Convergent routes to substituted naphthylamides

Article abstract of DOI:10.1039/c4ob00339j

Practical, convergent routes to variously substituted 1- and 2-naphthylamides have been developed. They exploit the ability of xanthates to undergo both intermolecular radical additions to vinyl pivalate and intramolecular radical cyclisations to aromatic

Full text of DOI:10.1039/c4ob00339j

Organic &
Biomolecular Chemistry
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PAPER
Convergent routes to substituted
naphthylamides†‡
Cite this: Org. Biomol. Chem., 2014,
12, 3251
Ngoc Diem My Tran and Samir Z. Zard*
Received 13th February 2014,
Accepted 13th March 2014
Practical, convergent routes to variously substituted 1- and 2-naphthylamides have been developed. They
exploit the ability of xanthates to undergo both intermolecular radical additions to vinyl pivalate and intra-
molecular radical cyclisations to aromatic rings. In the case of 1-naphthylamides, the existence of an
intramolecular hydrogen bond was used to facilitate the cyclisation step.
DOI: 10.1039/c4ob00339j
www.rsc.org/obc
Introduction
Even though naphthalenes have been known for a long time,
these classical aromatic compounds have found their impor-
tance growing over the years. Indeed, numerous applications
of naphthalenes have been reported in many different fields
such as organic synthesis, medicinal chemistry and materials
science.1 It is not surprising, therefore, that a plethora of
methods to access these structures have been developed.2
However, the preparation of the naphthylamine subfamily
remains a significant challenge, despite its importance in
the manufacture of dyes, rubber stabilisers, agrochemicals,
pharmaceuticals, etc.
For example, naphthionic acid (1-naphthylamine-4-sulpho-
nic acid) I is an important dye intermediate for Congo Red,
Fast Dye A and azo dyes in general; N-phenyl-1-naphthylamine
II is used as an antioxidant for rubber;3a N-1-naphthylphthala-
mic acid III (Naptalam) is a selective herbicide used for
soybean, peanut, and vine crops; compound IV is a potent
binder of the chemokine receptor CCR8;3b and rifampicin V is
a semisynthetic antibiotic of the ansa family that is in clinical
use (Fig. 1).3c
Fig. 1 Examples of important naphthylamines.
conditions.4 We have now exploited this chemistry for the
synthesis of both α- and β-naphthylamides.
Generally, naphthylamine derivatives are prepared by
nitration of naphthalene, followed by reduction of the nitro
group. The relatively harsh reaction conditions do not allow
easy control of regioselectivity. Thus, no simple method for
the regioselective synthesis of substituted naphthylamines has
been reported so far. We recently described a convenient
approach to synthesise substituted naphthalenes using a
xanthate radical addition–cyclisation sequence under mild
Synthesis of substituted 2-naphthylamides
Our initial synthesis of naphthalenes, depicted in the top part
of Scheme 1, hinges on the possibility of addition of a phena-
cyl type radical to vinyl pivalate and cyclisation onto the aro-
matic ring followed by aromatisation of the tetralone through
acid-induced elimination of pivalic acid.4a Introduction of a
protected amino group in the position adjacent to the carbonyl
group in the xanthate partner would allow a simple extension
of this approach to the synthesis of 2-naphthylamides, as out-
lined in the lower part of Scheme 1.
The main general synthetic scheme we adopted to access
the requisite tetralones 6 is depicted in Scheme 2. The readily
available α-bromoacetophenone precursors 1 were first treated
with potassium phthalimide in DMF at room temperature to
Laboratoire de Synthèse Organique, CNRS UMR 7652, Ecole Polytechnique, 91128
Palaiseau, France. E-mail: zard@poly.polytechnique.fr
†This article is dedicated to Professor Richard J. K. Taylor on the occasion of his
65th birthday.
‡Electronic supplementary information (ESI) available: NMR spectra of all new
compounds. See DOI: 10.1039/c4ob00339j
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Fig. 2 Examples of xanthates 4.
Table 1 Radical addition–cyclisation of xanthates 4
Xanthates 4 Tetralones 6
Yield (%)
42
Scheme 1 Proposed route to 2-naphthylamides.
45
40
37
41
Scheme 2 Synthesis of key tetralones.
furnish compounds 2, which were brominated with pyridi-
nium hydrobromide perbromide (PHP) in acetic acid at 70 °C.5
The α-bromine in compounds 3 thus obtained was easily sub- with a stoichiometric amount of DLP to induce cyclisation
stituted by the salt of potassium O-ethyl xanthate to provide onto the aromatic ring. In this manner, the desired tetralones
the starting xanthates 4 (Xa in all the schemes and tables cor- 6 were obtained successfully in a one-pot procedure in an
responds to EtOC(vS)S–). In this manner, xanthates 4a–4e dis- overall yield varying from 37% to 45% (Table 1).
played in Fig. 2 were readily prepared.
These moderate yields are mostly due to the difficult cycli-
With the starting xanthates 4 in hand, the addition–cyclisa- sation step. In any case, both the intermolecular addition to
tion sequence could be tested. The radical addition of vinyl pivalate and the ring-closure onto the aromatic ring are
xanthates 4 and vinyl pivalate to give adducts 5, precursors for not trivial processes and cannot be easily achieved by more
the next cyclisation step, was accomplished using 25–30 mol% conventional radical methods.
of dilauroyl peroxide (DLP) as the initiator and 1,2-dichloro-
For the aromatisation step, numerous methods such as oxi-
ethane (DCE) as the solvent. Once the starting xanthate was dation with DDQ or Pd/C at high temperature6 or heating
consumed, the solvent and excess vinyl pivalate were evapor- under acidic conditions4a have been reported. As in our pre-
ated and the residue taken up in chlorobenzene and treated vious study,4a tetralones 6 were treated with p-toluenesulfonic
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Table 2 Aromatisation of tetralones 6 into aminonaphthols 7
Tetralones 6
2-Naphthylamide 7
Yield (%)
83
Scheme 3 The Semmler–Wolff/Schroeter reaction.
78
72
80
79
Scheme 4 Ring closure of unprotected phenol derivatives.
acid in refluxing toluene using a Dean–Stark apparatus for
3 hours. After workup, the residue was easily purified by
simply washing with pentane or dichloromethane and pro-
vided the final products as crystalline solids. This efficient aro-
matisation (up to 83% yield) completed the sequence leading
to 2-naphthylamides 7a–e (Table 2).
No attempt was made to remove the phthalimide group
because of the reputed carcinogenicity of 2-naphthylamines in
general. It is interesting to note that the 2-amino-1-naphthol
motif is found at the core of the important rifamycin ansa
family of antibiotics (cf. rifampicin in Fig. 1 above). Further-
more, with the exception of the parent 2-amino-1-naphthol
corresponding to phthalimide 7a, none of the substituted
2-amino-1-naphthols corresponding to 7b–e has been described
in the open literature.
gas in refluxing AcOH/Ac2O. Yet, this method has rarely been
used because of the limited availability of substituted α-tetra-
lones and the harsh conditions that often lead to the Beck-
mann rearrangement lactam as a significant side product
(Scheme 3).7
Recently, the Stahl group developed the use of Pd as the
catalyst to improve the efficiency of this process.8 Even though
the transformation of tetralone to naphthylamine can now
be accomplished in high yield, a limitation of this approach
appeared with substrates bearing a bromide substituent
because of the competing oxidative addition of the bromoar-
enes to the palladium complex.
From our earlier experience with the synthesis of tetra-
lones,9 we had noted that the presence of a substituent ortho-
to the acyl chain, and especially a methoxy group, is quite det-
rimental to the cyclisation step. Thus, xanthate 8 furnishes
mostly prematurely reduced material 9 and only a very poor
Synthesis of substituted 1-naphthylamides
Apart from nitration and reduction, a classical method to yield of the corresponding tetralone. This is almost certainly
prepare 1-naphthylamines is the Semmler–Wolff/Schroeter aro- due to a combination of steric and dipole–dipole repulsions
matisation, which involves dehydration of the α-tetralone- favouring conformation A′ over A (Scheme 4). A simple and
derived oxime under acidic conditions using anhydrous HCl effective solution to this synthetic problem was to work with
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Table 3 Formation of xanthates 15
Precursors 11
Xanthate 15
Yield (%)
49
Scheme 5 Strategy for the synthesis of 1-naphthylamines.
53
48
63
40
Scheme 6 Synthesis of xanthate precursors 15. (a) PdCl2(PPh3)2 2 mol%,
CuI 1 mol%, TMSCCH, Et3N, THF, rt; (b) Ac2O, DCM, rt; (c) K2CO3, MeOH,
rt; (d) NBS, FeCl3 5 mol%, H2O : THF (1 : 1) reflux; (e) (EtO)2POH, Et3N,
THF, rt; (f) PHP, AcOH 50 °C; (g) CuBr2, CH3COOEt : CHCl3 (1 : 1) reflux;
(h) KXa, acetone, rt.
tives 14 by diethyl phosphite (EtO)2POH and triethylamine in
tetrahydrofuran at room temperature,13 which were then con-
verted into xanthates 15 by substitution of the bromine with
potassium O-ethyl xanthate in almost quantitative yield for the
two steps (Table 3). In cases where the 2-acetyl acetanilide was
available, a simple bromination delivered the desired α-bromo-
acetyl precursor 14. With xanthates 15 in hand, the synthesis
of tetralones 17 could be accomplished as outlined in
Scheme 7.
In this case, the additional products were obtained fairly
cleanly after the addition of only 10 mol% of DLP. We observed
that tetralones 17a and 17b started appearing after the con-
sumption of around 40% of starting xanthates 15a and 15b
respectively. This behaviour indicated that the corresponding
intermediates 16a and 16b began to cyclise during the inter-
molecular addition process. As a result, we decided to add a
stoichiometric amount of DLP to the mixture of xanthate 15
with vinyl pivalate in 10 mol% portions every hour to generate
directly tetralones 17a and 17b. This indicated that the cyclisa-
tion of these compounds proceeded smoothly under mild
conditions.
the naked phenol, which is able to form a strong hydrogen
bond with the ketone oxygen.9 This hydrogen bond freezes the
structure in the correct conformation B for cyclisation and, at
the same time, slows down considerately the rate of hydrogen
abstraction from the phenol.10 Indeed both the addition and
cyclisation steps could be accomplished on the unprotected
phenol, as illustrated by the conversion of xanthate 10 into
shinanolone by radical cyclisation followed by saponification
of the acetate group in a two-step one-pot process.
We decided therefore to incorporate this feature into our
synthesis of 1-naphthylamide derivatives. Thus, in the same
fashion, an N-acetyl group ortho to the ketone bearing side-
chain should exhibit
a hydrogen bonding encouraging
similarly the desired cyclisation and leading to a convenient
synthesis of N-acetyl naphthylamides (Scheme 5).
For the preparation of the requisite substituted xanthate
precursors 15, we applied the Sonogashira reaction on 2-iodo-
anilines, as pictured in Scheme 6.11 Acetylation with acetic
anhydride furnished acetanilides 12 in overall yields in excess
of 90%. The trimethylsilyl group was first cleaved off by potass-
ium carbonate in methanol at room temperature, followed by
heating with N-bromosuccinimide in the presence of the iron
trichloride catalyst in a refluxing mixture of water and tetra-
hydrofuran to provide the intermediate α-dibromo derivatives
13.12 This two-step sequence took place in around 60% yield.
Intermediates 13 were easily reduced into the α-bromo deriva-
In the case of the other xanthates, 17c, 17d and 17e, the
addition–cyclisation procedure was the same as that for the
synthesis of 2-naphthylamides. The overall yield for these one-
pot reactions was generally higher than that for the substituted
2-naphthylamides discussed above and varied from 48% to
65% (Table 4). These results are in accord with our hypothesis
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Scheme 7 Radical addition–cyclisation sequence.
Table 4 Cyclisation–aromatisation of xanthates 15
Scheme 8 Synthetic variant leading to a naphthylamide.
