Diversity oriented approach to polycyclic compounds through the diels-alder reaction and the Suzuki coupling

Article abstract of DOI:10.1002/ejoc.201200484

A diversity oriented strategy has been demonstrated to deliver small "drug like" molecules using alkylation, Diels-Alder reaction, and Suzuki-Miyaura cross-coupling as key steps. This methodology allows access a wide range of molecules using simple scaffolds such as indanes, tetralins and tetrahydroisoquinolines, which can enhance the chemical space for potential therapeutic molecules.

Full text of DOI:10.1002/ejoc.201200484

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DOI: 10.1002/ejoc.201200484
Diversity Oriented Approach to Polycyclic Compounds through the Diels–Alder
Reaction and the Suzuki Coupling
Sambasivarao Kotha,*[a] Shilpi Misra,[a] and Venu Srinivas[a]
Keywords: Synthesis design / Medicinal chemistry / Drug discovery / Template synthesis / Cross-coupling
A diversity oriented strategy has been demonstrated to de-
liver small “drug like” molecules using alkylation, Diels–
Alder reaction, and Suzuki–Miyaura cross-coupling as key
steps. This methodology allows access a wide range of mole-
cules using simple scaffolds such as indanes, tetralins and
tetrahydroisoquinolines, which can enhance the chemical
space for potential therapeutic molecules.
Introduction
The introduction of halogen atom(s) into biologically
active molecules can bring about profound changes in
physical, chemical, and medicinal properties (1–11; Fig-
ure 1).[1–2] Various chlorinated compounds such as rebecca-
mycin (1; antitumor),[3] neophyrolomycin (2; antitumor),[4]
substituted malonic-acid derivatives 3 (pesticide),[5] and
hexachlorophene 4 (β-catenine inhibitor)[6] can be high-
lighted for their useful biological activity.
The effect of bromine substitution in many medicinal
products is vital; however, it is difficult to generalize its
function. In many instances, a comparison with related
compounds is not available. The introduction of a bromine
atom into dyes often has beneficial effects. For example, the
sodium salt of phenoltetrabromophthalein disulponate dye
5[7a] is useful for testing the functional capacity of the liver,
and benzanthraquinone 6 is used as a dye for polyester fi-
bers.[7b] Agricultural applications of halogenated com-
pounds include the use of substituted derivatives of 2-ami-
noindan-2-phosphonic acid 7, which was found to act as an
inhibitor of buckwheat PAL, as well as inhibitors of antho-
cyanin biosynthesis in buckwheat hypocotyls.[8]
Similar to chloro compounds, fluorine substitution can
also lead to profound and often desirable biological proper-
ties.[9] For example, the presence of a fluorine substituent in
bioactive substrates enhances their lipophilicities and thus
increases their bioavailability. This change in properties is
due to the high electronegativity, relatively small size, and
very low polarizability of the fluorine atom compared with
other halogen atoms.[10] Fluorine-containing α-amino acids
(AAAs)[11] and large molecules have enjoyed widespread
Figure 1. Biologically active molecules containing halogen atoms.
bioorganic applications. For example, they are useful as
biological tracers,[12] enzyme inhibitors,[13] and in medical
applications[14] including control of blood pressure, al-
lergies, and tumor growth. Use of the anticancer agent
T138067[15] (8) leads to irreversible inhibition of tubulin.
Interestingly, the fluorinated derivative of 1,4-naphtho-
quinones 9–11 are highly potent inhibitors of Cdc25A and
Cdc25B phosphatase and are also useful against the growth
of tumor cells.[16]
[a] Department of Chemistry, Indian Institute of Technology –
Bombay,
Mumbai 400076, India
Fax: +91-22-2576-7152
E-mail: srk@chem.iitb.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200484.
