5 ppm; HRMS (EI) calcd for C30H25NO2S (M+) 463.1606,
found 463.1609.
5-methyl-4-p-tolyl-2-tosyl-2,3-dihydro-1H-benzo[f]isoindole (17b) and 7-methyl-4-p-tolyl-2-
tosyl-2,3-dihydro-1H-benzo[f]isoindole (17b’). Yield after column chromatography 29 mg, 67% as
1
a 66:34 mixture of 17b and 17b’; brown powder; Rf = 0.59 (Hex:EtOAc, 2:1); H NMR (300 MHz,
CDCl3) δ = 7.76 - 7.68 (m, 2 H), 7.68 - 7.63 (m, 1 H), 7.60 (s, 1 H), 7.57 - 7.46 (m, 1 H), 7.33 - 7.26
(m, 4 H), 7.21 (d, J = 7.7 Hz, 1 H), 7.16 - 7.12 (m, 1 H), 7.06 (d, J = 7.9 Hz, 1 H), 4.77 (s, 2 H), 4.47
(s, 1 H), 4.31 (s, 1 H), 2.46 (d, J = 2.9 Hz, 4 H), 2.38 (s, 3 H), 1.95 (s, 2 H) ppm; 13C NMR (75 MHz,
CDCl3) δ = 143.8, 138.8, 137.4, 135.9, 135.1, 134.8, 134.5, 133.3, 130.0, 129.6, 129.4, 129.2, 128.9,
128.4, 127.9, 127.8, 127.5, 127.1, 125.9, 125.7, 122.0, 120.0, 54.0, 53.8, 24.8, 22.7, 21.5, 21.4 ppm;
HRMS (EI) calcd for C27H25NO2S (M+) 427.1606, found 427.1603.
4-p-tolyl-1,3-dihydronaphtho[2,3-c]furan (18b). Yield after column chromatography 16 mg,
60%; yellow viscous liquid; Rf = 0.56 (Hex:EtOAc, 2:1); 1H NMR (300 MHz, CDCl3) δ = 7.86 (d, J =
7.9 Hz, 1 H), 7.73 - 7.66 (m, 2 H), 7.45 (t, J = 7.4 Hz, 1 H), 7.36 (dt, J = 1.1, 7.6 Hz, 2 H), 7.32 - 7.29
13
(m, 2 H), 7.25 - 7.23 (m, 1 H), 5.29 (s, 2 H), 5.03 (s, 2 H), 2.45 (s, 3 H) ppm; C NMR (75 MHz,
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CDCl3) δ = 137.9, 137.5, 137.1, 135.3, 133.9, 132.8, 132.1, 129.54, 129.49, 129.3, 129.1, 128.2,
126.0, 125.9, 125.8, 118.8, 73.5, 73.1, 21.3 ppm; HRMS (EI) calcd for C19H16O (M+) 260.1201, found
260.1202.
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diethyl 4-p-tolyl-1H-cyclopenta[b]naphthalene-2,2(3H)-dicarboxylate (19b). Yield (determined
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by H-NMR) after column chromatography 32 mg, 78% from a 30:70 mixture of 19b (24%) and
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starting material (54%); colorless liquid; Rf = 0.53 (Hex:EtOAc, 2:1); H NMR (300 MHz, CDCl3) δ
= 7.79 (d, J = 8.1 Hz, 1 H), 7.66 (s, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 7.43-7.36 (m, 4 H), 7.31 (d, J =
5.5 Hz, 4 H), 7.24 (br. s., 1 H), 4.17 (q, J = 7.2 Hz, 4 H), 3.78 (s, 2 H), 3.48 (s, 2 H), 2.46 (s, 3 H),
1.22 (t, J = 7.1 Hz, 6 H) ppm; 13C NMR (75 MHz, CDCl3) δ = 171.6, 170.0, 138.5, 138.1, 137.6,
137.2, 137.1, 136.9, 135.7, 135.1, 134.5, 134.1, 133.6, 132.0, 131.6, 129.8, 129.2, 129.01, 128.97,
128.6, 128.5, 127.8, 127.4, 126.3, 126.2, 125.9, 125.2, 125.1, 124.0, 123.6, 121.9, 120.2, 83.7, 83.6,
61.60, 61.58, 61.3, 60.6, 57.4, 40.4, 39.8, 36.5, 36.0, 23.7, 21.3, 21.2, 14.0, 13.9 ppm; HRMS (ESI)
calcd for C26H26O4 (M + H+) 403.1909, found 403.1903.