Conclusion
In summary, we have presented
a practical, convergent
Tetralones 17
Yield (%)
48
1-Naphthylamide 18
Yield (%)
74
approach to protected 1- and 2-naphthylamides. Both electron
withdrawing and electron donating substituents appear to be
tolerated, reflecting the broad tolerance of radical processes in
general. Numerous naphthylamines with a defined substi-
tution pattern can now be obtained by simply varying the sub-
stitution of the starting xanthates or by modifying the
tetralones prior to the aromatisation step. In the case of substi-
tuents in the meta position in starting xanthates 4, the radical
cyclisation leads normally to a mixture of two regioisomeric
tetralones.4 This regioselectivity issue can be resolved in prin-
ciple blocking temporarily the undesired position, for example
with a halogen atom that could be removed later, or by steri-
cally hindering the unwanted cyclisation mode by placing a
bulky protecting group on a neighbouring position.
51
60
72
74
65
57
60
70
Experimental
All reactions were carried out under dry, oxygen free nitrogen.
Flash chromatography was performed on silica gel (SDS, 60 Å
C.C. 40–63 mm) as the stationary phase. Thin Layer Chromato-
graphy (TLC) was performed on alumina plates pre-coated
with silica gel (Merck silica gel, 60 F254), which were visual-
ized by the quenching of UV fluorescence when applicable
(λmax = 254 nm and/or 366 nm) and/or by staining with vanillin
or anisaldehyde in acidic ethanol followed by heating. Infrared
spectra were recorded as solutions in CH2Cl2 using NaCl cells,
on a Perkin-Elmer FT 2000. Absorption maxima (nmax) are
reported in wavenumbers (cm−1) and only selected peaks are
reported. Magnetic resonance spectra were recorded at rt on a
Bruker Avance DPX 400 instrument. Proton magnetic reson-
ance spectra (1H NMR) were recorded at 400 MHz and coup-
ling constants (J) are reported to 0.5 Hz. The following
abbreviations were utilized to describe peak patterns where
appropriate: br = broad, s = singlet, d = doublet, t = triplet, bs
= broad singlet, bd = broad doublet, bt = broad triplet, q =
quartet. Carbon magnetic resonance spectra (13C NMR) were
recorded in the same instrument at 100.6 MHz. Chemical
shifts (δH, δC) are quoted in parts per million (ppm) and are
referenced to TMS (0 ppm). Low-resolution mass spectra (m/z)
were recorded by chemical ionization (CI/NH3) on a Hewlett-
Packard HP 5989B and only report molecular species
regarding the crucial role of the intermolecular hydrogen bond
in promoting the closure of the intermediate radical onto the
aromatic ring.
Tetralones 17 could also be converted into N-acetylnaphthyl-
amines by first reducing the ketone with NaBH4,14 followed by
acid mediated aromatisation. A mixture of acetic acid and acetic
anhydride was used as the solvent instead of toluene to prevent
the deacetylation. In this manner, tetralone 17c was transformed
into N-acetyl-4-trifluoromethyl-1-naphthylamine (Scheme 8).
Substituted 1- and 2-naphthylamides with the halogen sub-
stituents are important because they can easily undergo tran-
sition metal catalysed coupling reactions and can act as a
source of benzynes useful in Diels–Alder reactions.15 Most of
the naphthalene derivatives described herein are not readily
accessible by other approaches.
([M
+
H]+, [M
+
NH4]+) and other major fragments.
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High-resolution mass spectra were recorded by positive elec- HRMS (EI) Calcd for C19H14FNO4S2: 403.0348. Found:
tron impact ionization (EI+) at 70 eV on a JEOL JMS-GCmate II 403.0350.
mass spectrometer. The quoted masses are accurate to
S-2-(4-Bromophenyl)-1-(1,3-dioxoisoindolin-2-yl)-2-oxoethyl
5 ppm. The names of the molecules that appear in the follow- O-ethyl carbonodithioate (4c). Following general procedure I,
ing pages were generated using either Beilstein AutoNom 2000 after workup, the residue was purified by silica gel column
(CAS) or ChemBioDraw Ultra 10.0.
chromatography with a gradient of dichloromethane in pet-
roleum ether (30 : 70 to 50 : 50) to afford xanthate (4c) (1.25 g,
54%) as a white solid. Mp: 102–103 °C. 1H-NMR (CDCl3,
General procedure I for the formation of xanthates (4)
Step 1: Bromination of substituted acetophenones 2: A solu- 400 MHz) δ 7.90 (m, 2H), 7.81 (m, 3H), 7.76 (m, 2H), 7.60 (m,
tion of the 2-phthalimido-acetophenone (2) (5 mmol) in acetic 2H), 4.73 (m, 2H), 1.44 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3,
acid (15 mL) at rt was added pyridinium hydrobromide perbro- 100 MHz) δ 210.2 (CS), 188.6 (CO), 166.4 (2CO), 134.6 (2CH),
mide (880 mg, 5.5 mmol). The reaction mixture was heated at 132.4 (Cq), 132.2 (2CH), 131.7 (2Cq), 130.0(2CH), 129.3 (Cq),
70 °C for 4 hours, cooled and diluted with dichloromethane 124.0 (2CH), 72.0 (CH), 62.0 (CH2), 13.8 (CH3). IR (ν, cm−1):
(15 mL). The resulting solution was then washed with water, 1731, 1703, 1588, 1377, 1242, 1048. HRMS (EI) Calcd for
then with a saturated aqueous solution of NaHCO3 (2 times) C19H14BrNO4S2: 462.9548. Found: 462.9548.
and then with brine. The organic phase was dried with MgSO4
S-2-(4-Chlorophenyl)-1-(1,3-dioxoisoindolin-2-yl)-2-oxoethyl
and evaporated to dryness under reduced pressure. The crude O-ethyl carbonodithioate (4d). Following general procedure I,
residue contained the mixture of the desired product (around after workup, the residue was purified by silica gel column
60% by NMR) and the starting material. Step 2: Formation of chromatography with
a gradient of dichloromethane in
xanthate (4): To a stirred solution of the crude product of step toluene (30 : 70 to 50 : 50) to afford xanthate (4d) (1.15 g, 55%)
1 in acetone (10 mL) at rt was added portion-wise potassium as a light yellow solid. Mp: 84–85 °C. 1H-NMR (CDCl3,
O-ethyl xanthate (885 mg, 5.5 mmol). The reaction was stirred 400 MHz) δ 7.90 (m, 4H), 7.83 (s, 1H), 7.76 (m, 2H), 7.43 (m,
until the complete consumption of the starting material. The 2H), 4.72 (m, 2H), 1.45 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3,
acetone was evaporated and the reaction mixture was diluted 100 MHz) δ 210.2 (CS), 188.4 (CO), 166.4 (2CO), 140.5 (Cq),
with ethyl acetate. The organic phase was washed with water 134.6 (2CH), 131.9 (Cq), 131.7 (2Cq), 130.0 (2CH), 129.2 (2CH),
and brine, dried over MgSO4, filtered and evaporated to 123.9 (2CH), 72.0 (CH), 62.0 (CH2), 13.8 (CH3). IR (ν, cm−1
)
dryness under reduced pressure. The residue was purified by 1731, 1703, 1596, 1376, 1243, 1094, 1048. HRMS (EI) Calcd for
silica gel column chromatography or recrystallised to afford C19H14ClNO4S2: 419.0053. Found: 419.0045.
the desired xanthate.
S-1-(1,3-Dioxoisoindolin-2-yl)-2-oxo-2-(4-(trifluoromethyl)-phenyl)-
S-1-(1,3-Dioxoisoindolin-2-yl)-2-oxo-2-phenylethyl
O-ethyl ethyl O-ethyl carbonodithioate (4e). Following general pro-
carbonodithioate (4a). Following general procedure I, after cedure I, after workup, the residue was purified by silica gel
workup, the residue was washed with hot ethanol several column chromatography with a gradient of ethyl acetate in pet-
times to eliminate the starting un-brominated acetophenone roleum ether (5 : 95 to 15 : 85) to afford xanthate (4e) (1.2 g,
(2a) and afford the desired xanthate (4a) as a white solid (1.1 g, 53%) as a light yellow solid. Mp: 57–58 °C. 1H-NMR (CDCl3,
57%). Mp: 149–150 °C. 1H-NMR (CDCl3, 400 MHz) δ 7.95 (d, 400 MHz) δ 8.05 (m, 2H), 7.87 (m, 3H), 7.70–7.76 (m, 4H), 4.73
J = 8.0 Hz, 2H), 7.89 (m, 2H), 7.86 (s, 1H), 7.58 (t, 7.4 Hz, 1H), (m, 2H), 1.42 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3, 100 MHz)
7.75 (m, 2H), 7.45 (t, J = 7.4 Hz, 2H), 4.72 (m, 2H), 1.46 (t, J = δ 210.0 (CS), 188.9 (CO), 166.3 (2CO), 136.7 (Cq), 135.0 (q, J =
7.1 Hz, 3H). 13C-NMR (CDCl3, 100 MHz) δ 210.2 (CS), 189.4 33 Hz, Cq), 134.7 (2CH), 131.6 (2Cq), 128.9 (2CH), 125.9 (2CH),
(CO), 166.4 (2CO), 134.5 (2CH), 133.9 (2CH), 133.6 (Cq), 131.7 124.0 (2CH), 123.4 (q, J = 272 Hz, CF3), 72.2 (CH), 62.2 (CH2),
(2Cq), 128.8 (2CH), 128.6 (2CH), 123.9 (2CH), 71.8 (CH), 62.0 13.8 (CH3). IR (ν, cm−1): 1777, 1731, 1708, 1615, 1410, 1376,
(CH2), 13.8 (CH3). IR (ν, cm−1): 1704, 1653, 1558, 1231, 1113, 1324, 1242, 1175, 1140, 1048. HRMS (EI) Calcd for
1053. HRMS (EI) Calcd for C19H15NO4S2: 385.0442. Found: C20H14F3NO4S2: 453.0316. Found: 453.0321.
385.0442.
General procedure II for the synthesis of tetralones (6) by
radical addition and cyclisation
S-1-(1,3-Dioxoisoindolin-2-yl)-2-(4-fluorophenyl)-2-oxoethyl
O-ethyl carbonodithioate (4b). Following general procedure I,
after workup, the residue was purified by silica gel column A magnetically stirred solution of xanthate (1 mmol) and
chromatography with a gradient of dichloromethane in pet- olefin (2.5 mmol) in 1,2-dichloroethane (1 mL) was refluxed
roleum ether (30 : 70 to 50 : 50) to afford xanthate (4b) (1.09 g, for 15 min under a nitrogen flow. Dilauroyl peroxide (DLP)
54%) as a white solid. Mp: 131–132 °C. 1H-NMR (CDCl3, (5 mol%) was then added and additional DLP (2.5 mol%) was
400 MHz) δ 7.99 (m, 2H), 7.89 (m, 2H), 7.83 (m, 1H), 7.75 (m, added every 60 min until total consumption of the starting
2H), 7.13 (t, J = 8.6 Hz, 2H), 4.72 (m, 2H), 1.44 (t, J = 7.1 Hz, material or until no evolution could be detected by TLC analy-
3H). 13C-NMR (CDCl3, 100 MHz) δ 210.2 (CS), 187.9 (CO), 166.4 sis. The reaction mixture was then cooled to 20 °C and evapor-
(2CO), 166.2 (d, J = 256 Hz, Cq), 134.6 (2CH), 131.7 (2Cq), ated to dryness under reduced pressure. The residue was
131.5 (d, J = 9 Hz, CH), 129.9 (d, J = 3 Hz, Cq), 123.9 (2CH), then dissolved in 10 mL ethyl acetate or chlorobenzene.
116.1 (d, J = 22 Hz, 2CH), 71.9 (CH), 62.0 (CH2), 13.8 (CH3). IR The mixture was refluxed for 15 min under a nitrogen flow.