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These examples clearly illustrate that the design of small (D3); (4) use different gylcine equivalents[21] to prepare α-
molecules containing halogen atoms is worthy of systematic amino acid derivatives (D4, D8, and D10); (5) during the
investigation. To this end, we wanted to design simple stra- hydrolysis of isocyanide derivative, diverse protecting
tegies that can deliver privileged structures such as 1,2,3,4- groups[17d] can be introduced into the α-amino acid moiety
tetrahydroisoquinoline-3-carboxylic acid (Tic), indan, and (D9); (6) with the availability of more than a thousand com-
tetralin-based α-amino acid derivatives, which can enhance mercially available boronic acids, the SM cross-coupling
the chemical space for “drug like” molecules. The challenge step can be used to functionalize the Tic derivatives[22] and
here was to design these privileged structures using simple other unusual α-amino acid derivatives (indan and tetralin-
scaffolds in a combinatorial manner using only 3–5 steps.
based α-amino acid derivatives) (D5); (7) the substituents
present in the boronic acid can be used as an additional
handle for further synthetic manipulation (D6); (8) oxidat-
ive coupling[23] of the SM products can generate carbon-
rich[24] Tic derivatives (D7).
Results and Discussion
To design new strategies to deliver diverse halo-contain-
ing small “drug like” molecules, tetrahalo dibromide 12 was
selected as a starting material. In this regard an alkylation,
Diels–Alder (DA) reaction,[17] and Suzuki–Miyaura (SM)
cross-coupling strategy[18] was selected to introduce struc-
tural and chemical diversity (Scheme 1).
Towards the synthesis of 1,2-bis(bromomethyl)-3,4,5,6-
tetrabromobenzene (29a), the building block tetra-
bromophthalic anhydride (24a) was selected as starting ma-
terial (Scheme 2), which may be reduced to 1,2-bis(hydroxy-
methyl)tetrabromobenzene (26a). We initially attempted the
reduction of 24a under various reduction conditions.[25]
However, during the course of our investigation, we found
that the synthesis of 26a from the corresponding anhydride
24a was not feasible. Because the reduction of diethyl tetra-
flourophthalate (31)[26] was reported to take place with lith-
ium aluminum hydride (LAH), attention turned to the
preparation of diethyl tetrabromophthalate (25), which we
anticipated could also be reduced to 26a with LAH. Disap-
pointingly, all attempts to prepare 29a were unsuccessful.
Reduction of diethyl ester 25 thus seemed to be a more
challenging task than anticipated (Scheme 2). It was con-
cluded that the C–X bond is cleaved under the reduction
conditions, which resulted in the formation of a complex
reaction mixture. Having investigated thirty different reac-
tion conditions to generate compounds 26a and 26b from
the corresponding anhydrides 24a and 24b, efforts were fi-
nally directed to an alternative route to prepare compounds
29a and 29b starting with o-xylene 27.[27] Thus, aromatic
nuclear bromination followed by benzylic bromination gave
the key “building block” 29a.
With the dibromide 29a in hand, initial attempts focused
on the preparation of the o-xylylene intermediate 34 via the
sultine derivative 33 (Scheme 3). Later, the DA strategy gen-
erated halogenated (bromo, chloro, and fluoro) tetralin-
based α-amino acid derivatives and other halogenated poly-
Scheme 1. Halogenated constrained α-amino acid derivatives and
other polycyclic frames.
Starting with simple dibromo-derivative 12, various ring cyclic compounds. Thus, treatment of 29a with Rongalite[28]
systems (five, six, and polycyclic) can be prepared. We have in the presence of tetrabutylammonium bromide (TBAB)
designed strategies whereby ten diversity points are embed- as a phase-transfer catalyst (PTC), gave tetrabromo sultine
ded in the pathway. More importantly, polycycles and het- derivative 33 in 96% isolated yield. Next, the DA strategy
erocycles can be prepared. In principle, our approach to was attempted with various dienophiles to deliver a diverse
halogenated derivatives fulfils major goals of diversity ori- collection of polyhalogenated compounds and tetralin-
ented synthesis[19] (Scheme 1). The diversity points in our based α-amino acid derivatives. For example, tetra-
approach to the generation of a library of halogenated bromosultine 33 was treated with dimethyl acetylenedicar-
small “drug like” molecules are: (1) the opportunity to in- boxylate (DMAD; 35) in toluene at 90 °C to afford the cy-
troduce different halogen atoms in the aromatic ring (D1); cloadduct, which, on successive aromatization with 2,3-
(2) use of a variety of dienophiles during the DA step (D2); dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) under mi-
(3) thermal rearrangement of sultine 13 to give the corre- crowave (MW) irradiation conditions, gave the aromatized
sponding sulfone and subsequent alkylation of the sulfone product 37 in moderate yield (Scheme 3). Surprisingly, con-
moiety with electrophiles containing a terminally unsatu- ventional conditions involving heating the DA adduct and
rated tether, followed by intramolecular DA reaction[20] DDQ in toluene were found to be ineffective.