2-tosyl-4-(trimethylsilyl)-2,3-dihydro-1H-benzo[f]isoindole (21b).5g Yield after column
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chromatography 22 mg, 56%; orange liquid; Rf = 0.53 (Hex:EtOAc, 2:1); H NMR (300 MHz,
CDCl3) δ = 8.12 (d, J = 6.8 Hz, 1 H), 7.80 (d, J = 8.3 Hz, 2 H), 7.76 (d, J = 2.8 Hz, 1 H), 7.63 (s, 1 H),
7.49-7.41 (m, 2 H), 7.33 (d, J = 8.1 Hz, 2 H), 4.78 (s, 2 H), 4.68 (s, 2 H), 2.40 (s, 3 H), 0.50 (s, 9 H)
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ppm; C NMR (75 MHz, CDCl3) δ = 143.8, 141.6, 136.9, 134.1, 133.0, 129.9, 129.0, 128.2, 127.8,
125.5, 125.4, 123.2, 55.0, 52.4, 21.4, 2.2 ppm; HRMS (ESI) calcd for C22H25NO2SSi (M + H+)
396.1448, found 396.1447.
4-methyl-2-tosyl-2,3-dihydro-1H-benzo[f]isoindole (23b).19 Yield after column chromatography
5 mg, 15%; light yellow liquid; Rf = 0.60 (Hex:EtOAc, 2:1); 1H NMR (300 MHz, CDCl3) δ = 7.77 (d,
J = 8.1 Hz, 2 H), 7.34 - 7.29 (m, 5 H), 6.53 (s, 1 H), 6.58 (s, 1 H), 6.08 (dt, J = 6.8 Hz, 1 H), 4.05 (d, J
= 2.4 Hz, 2 H), 3.96 (d, J = 6.8 Hz, 2 H), 2.43 (s, 3 H), 1.59 - 1.54 (m, 3 H) ppm; 13C NMR (75 MHz,
CDCl3) δ = 143.8, 134.2, 133.6, 133.45, 133.38, 132.1, 129.9, 128.5, 128.1, 127.7, 125.9, 125.8,
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123.6, 119.3, 53.6, 53.0, 21.4, 15.1 ppm; HRMS (ESI) calcd for C20H19NO2S (M + H+) 338.1209,
found 338.1190.
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5-methyl-4-p-tolyl-2-tosylisoindoline (27b). Yield after column chromatography 14 mg, 56%;
yellow solid; m.p. 175-177 oC; Rf = 0.61 (Hex:EtOAc, 2:1); 1H NMR (300 MHz , CDCl3) δ = 7.70 (d,
J = 8.3 Hz, 2 H), 7.29 (d, J = 8.1 Hz, 2 H), 7.23 (d, J = 7.7 Hz, 2 H), 7.15 (d, J = 7.7 Hz, 1 H), 7.06 -
6.97 (m, 3 H), 4.63 (s, 2 H), 4.32 (s, 2 H), 2.41 (d, J = 3.9 Hz, 6 H), 2.08 (s, 3 H) ppm; 13C NMR (75
MHz, CDCl3) δ = 143.7, 137.4, 137.3, 135.8, 135.7, 134.0, 133.6, 129.95, 129.91, 129.6, 128.5, 127.8,
121.3, 54.1, 53.7, 21.5, 21.3, 19.8 ppm; HRMS (EI) calcd for C23H23NO2S (M+) 377.1449, found
377.1452.
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5-methyl-2-tosyl-4-(trimethylsilyl)isoindoline (29b).5g Yield after column chromatography 17
mg, 48% as a 29:71 mixture of 29a and 29b. Yield after recrystallization 10 mg, 29%; colorless oil;
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Rf = 0.51 (Hex:EtOAc, 2:1); H NMR (300 MHz, CDCl3) δ = 7.76 (d, J = 8.4 Hz, 1 H), 7.72 (d, J =
8.1 Hz, 2 H), 7.37 - 7.25 (m, 3 H), 7.03 (s, 0.84 H), 5.66 - 5.52 (dd, J = 8.8 Hz, 2 H), 4.62 (s, 0.84 H),
4.52 (s, 0.84 H), 3.97 (d, J = 13.0 Hz, 1 H), 3.82 - 3.71 (m, 2 H), 2.98 - 2.76 (m, 2 H), 2.72 - 2.61 (m,
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1 H), 2.46 - 2.36 (m, 6 H), 1.04 (d, J = 6.8 Hz, 3 H), 0.34 (s, 3 H), 0.12 (s, 9 H) ppm; C NMR (75
MHz, CDCl3) δ = 143.82, 143.80, 141.9, 133.8, 133.11, 133.05, 130.1, 130.0, 127.8, 123.4, 55.5, 52.9,
23.7, 21.5, 1.9 ppm; HRMS (ESI) calcd for C19H25NO2SSi (M + H+) 360.1448, found 360.1446.