(ν, cm−1): 1777, 1731, 1703, 1601, 1377, 1240, 1103, 1048. Dilauroyl peroxide (DLP) (20 mol%) was then added and
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additional DLP (20 mol%) was added every 60 min until total (s, 9H min). 13C-NMR (CDCl3, 100 MHz) δ 189.7 (CO min),
consumption of the starting material or until no evolution 189.0 (CO maj), 177.6 (CO maj), 177.5 (CO min), 167.7 (2CO
could be detected by TLC analysis. The reaction mixture was maj), 167.5 (2CO min), 166.6 (d, J = 256 Hz, Cq maj), 166.2 (d,
then cooled to 20 °C and evaporated to dryness under reduced J = 256 Hz, Cq min), 145.7 (d, J = 9 Hz, Cq maj), 142.2 (d, J =
pressure. The residue was purified by silica gel column 9 Hz, Cq min), 134.3 (d, J = 3 Hz, 2CH maj + min), 132.0 (2Cq
chromatography to yield the desired compounds.
maj + min), 131.6 (d, J = 10 Hz, CH maj), 131.4 (d, J = 10 Hz,
3-(1,3-Dioxoisoindolin-2-yl)-4-oxo-1,2,3,4-tetrahydronaphtha- CH min), 128.1 (d, J = 3 Hz, Cq min), 126.9 (d, J = 3 Hz, Cq
len-1-yl pivalate (6a). Following general procedure II, the reac- maj), 123.6 (2CH maj + min), 117.5 (d, J = 22 Hz, CH min),
tion was carried out using xanthate (4a) (385 mg, 1 mmol, 116.8 (d, J = 22 Hz, CH min), 116.3 (d, J = 22 Hz, CH maj),
1 equiv.) and vinyl pivalate (0.37 mL, 2.5 mmol, 2.5 equiv.) in 112.6 (d, J = 23 Hz, CH maj), 68.0 (CH maj), 67.9 (CH min),
refluxing 1,2-dichloroethane (1 mL); it needed 25 mol% DLP 52.9 (CH maj), 50.4 (CH min), 39.0 (Cq maj + min), 33.8 (CH2
to go to completion. After the reaction mixture was evaporated maj), 32.8 (CH2 min), 27.1 (3CH3 maj + min). IR (ν, cm−1):
to dryness under reduced pressure, the residue was dissolved 3412, 1783, 1724, 1612, 1551, 1389, 1264, 1142. HRMS (EI)
in chlorobenzene (10 mL), heated to reflux and treated with Calcd for C23H20FNO5: 409.1326. Found: 409.1327.
1.2 equiv. of DLP. After evaporation, the residue was purified
7-Bromo-3-(1,3-dioxoisoindolin-2-yl)-4-oxo-1,2,3,4-tetrahydro-
by silica gel column chromatography using a gradient of naphthalen-1-yl pivalate (6c). Following general procedure II,
dichloromethane in petroleum ether (30 : 70 to 50 : 50) to the reaction was carried out using xanthate (4c) (464 mg,
afford 187 mg mixture of (6a) contaminated with (2a) 1 mmol, 1 equiv.) and vinyl pivalate (0.37 mL, 2.5 mmol, 2.5
((6a) : (2a) = 1 : 0.2) as a yellow oil. The calculated NMR yield of equiv.) in refluxing 1,2-dichloroethane (1 mL); it needed
(6a) is 42%. 1H-NMR (CDCl3, 400 MHz) δ 8.16 (m, 1H), 7.90 25 mol% DLP to go to completion. The reaction mixture was
(m, 2H), 7.78 (m, 2H), 7.69 (m, 1H), (7.41–7.57, m, 2H), 6.35 then evaporated to dryness under reduced pressure, and the
(dd, J = 11.5 Hz, J = 5.0 Hz, 1H maj), 6.25 (m, 1H min), 5.54 residue was dissolved in chlorobenzene (10 mL), heated to
(dd, J = 13.3 Hz, J = 4.8 Hz, 1H min), 5.18 (dd, J = 14.2 Hz, J = reflux and treated with 1.2 equiv. of DLP. After evaporation,
4.6 Hz, 1H maj), 3.28 (dt, J = 13.3 Hz, J = 2.9 Hz, 1H min), 3.11 the residue was purified by silica gel column chromatography
(td, J = 14.2 Hz, J = 11.6 Hz, 1H maj), 2.66 (td, J = 11.6 Hz, J = with a gradient of dichloromethane in petroleum ether (30 : 70
1
4.6 Hz, 1H maj), 2.54 (m, 1H min), 1.31 (s, 9H maj), 1.22 (s, to 50 : 50) to afford 6c (187 mg, 40%) as a yellow oil. H-NMR
9H min). 13C-NMR (CDCl3, 100 MHz) δ 191.1 (CO min), 190.3 (CDCl3, 400 MHz) δ 7.79 (m, 1H), 7.86 (m, 2H), 7.52–7.75 (m,
(CO maj), 177.8 (CO maj + min), 167.7 (2CO maj), 167.6 (2CO 4H), 6.29 (dd, J = 11.6 Hz, J = 5.0 Hz, 1H maj), 6.17 (m, 1H
min), 142.4 (Cq maj), 139.2 (Cq min), 134.7 (CH min), 134.5 min), 5.49 (dd, J = 13.3 Hz, J = 4.8 Hz, 1H min), 5.16 (dd, J =
(CH maj), 134.3 (2CH maj + min), 132.9 (2Cq maj), 132.0 (2Cq 14.2 Hz, J = 4.6 Hz, 1H maj), 3.23 (dt, J = 2.9 Hz, J = 13.6 Hz,
min), 131.4 (Cq min), 130.3 (Cq maj), 130.1 (CH maj), 129.8 1H min), 3.07 (td, J = 11.6 Hz, J = 14.2 Hz, 1H maj), 2.64 (td,
(CH min), 128.5 (CH min), 128.2 (CH maj), 128.1 (CH min), J = 4.8 Hz, J = 11.6 Hz, 1H maj), 2.48 (m, 1H min), 1.31 (s, 9H
125.6 (CH maj), 123.6 (2CH maj + min), 68.6 (CH maj), 68.3 maj), 1.22 (s, 9H min). 13C-NMR (CDCl3, 100 MHz) δ 190.4 (CO
(CH min), 53.1 (CH maj), 50.7 (CH min), 39.1 (Cq maj + min), min), 189.6 (CO maj), 177.6 (CO maj), 177.5 (CO min), 167.6
33.8 (CH2 maj), 32.9 (CH2 min), 27.2 (3CH3 maj), 27.1 (3CH3 (2CO maj), 167.5 (2CO min), 144.0 (Cq maj), 140.7 (Cq min),
min). IR (ν, cm−1): 2974, 2909, 1725, 1605, 1390, 1230, 1145, 134.3 (2CH maj + min), 133.3 (CH min), 133.0 (CH min), 132.0
1003. HRMS (EI) Calcd for C23H20BrNO5: 391.1420. Found: (CH maj), 131.9 (2Cq maj), 131.8 (2Cq min), 130.1 (Cq maj +
391.1436.
min), 130.0 (Cq min), 129.9 (CH maj), 129.8 (CH min), 129.1
3-(1,3-Dioxoisoindolin-2-yl)-7-fluoro-4-oxo-1,2,3,4-tetrahydro- (Cq maj), 129.0 (CH maj), 123.7 (2CH maj + min), 67.9 (CH
naphthalen-1-yl pivalate (6b). Following general procedure II, min), 67.7 (CH maj), 52.9 (CH maj), 50.5 (CH min), 39.0 (Cq
the reaction was carried out using xanthate (4b) (403 mg, maj + min), 33.7 (CH2 maj), 32.8 (CH2 min), 27.2 (3CH3 maj),
1 mmol, 1 equiv.) and vinyl pivalate (0.37 mL, 2.5 mmol, 2.5 27.1 (3CH3 min). IR (ν, cm−1): 3481, 1726, 171à, 1589, 1470,
equiv.) in refluxing 1,2-dichloroethane (1 mL); it needed 1389, 1142. HRMS (EI) Calcd for C23H20BrNO5: 469.0525.
25 mol% DLP to go to completion. The reaction mixture was Found: 469.0520.
then evaporated to dryness under reduced pressure and the
7-Chloro-3-(1,3-dioxoisoindolin-2-yl)-4-oxo-1,2,3,4-tetrahydro-
residue was dissolved in chlorobenzene (10 mL), heated to naphthalen-1-yl pivalate (6d). Following general procedure II,
reflux and treated with 1.2 equiv. DLP. After evaporation, the the reaction was carried out using xanthate (4d) (420 mg,
residue was purified by silica gel column chromatography with 1 mmol, 1 equiv.) and vinyl pivalate (0.37 mL, 2.5 mmol, 2.5
a gradient of dichloromethane in petroleum ether (30 : 70 to equiv.) in refluxing 1,2-dichloroethane (1 mL); it needed
50 : 50) to afford (6b) (184 mg, 45%) as a yellow oil. 1H-NMR 30 mol% DLP to go to completion. The reaction mixture was
(CDCl3, 400 MHz) δ 8.16 (m, 1H), 7.85 (m, 2H), 7.73 (m, 2H), evaporated to dryness under reduced pressure and the residue
7.03–7.23 (m, 2H), 6.28 (dd, J = 11.6 Hz, J = 5.0 Hz, 1H maj), was dissolved in chlorobenzene (10 mL), heated to reflux and
6.19 (m, 1H min), 5.50 (dd, J = 13.2 Hz, J = 4.8 Hz, 1H min), treated with 1.2 equiv. of DLP. After evaporation, the residue
5.17 (dd, J = 14.2 Hz, J = 4.6 Hz, 1H maj), 3.26 (dt, J = 13.6 Hz, was purified by silica gel column chromatography with a gradi-
J = 2.9 Hz, 1H min), 3.08 (m, 1H maj), 2.65 (td, J = 11.5 Hz, J = ent of dichloromethane in petroleum ether (30 : 70 to 50 : 50)
4.8 Hz, 1H maj), 2.48 (m, 1H min), 1.30 (s, 9H maj), 1.22 to afford 6d (157 mg, 37%) as a yellow oil. 1H-NMR (CDCl3,
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400 MHz) δ 8.07 (m, 1H), 7.87 (m, 2H), 7.75 (m, 2H), 7.36–7.54 0.6 mmol, 3 equiv.) in refluxing toluene (3 mL). The residue
(m, 2H), 6.28 (dd, J = 11.6 Hz, J = 4.9 Hz, 1H maj), 6.16 (m, 1H was washed with dichloromethane to afford (7a) (48 mg, 83%).
min), 5.50 (dd, J = 13.2 Hz, J = 4.8 Hz, 1H min), 5.16 (dd, J = Mp: 287–288 °C. 1H-NMR (DMSO-D6, 400 MHz) δ 10.20 (bs,
14.2 Hz, J = 4.7 Hz, 1H maj), 3.24 (dt, J = 13.7 Hz, J = 2.9 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.90–7.99 (m, 5H), 7.55 (m, 2H),
1H min), 3.08 (m, 1H maj), 2.65 (m, 1H maj), 2.49 (m, 1H 7.45 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H). 13C-NMR
min), 1.31 (s, 9H). 13C-NMR (CDCl3, 100 MHz) δ 190.2 (CO (DMSO-D6, 100 MHz) δ 167.6 (2CO), 150.1 (Cq), 134.3 (2CH),
min), 189.4 (CO maj), 177.6 (CO maj + min), 167.6 (2CO maj), 132.5 (2Cq), 132.4 (Cq), 127.5 (CH), 127.4 (CH), 127.1 (CH),
167.5 (2CO min), 144.0 (Cq maj), 141.3 (Cq maj), 141.1 (Cq 125.3 (CH), 125.2 (Cq), 123.2 (2CH), 122.5 (CH), 118.7 (CH),
min), 140.7 (Cq min), 134.3 (2CH maj + min), 132.0 (2Cq min), 112.4 (Cq). IR (ν, cm−1): 3377, 1696, 1541, 1399, 1229,
131.9 (2Cq maj), 130.3 (CH min), 130.0 (CH min), 129.9 (CH 1083. HRMS (EI) Calcd for C18H11NO3: 289.0739. Found:
maj), 129.8 (CH min), 129.1 (CH maj), 128.7 (Cq maj + min), 289.0737.