2
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Diversity Oriented Approach to Polycycles
Scheme 3. DA reaction of tetrabromosultine with DMAD. Rea-
gents and conditions: (i) Rongalite, DMF, TBAB, 0–5 °C, 6 h; (ii)
DMAD (35), toluene, 90 °C; (iii) DDQ, toluene, MW (110 °C), 20–
25 min.
Scheme 4. Synthesis of functionalized polycyclic compounds
through DA reaction with sultine derivative 33. Reagents and condi-
tions: (i) 1. naphthalene-1,4-dione (38), toluene, 110 °C; 2. DDQ,
toluene, MW (110 °C), 20–25 min; (ii) tetracyano ethylene (42), tol-
uene, 110 °C; (iii) methyl 2-acetamido acrylate (40), toluene,
110 °C.
Scheme 2. Synthesis of 1,2-bis(bromomethyl)-3,4,5,6-tetrahaloben-
zene derivatives. Reagents and conditions: (i) conc. H2SO4, ethanol,
reflux; (ii) 1. LiAlH4, THF, room temp.-reflux; 2. LiAlH4, Et2O,
reflux; (iii) 1. Red-Al, benzene, room temp. to reflux; 2. Red-Al,
toluene, room temp. to reflux; 3. Red-Al, THF, 0–4 °C; 4. DIBAL-
H (1 m in THF), THF, 0 °C to room temp.; 5. DIBAL-H, toluene,
0–4 °C; 6. BH3/THF, 0 °C to room temp.; (iv) 1. Br2, Fe, 0 °C; 2.
AlCl3, DCE, SO2Cl2, room temp.-reflux; (v) NBS, AIBN, CCl4,
reflux; (vi) conc. H2SO4, ethanol, reflux; (vii) LiAlH4, Et2O, reflux;
(viii) HBr aq, H2SO4, reflux.
appropriate dienophiles for the synthesis of tetralin-based
α-amino acid derivatives or halogenated polycyclic com-
pounds. It was gratifying to note that the DA reaction with
sultine derivatives 33, 44, and 45 proceeded smoothly and
the subsequent aromatization reaction gave the correspond-
ing aromatized products in moderate yield. During the sult-
ine formation with 1,2-bis(bromomethyl)-3,4,5,6-tetra-
fluorobenzene (29c) it was found that the rate of the reac-
tion was much faster than with tetrabromo or tetrachloro
derivatives 29a and 29b. This enhanced rate of reaction can
be attributed to the presence of fluorine atoms in the sub-
strate. For example, sultine formation of tetrabromo or
chloro dibromide (29a and 29b) was complete in six hours
(3 h ice temperature and 3 h room temp.), whereas the reac-
tion of tetrafluoro dibromide 29c with Rongalite proceeded
much faster and the reaction was complete in two hours at
ice temperature.
Along similar lines, the DA reaction of tetrabromosultine
33 with a range of dienophiles [e.g., naphthalene-1,4-dione
(38), methyl 2-acetamidoacrylate (40), and tetracyano ethyl-
ene (42)] was explored (Scheme 4). When the DA reaction
was performed with dienophiles such as 38, 40, and 42 the
corresponding DA adducts were found to be sparingly solu-
ble in petroleum ether and ethyl acetate. All attempts to
purify these products by column chromatography resulted
in poor mass balance. Therefore, DA products were purified
by taking advantage of their differential solubility in vari-
ous solvents.