￭ ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
DFT calculation data for all compounds and Fe complexes in Figure 1 and 2.
1H NMR and 13C NMR for all synthesized compounds.
￭ AUTHOR INFORMATION
Corresponding Authors
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*E-mail: khahn@khu.ac.kr, ejkang24@khu.ac.kr
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ORCID
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Eun Joo Kang: 0000-0002-7600-3609
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Kwang-Hyun Ahn: 0000-0002-2812-4895
Notes
The authors declare no competing financial interest.
￭ ACKNOWLEDGMENTS
This study was supported by the Ministry of Education, Science and Technology, National Research
Foundation (grant numbers NRF-2015R1D1A1A01060349) and the GRRC program of Gyeonggi
province (GRRCKyungHee2017-A01, Novel and original technology research for platform synthesis
of incrementally modified synthetic global drug candidates).
￭ REFERENCES
1. (a) Diels, O.; Alder, K. Ann. Chem. 1928, 460, 98. (b) Dewar, M. J. S.; Olivella, S.; Stewart,
J. J. P. J. Am. Chem. Soc. 1986, 108, 5771. (c) Winkler, J. D. Chem. Rev. 1996, 96, 167. (d)
Jørgensen, K. A. Angew. Chem. Int. Ed. 2000, 39, 3558. (e) Takao, K.; Munakata, R.;
Tadano, K. Chem. Rev. 2005, 105, 4779. (f) Jiang, X.; Wang, R. Chem. Rev. 2013, 113, 5515.
2. This process has been generally called the dehydro-Diels-Alder (DDA) reaction, which
suggested by P. Wessig; (a) Wessig, P.; Müller, G. Chem. Rev. 2008, 108, 2051. (b) Wessig,
P.; Matthes, A.; Pick, C. Org. Biomol. Chem. 2011, 9, 7599. (c) Wessig, P.; Matthes, A.;
Schilde, U.; Kelling, A. Eur. J. Org. Chem. 2013, 2123. (d) Hoye, T. R.; Baire, B.; Niu, D.;
Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208. (e) Wang, T.; Hoye, T. R. J. Am.
Chem. Soc. 2016, 138, 13870. (f) Vandavasi, J. K.; Hu, W.-P.; Hsiao, C.-T.; Senadi, G. C.;
Wang, J.-J. RSC Adv. 2014, 4, 57547.
3. (a) Wagner-Jauregg, T. Synthesis 1980, 769. (b) Parker, K. A.; Ruder, S. M. J. Am. Chem.
Soc. 1989, 111, 5948.
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2
3
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4. Stille, J. K.; Chung, D. C. Macromolecules 1975, 8, 83.
5
6
7
8
9
5. (a) Klemm, L. H.; Gopinath, K. W. Tetrahedron Lett. 1963, 19, 1243. (b) Klemm, L. H.;
Klemm, R. A.; Santhanam, P. S.; White, D. V. J. Org. Chem. 1971, 36, 2169. (c) Klemm, L.
H.; McGuire, T. M.; Gopinath, K. W. J. Org. Chem. 1976, 41, 2571. (d) Toyota, M.;
Terashima, S. Tetrahedron Lett. 1989, 30, 829. (e) Chackalamannil, S.; Doller, D.; Clasby,
M.; Xia, Y.; Eagen, K.; Lin, Y.; Tsai, H.-A.; McPhail, A. T. Tetrahedron Lett. 2000, 41,
4043. (f) Ruijter, E.; Garcia-Hartjes, J.; Hoffmann, F.; vanꢀWandelen, L.; deꢀKanter, F.;
Janssen, E.; Orru, R. Synlett 2010, 2010, 2485. (g) Ozawa, T.; Kurahashi, T.; Matsubara, S.
Org. Lett. 2011, 13, 5390. (h) Fang, Z.; Liu, Y.; Barry, B.-D.; Liao, P.; Bi, X. Org. Lett. 2015,
17, 782. (i) For an extensive review on the recent progress in dehydro-Diels-Alder reactions,
see Li, W.; Zhou, L.; Zhang, J. Chem. Eur. J. 2016, 22, 1558.
10
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12
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49
50
51
52
53
54
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56
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58
59
60
6. (a) Kocsis, L. S.; Benedetti, E.; Brummond, K. M. Org. Lett. 2012, 14, 4430. (b) Kocsis, L.
S.; Brummond, K. M. Org. Lett. 2014, 16, 4158. (c) Kocsis, L. S.; Kagalwala, H. N.; Mutto,
S.; Godugu, B.; Bernhard, S.; Tantillo, D. J.; Brummond, K. M. J. Org. Chem. 2015, 80,
11686. (d) Brummond, K. M.; Kocsis, L. S. Acc. Chem. Res. 2015, 48, 2320.