125.8 (CH maj), 123.6 (2CH maj + min), 68.0 (CH min), 67.8
2-(6-Fluoro-1-hydroxynaphthalen-2-yl)isoindoline-1,3-dione
(CH maj), 52.9 (CH maj), 50.5 (CH min), 39.0 (Cq maj + min), (7b). Following general procedure III, the reaction was carried
33.7 (CH2 maj), 33.5 (CH2 min), 27.1 (3CH3). IR (ν, cm−1): out using (6b) (82 mg, 0.2 mmol, 1 equiv.) and PTSA (105 mg,
3486, 1782, 1727, 1595, 1470, 1389, 1230, 1142. HRMS (EI) 0.6 mmol, 3 equiv.) in refluxing toluene (3 mL). The residue
Calcd for C23H20ClNO5: 425.1030. Found: 425.1036.
was washed with dichloromethane to afford (7b) as a yellow
3-(1,3-Dioxoisoindolin-2-yl)-4-oxo-7-(trifluoromethyl)-1,2,3,4- solid (48 mg, 78%). Mp: 265–267 °C. 1H-NMR (DMSO-D6,
tetrahydronaphthalen-1-yl pivalate (6e). Following general pro- 400 MHz) δ 10.32 (bs, 1H), 8.30 (dd, J = 9.2 Hz, J = 5.9 Hz, 1H),
cedure II, the reaction was carried out using xanthate (4e) 7.90–7.99 (m, 4H), 7.70 (dd, J = 10.4 Hz, J = 2.6 Hz, 1H),
(455 mg, 1 mmol, 1 equiv.) and vinyl pivalate (0.37 mL, 7.37–7.46 (m, 3H). 13C-NMR (DMSO-D6, 100 MHz) δ 167.6
2.5 mmol, 2.5 equiv.) in refluxing 1,2-dichloroethane (1 mL); it (2CO), 160.9 (d, J = 245 Hz, Cq), 150.4 (Cq), 135.4 (d, J = 10 Hz,
needed 25 mol% DLP to go to completion. The reaction Cq), 134.3 (2CH), 132.5 (2Cq), 128.9 (CH), 125.8 (d, J = 9 Hz,
mixture was evaporated to dryness under reduced pressure CH), 123.2 (2CH), 122.4 (Cq), 118.2 (d, J = 5 Hz, CH), 115.2 (d,
and the residue was dissolved in chlorobenzene (10 mL), J = 25 Hz, CH), 112.1 (d, J = 2 Hz, Cq), 110.6 (d, J = 21 Hz, Cq).
heated to reflux and treated with 1.2 equiv. DLP. After evapor- IR (ν, cm−1): 3313, 1721, 1551, 1398, 1244. HRMS (EI) Calcd
ation, the residue was purified by silica gel column chromato- for C18H10FNO3: 307.0645. Found: 307.0644.
graphy with a gradient of dichloromethane in petroleum ether
2-(6-Bromo-1-hydroxynaphthalen-2-yl)isoindoline-1,3-dione
(30 : 70 to 50 : 50) to afford (6e) (188 mg, 41%) as a white solid. (7c). Following general procedure III, the reaction was carried
The product consisted of a 33 : 67 mixture of two diastereoi- out using (6c) (95 mg, 0.2 mmol, 1 equiv.) and PTSA (105 mg,
somers of (6e) and a pure sample of the major diastereoisomer 0.6 mmol, 3 equiv.) in refluxing toluene (3 mL). The residue
could be obtained by chromatography. Mp: 185–186 °C. was washed with dichloromethane to afford a yellow solid (7c)
1
1H-NMR (CDCl3, 400 MHz) δ 8.25 (d, J = 8.1 Hz, 1H), 7.67–7.89 (53 mg, 72%). Mp: 294–295 °C. H-NMR (DMSO-D6, 400 MHz)
(m, 6H), 6.36 (dd, J = 11.4 Hz, J = 4.9 Hz, 1H), 5.22 (dd, J = δ 10.40 (bs, 1H), 8.18 (m, 2H), 7.97–7.99 (m, 4H), 7.66 (m, 1H),
14.2 Hz, J = 4.7 Hz, 1H), 3.11 (m, 1H), 2.70 (m, 1H), 1.33 (s, 7.43 (m, 2H). 13C-NMR (DMSO-D6, 100 MHz) δ 167.5 (2CO),
9H). 13C-NMR (CDCl3, 100 MHz) δ 189.5 (CO), 177.6 (CO), 150.4 (Cq), 135.5 (Cq), 134.3 (2CH), 132.5 (2Cq), 129.3 (CH),
167.4 (2CO), 143.2 (Cq), 135.8 (q, J = 33 Hz, Cq), 134.4 (2CH), 128.9 (CH), 128.2 (CH), 125.0 (CH), 123.8 (Cq), 123.2 (2CH),
132.7 (Cq), 131.9 (2Cq), 129.1 (CH), 125.3 (q, J = 3.5 Hz, CH), 120.6 (Cq), 117.9 (CH), 113.0 (Cq). IR (ν, cm−1): 3301, 1701,
123.7 (2CH), 123.3 (q, J = 272 Hz, CF3), 123.0 (q, J = 3.9 Hz, 1550, 1398, 1103. HRMS (EI) Calcd for C18H10BrNO3: 366.9844.
CH), 67.8 (CH), 53.0 (CH), 39.1 (Cq), 33.7 (CH2), 27.1 (3CH3). Found: 366.9845.
IR (ν, cm−1): 3615, 1726, 1549, 1389, 1142. HRMS (EI) Calcd
for C24H20F3NO5: 459.1294. Found: 459.1283.
2-(6-Chloro-1-hydroxynaphthalen-2-yl)isoindoline-1,3-dione
(7d). Following general procedure III, the reaction was carried
out using (6d) (85 mg, 0.2 mmol, 1 equiv.) and PTSA (105 mg,
0.6 mmol, 3 equiv.) in refluxing toluene (3 mL). The residue
General procedure III for the aromatisation into
naphthylamine derivatives (7)
was washed with dichloromethane to afford a yellow solid (7d)
1
To a solution of tetralone (6) (1 mmol) in toluene (3 mL), (52 mg, 80%). Mp: 283–284 °C. H-NMR (DMSO-D6, 400 MHz)
p-toluenesulfonic acid (PTSA; 3 mmol) was added and the reac- δ 10.40 (bs, 1H), 8.25 (m, 2H), 7.91–8.05 (m, 4H), 7.40–7.56 (m,
tion mixture was heated to reflux using a Dean–Stark appar- 3H).13C-NMR (DMSO-D6, 100 MHz) δ 167.5 (2CO), 150.4 (Cq),
atus for 3 h. The reaction mixture was allowed to cool to rt, 135.5 (Cq), 134.3 (2CH), 132.5 (2Cq), 131.9 (CH), 128.9 (Cq),
diluted with saturated sodium carbonate solution, and 126.1 (Cq), 125.7 (CH), 125.0 (CH), 123.7 (2CH), 123.2 (Cq),
extracted with ethyl acetate. The combined organic layers were 118.0 (CH), 113.0 (Cq). IR (ν, cm−1): 3302, 1708, 1152, 1396,
dried and concentrated. The residue was washed with pentane 1265, 1082. HRMS (EI) Calcd for C18H10ClNO3: 323.0349.
or dichloromethane, and then filtered to afford the desired Found: 323.0349.
product.
2-(1-Hydroxy-6-(trifluoromethyl)naphthalen-2-yl)isoindoline-
2-(1-Hydroxynaphthalen-2-yl)isoindoline-1,3-dione (7a). Fol- 1,3-dione (7e). Following general procedure III, the reaction
lowing general procedure III, the reaction was carried out was carried out using (6e) (92 mg, 0.2 mmol, 1 equiv.) and
using (6a) (78 mg, 0.2 mmol, 1 equiv.) and PTSA (105 mg, PTSA (105 mg, 0.6 mmol, 3 equiv.) in refluxing toluene (3 mL).
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The residue was washed with dichloromethane to afford (7e) 2.0 mol%) and CuI (40 mg, 0.2 mmol, 1.0 mol%) in 40 mL
as a yellow solid (56 mg, 79%). Mp: 307–309 °C. 1H-NMR triethylamine in 40 mL THF, trimethylsilylacetylene (24 mmol,
(DMSO-D6, 400 MHz) δ 10.58 (bs, 1H), 8.43 (m, 2H), 7.91–8.00 3.42 mL, 1.2 equiv.) was added. After workup, the product was
(m, 4H), 7.78 (d, J = 8.9 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.52 dissolved in DCM (40 mL) and Ac2O (25 mmol, 2.36 mL, 1.25
(d, J = 8.7 Hz, 1H). 13C-NMR (DMSO-D6, 100 MHz) δ 167.4 equiv.) was added. Upon complete acetylation, the residue was
(2CO), 150.2 (Cq), 134.4 (2CH), 133.1 (Cq), 132.4 (2Cq), 129.1 purified by silica gel column chromatography with a gradient
(CH), 127.3 (q, J = 32 Hz, Cq), 126.7 (Cq), 125.4 (q, J = 5 Hz, of ethyl acetate in petroleum ether (5/95 to 25/75) to afford the
CH), 124.4 (q, J = 272 Hz, CF3), 124.3 (CH), 123.3 (2CH), 120.5 product (12b) as a white solid (5.90 g, 92%). Mp: 88–100 °C.
(d, J = 3 Hz, CH), 119.7 (CH), 114.7 (Cq). IR (ν, cm−1): 3333, 1H-NMR (CDCl3, 400 MHz) δ 8.31 (d, J = 8.9 Hz, 1H), 7.92 (bs,
1713, 1554, 1264, 1102. HRMS (EI) Calcd for C19H10F3NO3: 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.42 (dd, J = 8.9 Hz, J = 2.3 Hz,
357.0613. Found: 357.0615.
1H), 2.20 (s, 3H), 0.00 (s, 9H). 13C-NMR (CDCl3, 100 MHz)
δ 168.2 (CO), 138.7 (Cq), 134.0 (CH), 133.0 (CH), 120.5 (CH),
115.4 (Cq), 113.6 (Cq), 104.0 (CH), 98.8 (CH), 25.0 (CH3), 0.0
General procedure IV for the Sonogashira reaction
A
suspension of 2-iodoaniline (1.0 mmol), PdCl2(PPh3)2 (3CH3). IR (ν, cm−1): 3304, 2925, 2162, 1673, 1519, 1393, 1297.
(14.0 mg, 0.02 mmol, 2.0 mol%) and CuI (2.0 mg, 0.01 mmol, HRMS (EI) Calcd for C13H16BrNOSi: 309.0185. Found:
1.0 mol%) in 2 mL triethylamine and 2 mL THF was degassed 309.0185.
with argon and evacuated/backfilled with argon (3 cycles). The
N-(4-(Trifluoromethyl)-2-((trimethylsilyl)ethynyl)-phenyl)-
reaction mixture was stirred at rt for 10 minutes. After addition acetamide (12c). Following general procedure IV, the reaction
of the alkyne (1.2 mmol) the suspension was stirred for was carried out with a solution of 2-iodo-4-methylaniline
24 hours at rt under an argon atmosphere. The reaction (20 mmol, 5.74 g), PdCl2(PPh3)2 (280 mg, 0.4 mmol, 2.0 mol%)
mixture was evaporated to dryness under reduced pressure, and CuI (40 mg, 0.2 mmol, 1.0 mol%) in 40 mL triethylamine
then diluted with 2.0 mL water and extracted with EtOAc in 40 mL THF, to which trimethylsilylacetylene (24 mmol,
(2 × 2.0 mL). The combined organic phases were washed with 3.42 mL, 1.2 equiv.) was added. After workup, the product was
brine and dried over MgSO4. Removal of the solvent under dissolved in DCM (40 mL) and then Ac2O (25 mmol, 2.36 mL,
reduced pressure afforded the desired product. To a solution 1.25 equiv.) was added. Upon complete acetylation, the residue
of the Sonogashira product (1 mmol) in dichloromethane was purified by silica gel column chromatography with a gradi-
(2 mL) was added Ac2O (1.25 mmol) and the resulting solution ent of ethyl acetate in petroleum ether (5/95 to 35/65) to afford
was stirred at rt until complete consumption of the starting the product (12c) as a rose solid (5.45 g, 91%). Mp: 65–66 °C.
material. It was then diluted with dichloromethane, extracted 1H-NMR (CDCl3, 400 MHz) δ 8.55 (d, J = 8.7 Hz, 1H), 8.10 (bs,
with saturated solution of NaHCO3, brine, dried over MgSO4 1H), 7.67 (d, J = 1.9 Hz, 1H), 7.55 (dd, J = 8.7 Hz, J = 1.9 Hz,
and evaporated under reduced pressure. The residue was puri- 1H), 2.29 (s, 3H), 0.00 (s, 9H). 13C-NMR (CDCl3, 100 MHz)
fied by silica gel column chromatography with a gradient of δ 168.5 (CO), 142.0 (Cq), 128.7 (q, J = 4 Hz, CH), 127.0 (q, J =
ethyl acetate in petroleum ether (5/95 to 35/65) to afford the 4 Hz, CH), 125.3 (q, J = 33 Hz, Cq), 123.8 (q, J = 272 Hz, CF3),
product as a solid.