Synthesis of Fluoro, Chloro, and Bromo Tic Derivatives and
Indan-Based α-Amino Acid Derivatives
To generalize this strategy, we designed a series of o-xyl-
ylene intermediates that could be assembled from the cor-
responding sultine derivatives via Rongalite (Table 1). Later,
After the successful synthesis of halogenated tetralin-
these sultine derivatives were used in the DA reaction with based α-amino acid derivatives, this methodology was ex-
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Table 1. Halogenated tetralin-based α-amino acid derivatives and other polycylics by the DA strategy.
tended to other small “drug like” molecules. Toward this product 56; application of the Schmidt reaction conditions
end, ethyl isocyanoacetate (EICA) was alkylated with 29a gave the corresponding amino acid derivative 55a in 47%
to generate the expected indan-based α-amino acid deriva- yield (Scheme 6).
tives (Scheme 5). Treatment of 29a with EICA under PTC
condition gave isocyanide derivative 54a in 38% yield,
which, on hydrolysis with dilute HCl, gave the correspond-
ing α-amino acid derivative. Protection of the amino group
with acetic anhydride gave the acetyl derivative 55a. In the
case of the fluoro-derivative, attempts to purify isocyanide
derivative 54c by silica gel column chromatography resulted
in low yield of the coupling product due to its decomposi-
tion. It was therefore decided to proceed with further syn-
thetic steps with the crude material.
Scheme 6. Preparation of tetrabromo indan-based α-amino acid de-
rivative by using EAA. Reagents and conditions: (i) EAA, 4 m
NaOH, TBAHS, CH2Cl2, reflux, 46%; (ii) NaN3, MSA, CHCl3,
reflux, 47%.
Later, efforts were directed towards carbon-rich Tic de-
rivatives. To this end, tetrahalogenated (bromo 57a, chloro
57b, fluoro 57c) Tic derivatives were synthesized. The tet-
rahalo derivatives 29a–c were subjected to coupling reaction
with diethyl acetamidomalonate (DEAM) in the presence
of base to generate tetra-halogenated Tic derivatives 57a–c
(Table 2). Tetrabromo Tic derivative 57a was found to be a
suitable precursor for the synthesis of carbon-rich Tic deriv-
atives through the application of the SM cross-coupling re-
action. Thus, tetrabromo Tic derivative 57a was treated
with phenylboronic acid 58a in the presence of [Pd(PPh3)4]
Scheme 5. Synthesis of indan-based α-amino acid derivatives. Rea-
gents and conditions: (i) EICA, K2CO3, CH3CN, TBAHS, reflux;
(ii) ethanol, dil. HCl, room temp.; (iii) Ac2O, DMAP, CH2Cl2,
room temp.
We also extended our alkylation studies with ethyl aceto- under nitrogen (Scheme 7). Subsequently, various SM
acetate (EAA) as a new glycine equivalent towards the syn- cross-coupling products 59a–c were prepared by reaction of
thesis of unusual indan-based α-amino acid derivatives. To 57a with a range of boronic acids 58a–c under similar reac-
this end 29a was treated with EAA to deliver the alkylated tion conditions (Figure 2).
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Diversity Oriented Approach to Polycycles
Table 2. Halogenated indan-based α-amino acid and Tic derivatives.
Figure 2. Carbon-rich Tic derivatives prepared by SM cross-cou-
pling reaction starting from 57a.
Scheme 7. Preparation of tetrahalogenated Tic derivatives and ex-
tension to carbon-rich Tic derivatives through SM cross-coupling.
Reagents and conditions: (i) DEAM, K2CO3, CH3CN, reflux; (ii)
[Pd(PPh3)4], THF/toluene/H2O (1:1:1), Na2CO3, reflux, 24 h.