7. Zheng, M.; Wu, F.; Chen, K.; Zhu, S. Org. Lett. 2016, 18, 3554.
8. Xiao, Y.-C.; Yue, C.-Z.; Chen, P.-Q.; Chen, Y.-C. Org. Lett. 2014, 16, 3208.
9. (a) Muthukrishnan, I.; Vinoth, P.; Vivekanand, T.; Nagarajan, S.; Maheswari, C. U.;
Menendez, J. C.; Sridharan, V. J. Org. Chem. 2016, 81, 1116. (b) Yu, X.; Wang, J.; Xu, Z.;
Yamamoto, Y.; Bao, M. Org. Lett. 2016, 18, 2491.
10. (a) Jung, M. S.; Kim, W. S.; Shin, Y. H.; Jin, H. J.; Kim, Y. S.; Kang, E. J. Org. Lett., 2012,
14, 6262. (b) Kim, J. H.; Kim, S. W.; Jung, M. S.; Ahn, K-H.; Kang, E. J. Bull. Korean Chem.
Soc. 2015, 36, 2846.
11. Other Lewis acids such as InCl3, AgOTf, and Sn(OTf)2 were tested in this styrenyl
didehydro-Diels-Alder reaction, however all reactions resulted either C-N bond cleavage or
decomposition of styren-yne substrate.
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12. (a) Göttker-Schnetmann, I.; Brookhart M. J. Am. Chem. Soc. 2004, 126, 9330. (b) Ahuja, R.;
Punji, B.; Findlater, M.; Supplee, C.; Schinski, W.; Brookhart, M.; Goldman, A. S. Nat.
Chem. 2011, 3, 167. (c) Lyons, T. W.; Bézier, D.; Brookhart, M. Organometallics 2015, 34,
4058. (d) Liu, X.-J.; Wang, W.-P.; Huo, C.-D.; Wang, X.-C.; Quan, Z.-J. Catal. Sci. Technol.
2017, 7, 565.
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13. (a) Ilhan, F.; Tyson, D. S.; Meador, M. A. Org. Lett. 2006, 8, 577. (b) Zhang, W.; Ma, H.;
Zhow, L.; Sun, Z.; Du, Z.; Miao, H.; Xu, J. Molecules 2008, 13, 3236. (c) Ruijter, E.; Garcia-
Hartjes, J.; Hoffmann, F.; van Wandelen, L. T. M.; de Kanter, F. J. J.; Janssen, E.; Orru, R. V.
A. Synlett 2010, 16, 2485. (d) Abdelhamid, I. A.; Butenschön, H. Eur. J. Org. Chem. 2015,
226. (e) Bercaw, J. E.; Hazari, N.; Labinger, J. A. J. Org. Chem. 2008, 73, 8654. (f) Silva, L.
F.; Siqueira, F. A.; Pedrozo, E. C.; Vieira, F. Y. M.; Doriguetto, A. C. Org. Lett. 2007, 9,
1433.
14. (a) Sundararajan, G.; Prabagaran, N.; Varghese, B. Org. Lett. 2001, 3, 1973. (b) Gademann,
K.; Chavez, D. E.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2002, 41, 3095. (c) Li, P.;
Yamamoto, H. J. Am. Chem. Soc. 2009, 131, 16628. (d) Jiang, X.; Wang, R. Chem. Rev.
2013, 113, 5515. (e) Yan, X.; Ling, F.; Zhang, Y.; Ma, C. Org. Lett. 2015, 17, 3536. (f)
Duret, G.; Quinlan, R.; Martin, R. E.; Bisseret, P.; Neuburger, M.; Gandon, V.; Blanchard, N.
Org. Lett. 2016, 18, 1610.
15. To investigate the reaction mechanism, we checked the possibility of radical pathway in the
didehydro-Diels-Alder reaction. The addition of 1.5 equivalents of TEMPO resulted in
decreasing of the overall yield without any significant difference in the product ratio (32%
yield, 2a:2b = 16:84), which cannot strongly support the radical mechanism.
16. We employed a model catalyst as FeCl2 instead of Fe(acac)2 and N-mesyl functional group
instead of N-tosyl group to simplify the calculation.
17. Kolis, S. P.; Chordia, M. D.; Liu, R.; Kopach, M. E.; Harman, W. D. J. Am. Chem. Soc. 1998,
120, 2218.
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18. Das, J.; Mukherjee, R.; Basak, A. J. Org. Chem. 2014, 79, 3789.
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19. Wang, F.; Tong, X.; Cheng, J.; Zhang, Z. Chem. Eur. J. 2004, 10, 5338.
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