118.9 (CH), 112.0 (Cq), 104.3 (CuC), 98.8 (CuC), 25.1 (CH3),
N-(4-Methyl-2-((trimethylsilyl)ethynyl)phenyl)acetamide (12a). 0.0 (3CH3). IR (ν, cm−1): 3307, 2972, 2161, 1681, 1520, 1416,
Following general procedure IV, to a solution of 2-iodo-4- 1331. HRMS (EI) Calcd for C14H16F3NOSi: 299.0953. Found:
methylaniline (20 mmol, 4.66 g, 1.0 equiv.), PdCl2(PPh3)2 299.0955.
(280 mg, 0.4 mmol, 2.0 mol%) and CuI (40 mg, 0.2 mmol,
1.0 mol%) in 40 mL triethylamine in 40 mL THF, trimethylsily-
lacetylene (24 mmol, 3.42 mL, 1.2 equiv.) was added. After
General procedure V for the preparation of
dibromoacetylphenylacetamides (13)
workup, the product was dissolved in DCM (40 mL) and then To a solution of phenylacetamide (12) (1 mmol) in methanol
Ac2O (25 mmol, 2.36 mL, 1.25 equiv.) was added. Upon com- (2.5 mL), potassium carbonate was added (5 mol%). After
plete acetylation, the residue was purified by silica gel column 30 minutes, the solvent was evaporated and to the residue,
chromatography with a gradient of ethyl acetate in petroleum N-bromosuccinimide (2 mmol), FeCl3·6H2O (0.05 mmol),
ether (5/95 to 25/75) to afford the product (12a) as a pinkish water (2.0 mL) and tetrahydrofuran (2.0 mL) were added under
solid (4.6 g, 95%). Mp: 82–83 °C. 1H-NMR (CDCl3, 400 MHz) nitrogen at rt. The reaction temperature was raised to 80 °C for
δ 8.25 (d, J = 8.4 Hz, 1H), 7.90 (bs, 1H), 7.22 (d, J = 1.3 Hz, 1H), several hours. After the complete consumption of the starting
7.13 (dd, J = 8.4 Hz, J = 1.3 Hz, 1H), 2.27 (s, 3H), 2.09 (s, 3H), material, the reaction mixture was cooled to rt and quenched
0.00 (s, 9H). 13C-NMR (CDCl3, 100 MHz) δ 167.9 (CO), 137.2 with 2.0 mL of saturated NaHCO3 and then extracted with
(Cq), 132.8 (Cq), 131.7 (CH), 130.8 (CH), 118.9 (CH), 111.5 3 × 15 mL of ether. The combined extracts were dried over
(Cq), 101.8 (CuC), 100.6 (CuC), 24.8 (CH3), 20.7 (CH3), 0.0 MgSO4 and the solvent was evaporated in vacuo to afford the
(3CH3). IR (ν, cm−1): 3334, 2956, 2155, 1669, 1507, 1121. crude product, which was purified by silica gel column
HRMS (EI) Calcd for C14H19NOSi: 245.1236. Found: 245.1240.
chromatography with a gradient of ethyl acetate in toluene
N-(4-Bromo-2-((trimethylsilyl)ethynyl)phenyl)acetamide (12b). (0/100 to 8/92) to afford the product as a solid.
Following general procedure IV, to a solution of 2-iodo-4-bromo-
N-(2-(2,2-Dibromoacetyl)-4-methylphenyl)acetamide (13a).
aniline (20 mmol, 5.96 g), PdCl2(PPh3)2 (280 mg, 0.4 mmol, Following general procedure V, the reaction was carried
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out with a solution of compound (12a) (2.45 g, 10 mmol) 1693, 1586, 1515, 1421, 1299, 1131. HRMS (EI) Calcd for
in MeOH (25 mL) and potassium carbonate (70 mg). After C11H11Br2NO2: 400.8874. Found: 400.8883.
removing the methanol, N-bromosuccinimide (20 mmol,
General procedure VI for the preparation of monobromo-
ketones (14)
3.56 g), FeCl3·6H2O (0.5 mmol, 135 mg), water (20 mL)
and tetrahydrofuran (20 mL) were added under nitrogen at rt.
The reaction temperature was raised to 80 °C and kept for 3 h. To a mixture of dibromoketone (13) (1 mmol) and Et3N
After workup, the crude product was purified by silica (1.05 mmol) in THF (4 mL), (EtO)2POH (1.05 mmol) was added
gel column chromatography with a gradient of ethyl acetate at rt. After 30 min, the resulting reaction solution was
in toluene (0/100 to 8/92) to afford the product (13a) as quenched with 2 mL of saturated NaHCO3 and extracted with
a brown solid (1.98 g, 57%). Mp: 144–146 °C. 1H-NMR 3 × 15 mL of ethyl acetate. The combined extracts were dried
(CDCl3, 400 MHz) δ 11.00 (bs, 1H), 8.67 (d, J = 8.7 Hz, over MgSO4 and the solvent was evaporated in vacuo to afford
1H), 7.67 (s, 1H), 7.45 (d, J = 8.7 Hz, 1H), 6.92 (s, 1H), 2.37 the crude bromoketone (14), which was sufficiently pure for
(s, 3H), 2.24 (s, 3H). 13C-NMR (CDCl3, 100 MHz) the next step.
δ 189.4 (CO), 169.3 (CO), 140.5 (Cq), 137.7 (CH), 132.1
N-(2-(2-Bromoacetyl)-4-methylphenyl)acetamide (14a). Fol-
(Cq), 130.5 (CH), 121.6 (CH), 116.0 (Cq), 40.1 (CH), 25.6 (CH3), lowing general procedure VI, the reaction was carried out with
20.9 (CH3). IR (ν, cm−1): 3371, 1678, 1579, 1505, 1462, a solution of compound (13a) (1.74 g, 5 mmol, 1 equiv.), Et3N
1249 HRMS (EI) Calcd for C11H11Br2NO2: 346.9157. Found: (0.73 mL, 5.25 mmol, 1.05 equiv.) and (EtO)2POH (0.67 mL,
346.9162.
5.25 mmol, 1.05 equiv.) in THF (20 mL) at rt. The product
N-(4-Bromo-2-(2,2-dibromoacetyl)phenyl)acetamide
(13b). (14a) was obtained as a white solid (1.27 g, 95%). Mp:
1
Following general procedure V, the reaction was carried out 139–141 °C. H-NMR (CDCl3, 400 MHz) δ 11.25 (bs, 1H), 8.65
with a solution of compound (12b) (3.1 g, 10 mmol) in MeOH (d, J = 8.7 Hz, 1H), 7.64 (s, 1H), 7.41 (d, J = 8.7 Hz, 1H), 4.53 (s,
(25 mL) and potassium carbonate (70 mg). After removing the 2H), 2.37 (s, 3H), 2.22 (s, 3H). 13C-NMR (CDCl3, 100 MHz)
methanol, N-bromosuccinimide (20 mmol, 3.56 g), FeCl3·6H2O δ 195.1 (CO), 169.4 (CO), 139.6 (Cq), 137.0 (CH), 132.0 (Cq),
(0.5 mmol, 135 mg), water (20 mL) and tetrahydrofuran 131.2 (CH), 121.2 (CH), 118.9 (Cq), 32.6 (CH2), 25.6 (CH3), 20.9
(20 mL) were added under nitrogen at rt. The reaction temp- (CH3). IR (ν, cm−1): 3244, 1682, 1659, 1597, 1506, 1366, 1300,
erature was raised to 80 °C and kept for 3 h. After workup, the 1173. HRMS (EI): Calcd for C11H12BrNO2: 269.0051. Found:
crude product was purified by silica gel column chromato- 269.0056.
graphy with a gradient of ethyl acetate in toluene (0/100 to
N-(4-Bromo-2-(2-bromoacetyl)phenyl)acetamide (14b). Fol-
8/92) to afford the product (13b) as a brown solid (2.69 g, lowing general procedure VI, the reaction was carried out with
1
65%). Mp 140–141 °C. H-NMR (CDCl3, 400 MHz) δ 11.00 (bs, a solution of compound (13b) (2.07 g, 5 mmol, 1 equiv.), Et3N
1H), 8.74 (d, J = 9.1 Hz, 1H), 8.03 (d, J = 2.3 Hz, 1H), 7.72 (d, J = (0.73 mL, 5.25 mmol, 1.05 equiv.) and (EtO)2POH (0.67 mL,
9.1 Hz, J = 2.3 Hz, 1H), 6.80 (s, 1H), 2.27 (s, 3H). 13C-NMR 5.25 mmol, 1.05 equiv.) in THF (20 mL) at rt. The product
(CDCl3, 100 MHz) δ 194.3 (CO), 169.5 (CO), 140.9 (Cq), 138.8 (14b) was obtained as a white solid (1.6 g, 96%). Mp:
1
(CH), 133.6 (CH), 122.9 (CH), 120.2 (Cq), 114.7 (Cq), 32.0 (CH), 188–190 °C. H-NMR (CDCl3, 400 MHz) δ 11.26 (bs, 1H), 8.72
25.6 (CH3). IR (ν, cm−1): 3330, 1682, 1564, 1495, 1393, 1295, (d, J = 9.1 Hz, 1H), 7.97 (d, J = 2.3 Hz, 1H), 7.68 (dd, J = 9.1 Hz,
1195. HRMS (EI): Calcd for C10H8Br3NO2: 410.8105. Found: J = 2.3 Hz, 1H), 4.49 (s, 2H), 2.24 (s, 3H). 13C-NMR (CDCl3,
410.8105.
100 MHz) δ 194.3 (CO), 169.5 (CO), 140.9 (Cq), 138.8 (CH),
N-(2-(2,2-Dibromoacetyl)-4-(trifluoromethyl)-phenyl)acetamide 133.6 (CH), 123.0 (CH), 120.3 (Cq), 114.7 (Cq), 32.6 (CH2), 25.6
(13c). Following general procedure V, the reaction was carried (CH3). IR (ν, cm−1): 3234, 1668, 1599, 1580, 1505, 1372, 1290,
out with a solution of compound (12c) (3 g, 10 mmol, 3.0 g, 1178. HRMS (EI): Calcd for C10H9Br2NO2: 332.9000. Found:
1
equiv.) in MeOH (25 mL) and potassium carbonate 332.8994.
(0.5 mmol, 70 mg, 5 mol%). After removing the methanol, N-(2-(2-Bromoacetyl)-4-(trifluoromethyl)phenyl)acetamide (14c).