works described here and the simplicity of the procedure,
the present methodology is likely to find useful application
in the design of medicinally important compounds.[30]
Conclusions
Experimental Section
In this study, a diversity-oriented strategy has been dem- General: Melting points were recorded with a Labhosp or Veego
melting point apparatus. Boiling points refer to the bath tempera-
tures. Infrared (IR) spectra were recorded with an Nicolet Impact-
400 FT IR spectrometer in KBr/CHCl3/CCl4. 1H (300 and
400 MHz), 13C (75.4 and 100.6 MHz) NMR spectroscopic data
were determined at room temp. with AV 400 (Bruker), AMX-400
(Varian), or VXR-300S (Varian) spectrometers in CDCl3, [D6]-
DMSO or [D6]acetone solutions; coupling constants (J values) are
given in Hertz (Hz). High-resolution mass measurements were car-
ried out using a Micromass Q-Tof spectrometer. Elemental analysis
was performed with a Carlo–Erba MOD 1106 CHN analyzer. Ana-
onstrated to deliver a library of α-amino acid derivatives
and polycycles[29] using DA chemistry and SM cross-cou-
pling as key steps. This methodology allows access to a di-
verse range of small molecules, for example indans, tetra-
lins, naphthalene, polycyclic, and heterocyclic compounds
starting from o-xylene. The methodology related to α-
amino acid derivatives may easily be extendable to the syn-
thesis of carbon-rich Tic derivatives and also indan-based
α-amino acid derivatives using oxidative coupling as a key
step. In view of the importance of the molecular frame- lytical thin layer chromatography (TLC) was performed on (10ϫ
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5 cm) glass plates coated with Acme’s silica gel G or GF 254 (con-
taining 13% calcium sulfate as a binder). Silica gel was coated on
the glass plates using the “Sandwich Technique”. Chromatography
was performed with Acme’s silica gel (100–200 mesh) using double
spray bellows for application of pressure; the column was typically
eluted with ethyl acetate/petroleum ether mixtures. All microwave-
irradiated reactions[31] were performed with a Discover SP CEM
Microwave apparatus. The reactions were carried out in 10 mL
glass tubes, sealed with Teflon™ septum and placed in the micro-
wave cavity. The reaction mixture was irradiated at a required ceil-
ing temperature using maximum power for the stipulated time; the
reaction mixture temperatures were measured by an external IR
sensor.
(TLC monitoring), the solution was concentrated under reduced
pressure. The reaction mixture was cooled to room temp. and the
solvent was removed under reduced pressure to deliver the crude
material, which was purified by column chromatography. Unaro-
matized DA adduct compound (1 equiv.) and DDQ (2 equiv.) were
taken in a CEM Express reaction vial. Toluene (5 mL) was added
and the resulting solution was heated in a microwave oven at 110 °C
[method: ramp of 5 min to 110 °C (max. 200 W) then 20–25 min
at 110 °C (max. 200 W)]. At the conclusion of the reaction (TLC
analysis), the reaction mixture was allowed to cool to room tem-
perature and then concentrated under reduced pressure and crude
product obtained was purified by column chromatography to de-
liver the desired product.
General Procedure for the Synthesis of Sultine Derivatives: To a
Dimethyl
5,6,7,8-Tetrabromo-1,4-dihydronaphthalene-2,3-dicarb-
stirred suspension of the dibromide (1 equiv.) and TBAB (1 equiv.)
oxylate (36): Obtained according to the general procedure. To sult-
in DMF (10–20 mL), Rongalite (10–20 equiv.) was added at 0 °C ine 33 (100 mg, 0.20 mmol) in toluene (15 mL) was added DMAD
and the reaction mixture was stirred at 0 °C for 3 h and then at
room temp. for 3 h. At the conclusion of the reaction (TLC moni-
toring), reaction mixture was quenched with water (10 mL). The
aqueous layer was extracted EtOAc (25 mL) and the combined or-
ganic layers were washed with water (15 mL), brine (10 mL), and
dried with Na2SO4. The solvent was evaporated and the crude
product was purified by silica gel column chromatography.
35 (28.4 mg, 0.20 mmol) and the reaction mixture was heated to
reflux at 90 °C for 48 h to give a white solid (67 mg, 52%); Rf =
0.40 (silica gel; EtOAc/petroleum ether, 20%); m.p. 224–226 °C. 1H
NMR (400 MHz, CDCl3): δ = 3.81 (s, 4 H, CH2 ϫ2), 3.84 (s, 6 H,
CO2CH3 ϫ2) ppm. 13C NMR (74.5 MHz, CDCl3): δ = 35.9, 52.7,
127.1, 127.9, 131.7, 133.7, 167.2 ppm. IR (KBr): ν = 2987, 1734,
˜
1648, 1437, 1322, 1126 cm–1. HRMS (Q-Tof): calcd. for
C14H11Br4O4 [M + H] 558.7391; found 558.7386.