N-bromosuccinimide (20 mmol, 3.56 g, 2 equiv.), FeCl3·6H2O Following general procedure VI, the reaction was carried out
(0.5 mmol, 135 mg, 5 mol%), water (20 mL) and tetrahydro- with a solution of compound (13c) (2.0 g, 5 mmol, 1 equiv.),
furan (20 mL) were added under nitrogen at rt. The reaction Et3N (0.73 mL, 5.25 mmol, 1.05 equiv.) and (EtO)2POH
temperature was raised to 80 °C and kept for 3 h. After (0.67 mL, 5.25 mmol, 1.05 equiv.) in THF (20 mL) at rt. The
workup, the crude product was purified by silica gel column product (14c) was obtained as a white solid (1.55 g, 96%). Mp:
1
chromatography with a gradient of ethyl acetate in toluene 110–112 °C. H-NMR (CDCl3, 400 MHz) δ 11.50 (bs, 1H), 8.96
(0/100 to 8/92) to afford the product (13c) as a brown solid (d, J = 8.9 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 8.9 Hz,
(2.40 g, 60%). Mp: 133–134 °C. 1H-NMR (CDCl3, 400 MHz) J = 2.0 Hz, 1H), 4.54 (s, 2H), 2.29 (s, 3H). 13C-NMR (CDCl3,
δ 11.26 (bs, 1H), 8.98 (d, J = 9.0 Hz, 1H), 8.22 (d, J = 1.4 Hz, 100 MHz) δ 194.7 (CO), 169.7 (CO), 144.6 (Cq), 132.5 (q, J =
1H), 7.85 (dd, J = 9.0 Hz, J = 1.4 Hz, 1H), 6.85 (s, 1H), 2.31 4 Hz, CH), 128.3 (q, J = 4 Hz, CH), 124.2 (q, J = 33 Hz, Cq),
(s, 3H).13C-NMR (CDCl3, 100 MHz) δ 187.8 (CO), 168.7 (CO), 123.4 (q, J = 272 Hz, CF3), 121.4 (CH), 118.2 (Cq), 31.8 (CH2),
144.3 (Cq), 131.9 (q, J = 4 Hz, CH), 126.9 (q, J = 4 Hz, CH), 25.7 (CH3). IR (ν, cm−1): 3282, 1719, 1660, 1590, 1525, 1292,
123.18 (q, J = 33.8 Hz, Cq), 122.2 (q, J = 272.0 Hz, CF3), 120.7 1135. HRMS (EI): Calcd for C11H9BrF3NO2: 322.9769. Found:
(CH), 114.2 (Cq), 38.4 (CH), 24.7 (CH3). IR (ν, cm−1): 3296, 322.9764.
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General procedure VII for the formation of xanthates (15)
IR (ν, cm−1) 3279, 1714, 1660, 1591, 1524, 1419, 1340, 1293,
1230, 1134, 1053. HRMS (EI): Calcd for C14H14F3NO3S2:
365.0367. Found: 365.0369.
To a stirred solution of 2-bromoacetylphenylacetamide (14)
(1 mmol) in acetone (2 mL) at rt was added portion-wise pot-
assium ethyl xanthate (1.1 mmol). The reaction was stirred
until complete consumption of the starting material. The
solvent was evaporated, and the residue was diluted with ethyl
acetate. The organic phase was washed with brine, and the
organic layer was washed with water, dried over MgSO4, fil-
tered and concentrated in vacuo. The residue was recrystallised
from ethanol to afford the desired xanthate (15).
S-2-(2-Acetamido-5-methylphenyl)-2-oxoethyl O-ethyl carbo-
nodithioate (15a). Following general procedure VII, the reac-
tion was carried out with a solution of compound (14a)
(1.08 g, 4 mmol, 1 equiv.) in acetone (8 mL) and potassium
ethyl xanthate (705 mg, 4.4 mmol, 1.1 equiv.) at rt for 1 h.
Xanthate (15a) was obtained as a white solid (1.18 g, 95%).
Mp: 149–150 °C (from EtOH). 1H-NMR (CDCl3, 400 MHz)
δ 11.22 (bs, 1H), 8.65 (d, J = 8.7 Hz, 1H), 7.79 (s, 1H), 7.42 (d,
J = 8.7 Hz, 1H), 4.74 (s, 2H), 4.66 (q, J = 7.1 Hz, 2H), 2.40 (s,
3H), 2.20 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3,
100 MHz) δ 213.1 (CS), 196.1 (CO), 169.4 (CO), 138.9 (Cq),
136.7 (CH), 132.1 (Cq), 130.8 (CH), 121.1 (Cq), 120.8 (CH), 71.0
(CH2), 45.0 (CH2), 25.6 (CH), 20.9 (CH3), 13.8 (CH3). IR (ν,
cm−1): 2989, 1698, 1667, 1587, 1505, 1356, 1295, 1234, 1111,
1049. HRMS (EI): Calcd for C14H17NO3S2: 311.0650. Found:
311.0653.
S-2-(2-Acetamido-5-bromophenyl)-2-oxoethyl O-ethyl carbono-
dithioate (15b). Following general procedure VII, the reaction
was carried out with a solution of compound (14b) (1.34 g,
4 mmol, 1 equiv.) in acetone (8 mL) and potassium ethyl
xanthate (705 mg, 4.4 mmol, 1 equiv.) at rt for 1 h. Xanthate
(15b) was obtained as a pinkish solid (1.4 g, 93%). Mp:
144–145 °C (from EtOH). 1H-NMR (CDCl3, 400 MHz) δ 11.20
(bs, 1H), 8.68 (d, J = 9.1 Hz, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.66
(dd, J = 9.1 Hz, J = 2.3 Hz, 1H), 4.67 (s, 2H), 4.64 (q, J = 7.1 Hz,
2H), 2.19 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3,
100 MHz) δ 212.8 (CS), 195.3 (CO), 169.5 (CO), 140.2 (Cq),
138.4 (CH), 133.1 (CH), 122.8 (CH), 122.3 (Cq), 114.8 (Cq), 71.2
(CH2), 44.7 (CH2), 25.6 (CH), 13.8 (CH3). IR (ν, cm−1): 3290,
1673, 1574, 1496, 1394, 1288, 1229, 1113, 1048. HRMS (EI):
Calcd for C13H14BrNO3S2: 374.9598. Found: 374.9600.
S-2-(2-Acetamido-5-(trifluoromethyl)phenyl)-2-oxoethyl O-ethyl
carbonodithioate (15c). Following general procedure VII, the
reaction was carried out with a solution of compound (14c)
(1.30 g, 4 mmol, 1 equiv.) in acetone (8 mL) and potassium
ethyl xanthate (705 mg, 4.4 mmol, 1.1 equiv.) at rt. The reac-
tion finished in one hour. Xanthate (15c) was obtained as a
pinkish solid (1.34 g, 92%). Mp: 85–86 °C (from EtOH).
1H-NMR (CDCl3, 400 MHz) δ 11.50 (bs, 1H), 8.94 (d, J = 8.9 Hz,
1H), 8.25 (m, 1H), 7.82 (dd, J = 9.0 Hz, J = 1.9 Hz, 1H), 4.74 (s,
2H), 4.66 (q, J = 7.1 Hz, 2H), 2.25 (s, 3H), 1.42 (t, J = 7.1 Hz,
3H). 13C-NMR (CDCl3, 100 MHz) δ 212.7 (CS), 195.8 (CO), 169.8
(CO), 143.9 (Cq), 132.2 (q, J = 3 Hz, CH), 127.7 (q, J = 4 Hz,
CH), 124.4 (q, J = 33 Hz, Cq), 123.5 (q, J = 272 Hz, CF3), 121.4
(CH), 120.3 (Cq), 71.3 (CH2), 44.5 (CH2), 25.7 (CH), 13.8 (CH3).
S-2-(2-Acetamido-4-fluorophenyl)-2-oxoethyl O-ethyl carbono-
dithioate (15d). Starting with N-(2-acetyl-5-fluorophenyl)-
acetamide (11d) (976 mg, 5 mmol) and pyridinium hydro-
bromide perbromide (880 g, 5.5 mmol) in 15 mL acetic acid at
rt, general procedure I was followed, but the reaction mixture
was heated to only 50 °C in the first step. After the substitution
of bromine by potassium O-ethyl xanthate, the residue was
purified by silica gel column chromatography with a gradient
of ethyl acetate in toluene (0 : 100 to 5 : 95) to afford xanthate
(15d) (995 g, 63%) as a white solid. Mp: 98–100 °C. 1H-NMR
(CDCl3, 400 MHz) δ 11.57 (bs, 1H), 8.59 (dd, J = 2.6 Hz, J =
12.0 Hz, 1H), 8.04 (dd, J = 9.0 Hz, J = 6.2 Hz, 1H), 6.84 (ddd, J =
9.1 Hz, J = 7.3 Hz, J = 2.6 Hz, 1H), 4.69 (s, 2H), 4.66 (q,
J = 7.1 Hz, 2H), 2.21 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C-NMR
(CDCl3, 100 MHz) δ 213.0 (CS), 195.1 (CO), 169.7 (CO), 166.8
(d, J = 256 Hz, Cq), 144.1 (d, J = 13 Hz, Cq), 133.3 (d, J = 11 Hz,
CH), 117.2 (d, J = 3 Hz, Cq), 109.9 (d, J = 23 Hz, CH), 108.0 (d,
J = 28 Hz, CH), 71.0 (CH2), 44.8 (CH2), 25.6 (CH3), 13.8 (CH3).
IR (ν, cm−1): 3271, 1711, 1652, 1592, 1554, 1431, 1234, 1113,
1052. HRMS (EI): Calcd for C20H14F3NO4S2: 315.0399. Found:
315.0413.
S-2-(6-Acetamidobenzo[d][1,3]dioxol-5-yl)-2-oxoethyl O-ethyl
carbonodithioate (15e). To a refluxing solution of CuBr2
(2.25 g, 10.1 mmol, 2.01 equiv.) in 11 mL AcOEt was added
dropwise a solution of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)aceta-
mide (11e) (1.1 g, 5 mmol, 1 equiv.) in 11 mL CHCl3. Reflux
was continued for 8 hours (or until a white precipitate was
formed). Then, the solvent was evaporated and the remaining
solid was boiled in the 1 : 1 mixture of ethanol and chloroform
and filtered off while hot. The filtrate was left to cool down
and the resulting solid was collected. The crude solid was dis-
solved in acetone (10 mL) and potassium O-ethyl xanthate
(805 mg, 5 mmol) was added at rt. After completion of the
reaction, the acetone was evaporated and the mixture was
diluted with ethyl acetate. The organic layer was washed with
water, brine, dried over MgSO4, filtered and concentrated
in vacuo. The residue was purified by silica gel column chrom-
atography with a gradient of dichloromethane in petroleum
ether (50/50 to 90/10) to afford the desired xanthate (15e) as a
white solid (684 mg, 40%). Mp: 132 °C. 1H-NMR (CDCl3,
400 MHz) δ 11.57 (bs, 1H), 8.41 (s, 1H), 7.39 (s, 1H), 6.06 (s,
2H), 4.66 (q, J = 7.1 Hz, 2H), 4.63 (s, 2H), 2.20 (s, 3H), 1.42 (t,
J = 7.1 Hz, 3H). 13C-NMR (CDCl3, 100 MHz) δ 213.0 (CS), 193.9
(CO), 169.5 (CO), 153.7 (Cq), 142.7 (Cq), 140.9 (Cq), 113.9 (Cq),
108.6 (CH), 102.4 (CH), 101.8 (CH2), 71.0 (CH2), 44.9 (CH2),
25.6 (CH3), 13.8 (CH3). IR (ν, cm−1): 3124, 1704, 1614, 1541,
1435, 1354, 1274, 1051. HRMS (EI): Calcd for C14H15NO5S2:
341.0392. Found: 341.0395.
General procedure VIII for the synthesis of tetralones (17) by
radical addition and cyclisation
A magnetically stirred solution of xanthate (1 mmol) and vinyl
pivalate (2.5 mmol) in 1,2-dichloroethane (2 mL) was refluxed
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for 15 min under a slightly positive nitrogen pressure. Dilaur- 1H), 8.94 (d, J = 9.1 Hz, 1H), 7.87 (d, J = 9.1 Hz, 1H), 6.35
oyl peroxide (DLP) (10 mol%) was then added and additional (m, 1H), 2.934 (m, 1H), 2.70 (m, 1H), 2.54 (m, 1H), 2.28 (s, 3H),
DLP (10 mol%) was added every 60 min until total consump- 2.21 (m, 1H), 1.15 (s, 9H). 13C-NMR (CDCl3, 100 MHz) δ 202.3
tion of the starting material or until no evolution could be (CO), 177.0 (CO), 170.0 (CO), 144.7 (Cq), 139.8 (Cq), 132.8
detected by TLC analysis. The reaction mixture was then (q, J = 5.7 Hz, CH), 123.5 (q, J = 272 Hz, CF3), 122.8 (q, J =
cooled to 20 °C and evaporated to dryness under reduced 31.2 Hz, Cq), 121.0 (CH), 118.7 (Cq), 64.9 (CH2), 39.0 (Cq), 33.7
pressure. The residue was purified by silica gel column (CH2), 27.0 (3CH3), 26.1 (CH2), 25.8 (CH3). IR (ν, cm−1): 3215,
chromatography to yield the desired compound.