Tetrabromo Sultine Derivative 33: Obtained according to the gene-
ral procedure. To 29a (300 mg, 0.51 mmol) and TBAB (165 mg,
0.51 mmol) in DMF (12 mL) was added Rongalite (785 mg,
5.11 mmol) to give a white powder (240 mg, 96%); Rf = 0.40 (silica
gel; EtOAc/petroleum ether, 20%); m.p. 182–184 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 4.07 (1/2 ABq, J = 16.4 Hz, 1 H,
CHSO), 4.43 (1/2 ABq, J = 16.4 Hz, 1 H, CHSO), 5.00 (1/2 ABq,
Dimethyl 5,6,7,8-Tetrabromonaphthalene-2,3-dicarboxylate (37):
Obtained according to the general procedure; compound 36
(50 mg, 0.09 mmol) was mixed with DDQ (40 mg, 0.18 mmol) in
toluene (5 mL) and then irradiated in a microwave oven at 110 °C
for 20 min to give a white crystalline solid (35 mg, 65%); Rf = 0.40
(silica gel; EtOAc/petroleum ether, 20%); m.p. 244–246 °C. 1H
J = 15.2 Hz, 1 H, CHSO), 5.15 (1/2 ABq, J = 15.2 Hz, 1 H, NMR (400 MHz, CDCl3): δ = 4.0 (s, 6 H, CO2CH3 ϫ2), 8.72 (s,
CHSO) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 55.3, 62.7, 2 H, Ar-H ϫ2) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 53.1,
123.3, 128.5, 128.6, 128.8, 129.1, 134.4 ppm. IR (KBr): ν = 766, 126.8, 130.0, 131.6, 132.7, 166.9 ppm. IR (KBr): ν = 2927, 1736,
˜
˜
1001, 1351, 1594, 3523 cm–1. HRMS (Q-Tof): calcd. for 1635, 1422, 1376, 1135 cm–1. HRMS (Q-Tof): calcd. for
C8H4SBr4O2Na [M + Na] 502.6563; found 502.6548.
C14H9Br4O4 [M + H] 556.7234; found 556.7242.
Tetrachloro Sultine Derivative 44: Obtained according to the gene-
ral procedure. To 29b (1.0 g, 2.48 mmol) and TBAB (808 mg,
2.48 mmol) in DMF (25 mL) was added Rongalite (3.8 g,
24.86 mmol) to give a white solid (500 mg, 66%); Rf = 0.50 (silica
gel; EtOAc/petroleum ether, 20%); m.p. 152–154 °C. 1H NMR
Dimethyl
5,6,7,8-Tetrachloro-1,4-dihydronaphthalene-2,3-dicarb-
oxylate (46): Obtained according to the general procedure; a mix-
ture of tetrachloro sultine 44 (75 mg, 0.24 mmol) and DMAD 35
(34 mg, 0.24 mmol) in toluene (10 mL) was heated at 90 °C for 48 h
to give a white solid (45 mg, 50%); Rf = 0.41 (silica gel; EtOAc/
(400 MHz, CDCl3): δ = 3.84 (1/2 ABq, J = 16.4 Hz, 1 H, CHSO), petroleum ether, 10%); m.p. 178–180 °C. 1H NMR (400 MHz,
4.09 (1/2 ABq, J = 16.4 Hz, 1 H, CHSO), 5.17 (s, 2 H,
CDCl3): δ = 3.77 (s, 4 H, CH2 ϫ2), 3.86 (s, 6 H, CO2CH3
CH2SO) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 51.0, 57.8,
ϫ2) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 31.3, 52.7, 130.9,
124.3, 129.3, 130.4, 132.7, 133.5 ppm. IR (KBr): ν = 2987, 1387,
131.2, 131.5, 131.8, 167.3 ppm. IR (KBr): ν = 2987, 1735, 1677,
˜
˜
1340, 1178, 1123, 1009 cm–1. HRMS (Q-Tof): calcd. for 1339, 1265, 1166 cm–1. HRMS (Q-Tof): calcd. for C14H10Cl4O4Na
C8H5SCl4O2 [M + H] 304.8764; found 304.8776.