1737, 1713, 1662, 1595, 1398, 1286, 1135. HRMS (EI) Calcd for
5-Acetamido-8-methyl-4-oxo-1,2,3,4-tetrahydronaphthalen- C17H20F3NO4: 371.1344. Found: 371.1339.
1-yl pivalate (17a). Following general procedure VIII, the reac-
5-Acetamido-7-fluoro-4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl
tion was carried out using xanthate (15a) (310 mg, 1 mmol, pivalate (17d). Following general procedure II, the reaction
1 equiv.) with vinyl pivalate (0.37 mL, 2.5 mmol, 2.5 equiv.) in was carried out using xanthate (15d) (315 mg, 1 mmol,
refluxing dichloroethane and needed 1.2 equiv. of DLP 1 equiv.) and vinyl pivalate (0.37 mL, 2.5 mmol, 2.5 equiv.) in
(478 mg) to go to completion (7 h). The residue after evapor- refluxing dichloromethane (1 mL) and needed 10 mol% DLP
ation of the solvent was purified by silica gel column chrom- to go to completion. The reaction mixture was evaporated to
atography with a gradient of ethyl acetate in petroleum ether dryness under reduced pressure and the residue was dissolved
(5 : 95 to 15 : 85) to afford (17a) (152 mg, 48%) as a white solid. in ethyl acetate (10 mL), heated to reflux and treated with
1
Mp: 104–105 °C. H-NMR (CDCl3, 400 MHz) δ 12.03 (bs, 1H), 1.0 equiv. DLP. After evaporation, the residue was purified by
8.68 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 6.18 (m, 1H), silica gel column chromatography with a gradient of ethyl
2.92 (m, 1H), 2.61 (m, 1H), 2.37 (m, 1H), 2.31 (s, 3H), 2.23 (s acetate in petroleum ether (5 : 95 to 15 : 85) to afford (17d)
+ m, 4H), 1.18 (s, 9H). 13C-NMR (CDCl3, 100 MHz) δ 203.1 (208 mg, 65%) as a white solid. Mp: 119–120 °C. 1H-NMR
(CO), 177.8 (CO), 169.6 (CO), 140.0 (Cq), 138.3 (Cq), 137.9 (CDCl3, 400 MHz) δ 12.24 (bs, 1H), 8.55 (dd, J = 11.8 Hz, J =
(CH), 131.5 (Cq), 121.1 (CH), 118.2 (Cq), 66.2 (CH2), 39.2 (Cq), 2.5 Hz, 1H), 6.78 (dd, J = 8.4 Hz, J = 2.5 Hz, 1H), 5.99 (dd, J =
34.4 (CH2), 27.2 (3CH3), 26.7 (CH2), 25.7 (CH3), 18.6 (CH3). IR 7.0 Hz, J = 3.7 Hz, 1H), 2.91 (m, 1H), 2.70 (m, 1H), 2.33
(ν, cm−1): 3228, 1730, 1703, 1655, 1541, 1256, 1143. HRMS (EI) (m, 1H), 2.19 (s + m, 4H), 1.12 (s, 9H). 13C-NMR (CDCl3,
Calcd for C18H23NO4: 317.1627. Found: 317.1627.
100 MHz) δ 200.5 (CO), 177.5 (CO), 169.8 (CO), 166.4 (d, J =
5-Acetamido-8-bromo-4-oxo-1,2,3,4-tetrahydronaphthalen- 256 Hz, Cq), 145.5 (d, J = 10 Hz, Cq), 144.7 (d, J = 14 Hz, Cq),
1-yl pivalate (17b). Following general procedure VIII, the reac- 113.9 (d, J = 3 Hz, Cq), 109.3 (d, J = 23 Hz, CH), 107.4 (d, J =
tion was carried out using xanthate (15b) (375 mg, 1 mmol, 28 Hz, CH), 69.1 (CH2), 39.0 (Cq), 35.8 (CH2), 27.7 (CH2), 27.1
1 equiv.) and vinyl pivalate (0.37 mL, 2.5 mmol, 2.5 equiv.) in (3CH3), 25.6 (CH3). IR (ν, cm−1): 3217, 1734, 1654, 1542, 1445,
refluxing dichloroethane and needed 1.1 equiv. of DLP 1142. HRMS (EI) Calcd for C17H20FNO4: 321.1376. Found:
(438 mg) to go to completion (6 h). After evaporation of the 321.1374.
solvent, the residue was purified by silica gel column chrom-
5-Acetamido-6-oxo-6,7,8,9-tetrahydronaphtho[2,1-d][1,3]-
atography with dichloromethane to afford (17b) (195 mg, 51%) dioxol-9-yl pivalate (17e). Following general procedure II, the
1
as a white solid. Mp: 202–203 °C. H-NMR (CDCl3, 400 MHz) reaction was carried out using xanthate (15e) (341 mg,
δ 12.08 (bs, 1H), 8.74 (d, J = 9.1 Hz, 1H), 7.77 (d, J = 9.2 Hz, 1 mmol, 1 equiv.) and vinyl pivalate (0.37 mL, 2.5 mmol,
1H), 6.27 (m, 1H), 2.94 (m, 1H), 2.65 (m, 1H), 2.43 (m, 1H), 2.5 equiv.) in refluxing dichloromethane (1 mL) and needed
2.31 (s + m, 4H), 1.21 (s, 9H). 13C-NMR (CDCl3, 100 MHz) 10 mol% DLP to go to completion. The reaction mixture was
δ 202.3 (CO), 177.3 (CO), 169.7 (CO), 141.3 (Cq), 139.7 (CH), evaporated to dryness under reduced pressure and the residue
139.2 (Cq), 122.6 (CH), 119.6 (Cq), 118.1 (Cq), 68.9 (CH2), 39.2 was dissolved in ethyl acetate (10 mL), heated to reflux and
(Cq), 34.3 (CH2), 27.2 (3CH3), 26.3 (CH2), 25.7 (CH3). IR (ν, treated with 1.0 equiv. DLP to go to completion. After evapor-
cm−1): 3227, 1734, 1709, 1660, 1541, 1507, 1138, 1037. HRMS ation, the residue was purified by silica gel column chromato-
(EI) Calcd for C17H20BrNO4: 381.0576. Found: 381.0595.
graphy with a gradient of ethyl acetate in petroleum ether
5-Acetamido-4-oxo-8-(trifluoromethyl)-1,2,3,4-tetrahydro- (5 : 95 to 30 : 70) to afford (17e) (198 mg, 57%) as a white solid.
1
naphthalen-1-yl pivalate (17c). Following general procedure II, Mp: 120–121 °C. H-NMR (CDCl3, 400 MHz) δ 12.36 (bs, 1H),
the reaction was carried out using xanthate (15c) (365 mg, 8.39 (s, 1H), 6.19 (s, 1H), 6.02 (d, J = 8.4 Hz, 2H) 2.85 (m, 1H),
1 mmol, 1 equiv.) and vinyl pivalate (0.37 mL, 2.5 mmol, 2.57 (m, 1H), 2.20 (s + m, 5H), 1.17 (s, 9H). 13C-NMR (CDCl3,
2.5 equiv.) in refluxing dichloromethane (1 mL) and needed 100 MHz) δ 200.0 (CO), 177.5 (CO), 169.7 (CO), 153.2 (Cq),
10 mol% DLP to go to completion. Then the reaction mixture 140.6 (Cq), 140.1 (Cq), 120.0 (CH), 111.1 (Cq), 102.5 (CH2),
was evaporated to dryness under reduced pressure. The 101.5 (CH), 63.8 (CH), 39.0 (Cq), 34.8 (CH2), 27.1 (3CH3
+
residue was dissolved in ethyl acetate (10 mL), heated to reflux, CH2), 25.6 (CH3). IR (ν, cm−1): 3124, 1733, 1703, 1653, 1625,
and needed 1 equiv. DLP to go to completion. After evapor- 1503, 1503, 1470, 1367, 1257, 1142. HRMS (EI) Calcd for
ation, the residue was purified by silica gel column chromato- C17H21FNO4: 347.1369. Found: 347.1373.
graphy with a gradient of petroleum ether in dichloromethane
N-(8-Hydroxy-4-methylnaphthalen-1-yl)acetamide (18a). Fol-
(40 : 60 to 100 : 0) to afford (17c) (222 mg, 60%) as a white lowing general procedure III, the reaction was carried out
1
solid. Mp: 150–151 °C. H-NMR (CDCl3, 400 MHz) δ 12.28 (bs, using (17a) (64 mg, 0.2 mmol, 1 equiv.) and PTSA (105 mg,
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0.6 mmol, 3 equiv.) in refluxing toluene (3 mL) and needed 103.6 (d, J = 31 Hz, CH), 25.3 (s, CH3). IR (ν, cm−1): 2500, 1545,
3 hours to go to completion. The product was recrystallised 1360. HRMS (EI) Calcd for C12H10FNO2–H2O = 201.0590.
from dichloromethane to afford a pinkish solid (18a) (32 mg, Found: 201.0589.
74%). Mp: 143–145 °C. 1H-NMR (acetone-D6, 400 MHz) δ 10.93
N-(6-Hydroxynaphtho[2,1-d][1,3]dioxol-5-yl)acetamide (18e).
(bs, 1H), 10.09 (bs, 1H), 8.43 (d, J = 7.9 Hz, 1H), 7.42 (dd, J = Following general procedure III, the reaction was carried out
1.0 Hz, J = 8.5 Hz, 1H), 7.25 (m, 1H), 7.16 (d, J = 7.9 Hz, 1H), using (17e) (70 mg, 0.2 mmol, 1 equiv.) and PTSA (105 mg,
6.91 (dd, J = 7.6 Hz, J = 1.0 Hz, 1H), 2.46 (s, 3H), 2.05 (s, 3H). 0.6 mmol, 3 equiv.) in refluxing toluene (3 mL) and needed
13C-NMR (acetone-D6, 100 MHz) δ 168.2 (CO), 154.4 (Cq), 136.3 3 hours to go to completion. The residue was washed with
(Cq), 135.5 (Cq), 129.1 (Cq), 127.9 (CH), 126.8 (CH), 117.7 pentane to afford a white solid (18e) (34.3 mg, 70%). Mp:
(CH), 116.3 (Cq), 115.6 (CH), 111.2 (CH), 25.6 (CH3), 20.0 189–190 °C. 1H-NMR (DMSO-D6, 400 MHz) δ 11.3 (bs, 2H),
(CH3). IR (ν, cm−1): 3733, 2359, 1542. HRMS (EI) Calcd for 8.26 (s, 1H), 7.27 (m, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.74 (d, J =
C13H13NO2: 215.0946. Found: 215.0947.