[M + Na] 404.9231; found 404.9231.
Tetrafluoro Sultine Derivative 45: Obtained according to the general
procedure. To 29c (170 mg, 0.50 mmol) and TBAB (163 mg,
Dimethyl 5,6,7,8-Tetrachloronaphthalene-2,3-dicarboxylate (47):
Obtained according to the general procedure; compound 46
0.50 mmol) in DMF (20 mL), was added Rongalite (770 mg, (45 mg, 0.12 mmol) was mixed with DDQ (53 mg, 0.23 mmol) in
5.0 mmol) to give a low-melting solid (100 mg, 55%); Rf = 0.32
(silica gel; EtOAc/petroleum ether, 20%). 1H NMR (400 MHz,
CDCl3): δ = 3.63 (1/2 ABq, J = 15.9 Hz, 1 H, CHSO), 4.07 (1/2
ABq, J = 16.1 Hz, 1 H, CHSO), 5.10, 5.19 (ABq, J = 14.6 Hz, 2
toluene (5 mL) and then irradiated in a microwave oven at 110 °C
for 20 min to give a white crystalline solid (30 mg, 67%); Rf = 0.37
(silica gel; EtOAc/petroleum ether, 20%); m.p. 174–176 °C. 1H
NMR (400 MHz, CDCl3): δ = 4.0 (s, 6 H, CO2CH3 ϫ2), 8.68 (s,
H, CH2SO) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 46.2, 54.0, 2 H, Ar-H ϫ2) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 53.2,
138.7, 138.9, 139.1, 139.2, 141.3, 141.6, 142.3, 142.4, 144.8, 127.6, 130.4, 131.1, 131.3, 133.0, 167.1 ppm. IR (KBr): ν = 2986,
˜
147.3 ppm. IR (thin film): ν = 2927, 1363, 1305, 1167, 1123, 1734, 1638, 1421, 1134 cm–1. HRMS (Q-Tof): calcd. for
˜
920 cm–1. HRMS (Q-Tof): calcd. for C8H5SF4O2 [M
240.9946; found 240.9958.
+
H] C14H8Cl4O4Na [M + Na] 402.9074; found 402.9057.
Dimethyl 5,6,7,8-Tetrafluoro-1,4-dihydronaphthalene-2,3-dicarb-
General Procedure for the Synthesis of DA Product with DMAD oxylate (48): Obtained according to the general procedure. To tetra-
and Aromatization: A solution of sultine (1 equiv.) and DMAD 35
(1 equiv.) in anhydrous toluene (15 mL) was heated at 90 °C (oil
bath temperature) under nitrogen. After completion of the reaction
fluoro sultine 45 (50 mg, 0.20 mmol) in toluene (5 mL) was added
DMAD 35 (30 mg, 0.20 mmol) and the reaction mixture was
heated to reflux at 90 °C for 24 h to give a white solid (45 mg,
6
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Job/Unit: O20484
/KAP1
Date: 11-06-12 16:00:05
Pages: 12
Diversity Oriented Approach to Polycycles
66%); Rf = 0.51 (silica gel; EtOAc/petroleum ether, 10%); m.p.