7.5 Hz, 1H), 6.14 (s, 2H), 2.12 (s, 3H). 13C-NMR (DMSO-D6,
N-(4-Bromo-8-hydroxynaphthalen-1-yl)acetamide (18b). Fol- 100 MHz) δ 167.0 (CO), 154.6 (Cq), 142.2 (CH), 136.0 (Cq),
lowing general procedure III, the reaction was carried out 131.1 (Cq), 127.2 (CH), 121.2 (CH), 11.1 (Cq), 110.4 (Cq), 108.1
using (17b) (77 mg, 0.2 mmol, 1 equiv.) and PTSA (105 mg, (CH), 101.3 (CH2), 100.1 (Cq), 25.1 (CH3). IR (ν, cm−1): 2918,
0.6 mmol, 3 equiv.) in refluxing toluene (3 mL) and needed 1550, 1264. HRMS (EI) Calcd for C13H11NO4: 245.0688. Found:
3 hours to go to completion. The product was washed with 245.0688.
dichloromethane to afford a greyish solid (18b) (40.2 mg,
N-(4-(Trifluoromethyl)naphthalen-1-yl)acetamide (19c). To a
72%). Mp: 149–150 °C. 1H-NMR (acetone-D6, 400 MHz) δ 11.01 solution of (17c) (74 mg, 0.2 mmol, 1 equiv.) in methanol
(bs, 1H), 10.38 (bs, 1H), 8.45 (d, J = 8.5 Hz, 1H), 7.64 (m, 2H), (3 mL), NaBH4 (12 mg, 0.3 mmol, 1.5 equiv.) was added and
7.34 (m, 1H), 6.97 (dd, J = 0.6 Hz, 7.6 Hz, 1H), 2.05 (s, 3H). the mixture was stirred for 1 hour at rt. A saturated solution of
13C-NMR (acetone-D6, 100 MHz) δ 168.5 (CO), 154.5 (Cq), 137.5 NH4Cl was added to the reaction and the mixture was extracted
(Cq), 135.0 (Cq), 131.4 (CH), 128.5 (CH), 120.6 (CH), 117.4 with ethyl acetate. The organic layer was washed twice with
(Cq), 116.1 (Cq), 116.0 (CH), 112.3 (CH), 25.6 (CH3). IR H2O, brine, dried with MgSO4 and then filtered. The solvent
(ν, cm−1): 2360, 1542, 1258. HRMS (EI) Calcd for C12H10BrNO2: was removed under reduced pressure to provide a brown
278.9895. Found: 278.9899.
residue. Following general procedure III, the second step was
N-(8-Hydroxy-4-(trifluoromethyl)naphthalen-1-yl)acetamide carried out with the residue and PTSA (105 mg, 0.6 mmol,
(18c). Following general procedure III, the reaction was 3 equiv.) in refluxing Ac2O–AcOH (1 mL/2 mL) and needed
carried out using (17c) (74 mg, 0.2 mmol, 1 equiv.) and PTSA 3 hours to go to completion. The product was washed with
(105 mg, 0.6 mmol, 3 equiv.) in refluxing toluene (3 mL) and pentane to afford a light pink solid (19c) (36 mg, 71%). Mp:
needed 3 hours to go to completion. The product was washed 185–186 °C. 1H-NMR (acetone-D6, 400 MHz) δ 9.20 (bs, 1H),
with pentane to afford a light pinkish solid (18c) (40 mg, 8.09 (d, J = 8.2 Hz, 1H), 7.93 (m, 2H), 7.70 (d, J = 8.1 Hz, 1H),
74%). Mp: 177–178 °C. 1H-NMR (acetone-D6, 400 MHz) δ 11.22 7.48 (ddd, J = 8.2 Hz, J = 6.9 Hz, J = 1.3 Hz, 1H), 7.41 (ddd, J =
(bs, 1H), 10.42 (bs, 1H), 8.59 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.1 Hz, J = 6.9 Hz, J = 1.3 Hz, 1H), 2.57 (s, 3H). 13C-NMR
8.5 Hz, 1H), 7.51 (m, 1H), 7.35 (m, 1H), 6.97 (d, J = 7.6 Hz, 1H), (acetone-D6, 100 MHz) δ 169.8 (CO), 139.3 (Cq), 130.4 (Cq),
1.89 (s, 3H). 13C-NMR (Acetone-D6, 100 MHz) δ 168.9 (CO), 128.7 (CH), 128.0 (Cq), 127.4 (CH), 126.1 (q, J = 6 Hz, CH),
154.7 (Cq), 141.5 (Cq), 133.0 (Cq), 129.0 (CH), 127.1 (q, J = 125.0 (q, J = 2 Hz, CH), 126.0 (q, J = 272 Hz, CF3), 123.6 (CH),
6 Hz, CH), 126.1 (q, J = 272 Hz, CF3), 120.0 (q, J = 30 Hz, Cq), 122.1 (q, J = 30 Hz, Cq), 118 (CH), 24.2 (CH3). IR (ν, cm−1):
117.3 (q, J = 3 Hz, CH), 116.3 (Cq), 113.2 (CH), 112.2 (CH), 25.7 3464, 1714, 1558, 1338, 1125. HRMS (EI) Calcd for
(CH3). IR (ν, cm−1): 2592, 1549, 1291. HRMS (EI) Calcd for C13H10F3NO2: 253.0714. Found: 253.0713.
C13H10F3NO2–H2O = 251.0558. Found: 251.0555.
N-(3-Fluoro-8-hydroxynaphthalen-1-yl)acetamide (18d). Fol-
lowing general procedure III, the reaction was carried out
using (17d) (65 mg, 0.2 mmol, 1 equiv.) and PTSA (105 mg,
Acknowledgements
0.6 mmol, 3 equiv.) in refluxing toluene (3 mL) and needed We thank Ecole Polytechnique for a scholarship to one of us
3 hours to go to completion. After evaporation of the solvent, (N. D. M. T.).
the residue was purified by silica gel column chromatography
with a gradient of ethyl acetate in toluene (10 : 90 to 30 : 70)
to afford (18d) as a pinkish solid (26.5 mg, 60%). Mp:
Notes and references
193–194 °C. 1H-NMR (DMSO-D6, 400 MHz) δ 11.49 (bs, 1H),
11.31 (bs, 1H), 8.37 (dd, J = 12.2 Hz, J = 2.7 Hz, 1H), 7.32 (m,
1H), 7.31 (m, 1H), 7.27 (dd, J = 9.6 Hz, J = 2.7 Hz, 1H), 6.86 (m,
1H), 2.18 (s, 3H). 13C-NMR (DMSO-D6, 100 MHz) δ 168.2 (CO),
159.5 (d, J = 240 Hz, Cq), 153.6 (Cq), 138.0 (d, J = 13 Hz, Cq),
136.5 (d, J = 11 Hz, Cq), 127.5 (CH), 119.5 (d, J = 5 Hz, CH),
112.1 (Cq), 109.6 (d, J = 2 Hz, CH), 105.3 (d, J = 21 Hz, CH),
1 (a) M. D. Watson, A. Fechtenkötter and K. Müllen, Chem.
Rev., 2001, 101, 1267; (b) M. Medarde, A. B. S. Maya and
C. J. Pérez-Melero, Enzyme Inhib. Med. Chem., 2004, 19, 521;
(c) T. Ukita, Y. Nakamura, A. Kubo, Y. Yamamoto,
M. Takahashi, J. Kotera and T. Ikeo, J. Med. Chem., 1999,
42, 1293; (d) A. R. Katrizky, G. Zhang and L. Xie, J. Org.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 3251–3264 | 3263

View Article Online
Paper
Organic & Biomolecular Chemistry
Chem., 1997, 62, 721; (e) R. S. Ward, Nat. Prod. Rep., 1995,
6 (a) L. Martarello, D. Joseph and G. Kirsch, Heterocycles,
1996, 43, 367; (b) D. Joseph, L. Martarello and G. Kirsch,
J. Chem. Res. (S), 1995, 448; (c) S. Sekiguchi, M. Hirai,
E. Ota, H. Hiratsuka, Y. Mori and S. Tanaka, J. Org. Chem.,
1985, 50, 5105.
7 (a) W. Semmler, Ber. Dtsch. Chem. Ges., 1892, 25, 3352;
(b) L. Wolff, Justus Liebigs Ann. Chem., 1902, 332, 351;
(c) G. Schroeter, A. Gluschke, S. Götzky, J. Huang,
G. Irmisch, E. Laves, O. Chrader and G. Stier, Ber. Dtsch.
Chem. Ges., 1930, 63, 1308.
12, 183; (f) J. M. Trujillo, R. E. Jorge, E. Navarro and
J. Boada, Phytochemistry, 1990, 29, 2991; (g) H. Brockmann
and A. Zeeck, Chem. Ber., 1970, 103, 1709.
2 For reviews, see: (a) C. B. de Koning, A. L. Rousseau and
W. A. L. van Otterlo, Tetrahedron, 2003, 59, 7; (b) S. Saito
and Y. Yamamoto, Chem. Rev., 2000, 100, 2901 For selected
recent syntheses, see: (c) L. Ilies, A. Matsumoto,
M. Kobayashi, N. Yoshikai and E. Nakamura, Synlett, 2012,
2381; (d) R. Balamurugan and V. Gudla, J. Org. Chem.,
2011, 76, 9919; (e) R. Balamurugan and V. Gudla, Org. Lett.,
2009, 11, 3116; (f) N. Asao, Synlett, 2006, 1645; (g) X. Xie
and M. C. Kozlowski, Org. Lett., 2001, 3, 2661;
8 W. P. Hong, A. V. Iosub and S. S. Stahl, J. Am. Chem. Soc.,
2013, 135, 13664.
9 L. Petit and S. Z. Zard, Chem. Commun., 2012, 46, 5148.
(h) A. D. Martinez, J. P. Deville, J. L. Stevens and V. Behar, 10 D. V. Avila, K. U. Ingold, J. Lusztyk, W. H. Green and
J. Org. Chem., 2003, 69, 991; (i) G. W. Kabalka, Y. Ju and D. R. Procopio, J. Am. Chem. Soc., 1995, 117, 2929.
Z. Wu, J. Org. Chem., 2003, 68, 7915; ( j) G. S. Viswanathan, 11 (a) R. Chinchilla and C. Nájera, Chem. Soc. Rev., 2011, 40,
M. Wang and C. J. Li, Angew. Chem., Int. Ed., 2002, 41,
2138; (k) A. T. Hopper, D. T. Witiak and J. Ziemniak, J. Med.
Chem., 1998, 41, 420.
3 (a) H. Zweifel, Stabilization of Polymeric Materials, Springer,
Berlin, 1997; (b) T. J. Jenkins, B. Guan, M. Dai, G. Li,
5084; (b) A. Wetzel and F. Gagosz, Angew. Chem., Int. Ed.,
2011, 30, 7354; (c) S. Urgaonkar and J. G. Verkade, J. Org.
Chem., 2004, 69, 5752; (d) K. Sonogashira, in Metal-Cata-
lyzed Reactions, ed. F. Diederich and P. J. Stang, Wiley-VCH,
NewYork, 1998.
T. E. Lightburn, S. Huang, B. S. Freeze, D. F. Burdi, 12 (a) Y. Zu, F. Jie, M. Liu and A. Wu, Org. Lett., 2012, 14,
S. Jacutin-Porte, R. Bennett, W. Chen, C. Minor, S. Ghosh,
C. Blackburn, K. M. Gigstad, M. Jones, R. Kolbeck, W. Yin,
S. Smith, D. Cardillo, T. D. Ocain and G. C. Harriman,
J. Med. Chem., 2007, 50, 566; (c) K. L. Rinehart Jr., Acc.
Chem. Res., 1972, 5, 57.
4414; (b) J. S. Yadav, B. V. S. Reddy, A. P. Singh and
A. K. Basak, Tetrahedron Lett., 2008, 49, 5880; (c) X. Yang,
L. Yuan, K. Yamato, A. L. Brown, W. Feng, M. Furukawa,
X. C. Zeng and B. Gong, J. Am. Chem. Soc., 2004, 126, 3148;
(d) J. Liu, W. Li, C. Wang and Z. Li, Tetrahedron Lett., 2001,
52, 4320.
4 (a) A. Cordero-Vargas, I. Pérez-Martin, B. Quiclet-Sire and
S. Z. Zard, Org. Biomol. Chem., 2004, 2, 3018; (b) A. Cordero- 13 Z. Diwu, C. Beachdel and D. H. Klaubert, Tetrahedron Lett.,
Vargas, B. Quiclet-Sire and S. Z. Zard, Org. Lett., 2003, 5, 1998, 39, 4987.
3717; (c) A. Liard, B. Quiclet-Sire and S. Z. Zard, Tetrahedron 14 (a) S. Eagon, J. Kim, K. Yan, D. Haddenham and
Lett., 1997, 38, 1759.
B. Singaram, Tetrahedron Lett., 2007, 48, 9025; (b) C. Wiles,
P. Watts and S. J. Haswell, Tetrahedron Lett., 2006, 47, 5261;
(c) A. V. Vorogushin, X. Huang and S. L. Buchwald, J. Am.
Chem. Soc., 2005, 127, 8146.
5 (a) Y. Liu, B. Jiang, W. Zhang and Z. Xu, J. Org. Chem.,
2013, 78, 966; (b) D. W. Low, G. Pattison, M. D. Wieczysty,
G. H. Churchill and H. W. Lam, Org. Lett., 2012, 14, 2548;
(c) A. Arrieta, I. Ganboa and C. Palomo, Synth. Commun., 15 R. W. Hoffmann, Dehydrobenzene and cycloalkynes,
1984, 14, 939.
Academic Press, New York, 1967, pp. 200–239.
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