(10 mL) was heated to give the crude product, which was purified
90 °C. 1H NMR (400 MHz, CDCl3): δ = 3.68 (s, 4 H, CH2 ϫ2), by silica gel column chromatography (EtOAc/petroleum ether,
3.85 (s, 6 H, CO2CH3 ϫ2) ppm. 13C NMR (100.6 MHz, CDCl3):
40%) to afford 50 as a white solid (35 mg, 50%); Rf = 0.20 (silica
gel; EtOAc/petroleum ether, 40%); m.p. 259 °C. 1H NMR
(400 MHz, CDCl3): δ = 1.98 (s, 3 H, NHCOCH3), 2.08–2.11 (m, 1
H, CH), 2.55–2.59 (m, 1 H, CH), 2.76–2.77 (m, 1 H, CH), 2.91–
2.93 (m, 1 H, CH), 3.30 (1/2 ABq, J = 17.7 Hz, 1 H, CH), 3.18 (1/
2 ABq, J = 18.0 Hz, 1 H, CH), 3.78 (s, 3 H, CO2CH3), 5.59 (s, 1
H, NHCOCH3) ppm. 13C NMR (100.6 MHz, DMSO): δ = 22.2,
25.0, 27.1, 35.89, 52.2, 56.0, 128.9, 131.2, 131.8, 134.4, 135.3, 169.9,
δ = 24.5, 52.7, 130.7, 131.1, 132.0, 167.4 ppm. IR (KBr): ν = 2925,
˜
1736, 1668, 1490, 1266, 1120 cm–1. HRMS (Q-Tof): calcd. for
C14H10F4O4Na [M + Na] 341.0413; found 341.0418.
Dimethyl 5,6,7,8-Tetrafluoronaphthalene-2,3-dicarboxylate (49):[32]
Obtained according to the general procedure; compound 48
(30 mg, 0.09 mmol) was mixed with DDQ (42 mg, 0.18 mmol) in
toluene (5 mL) then irradiated in a microwave oven at 110 °C for
25 min to obtain a white crystalline solid (20 mg, 66%); Rf = 0.51
(silica gel; EtOAc/petroleum ether, 10%); m.p. 142 °C. 1H NMR
(400 MHz, CDCl3): δ = 4.32 (s, 6 H, CO2CH3 ϫ2), 8.68 (s, 2 H,
Ar-H ϫ2) ppm.
173.2 ppm. IR (KBr): ν = 1429, 1530, 1644, 1720, 3235, 3626 cm–1.
˜
HRMS (Q-Tof): m/z calcd: 383.9728 for C14H14NCl4O3 [M + H],
found 383.9719.
Methyl 2-Acetamido-5,6,7, 8-tetrafluoro-1,2,3,4-tetrahydronaphth-
alene-2-carboxylate (51): Obtained according to the general pro-
cedure. To tetrafluoro sultine 45 (40 mg, 0.16 mmol) in anhydrous
toluene (10 mL) was added methyl 2-acetamidoacrylate 40 (46 mg,
0.33 mmol) to give crude product, which was purified by silica gel
column chromatography (50% EtOAc/petroleum ether) to afford
51 as a white amorphous solid (33 mg, 63%); Rf = 0.32 (silica gel;
EtOAc/petroleum ether, 40%); m.p. 128 °C. 1H NMR (400 MHz,
CDCl3): δ = 1.98 (s, 3 H, NHCOCH3), 2.05–2.11 (m, 1 H, CH),
2.50–2.53 (m, 1 H, CH), 2.69–2.71 (m, 1 H, CH), 2.81–2.84 (m, 1
H, CH), 3.08 (1/2 ABq, J = 17.4 Hz, 1 H, CH), 3.24 (1/2 ABq, J
= 17.4 Hz, 1 H, CH), 3.76 (s, 3 H, CO2CH3), 5.68 (s, 1 H,
NHCOCH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 18.3, 23.1,
27.2, 30.0, 52.9, 56.5, 117.0, 118.9, 137.2, 140.6, 146.9, 170.4,
7,8,9,10-Tetrabromotetracene-5,12-dione (39): To a solution of sult-
ine 33 (50 mg, 0.10 mmol) in anhydrous toluene (5 mL) was added
naphthalene-1,4-dione 38 (24 mg, 0.15 mmol) and the reaction mix-
ture was heated to reflux. After completion of the reaction (TLC
monitoring), the solution was concentrated under reduced pressure
and the crude product was purified by washing with EtOAc. Un-
aromatized DA adduct (40 mg, 0.07 mmol) and DDQ (32 mg,
0.14 mmol) was taken in toluene (5 mL) and the resulting solution
was irradiated in a microwave oven at 110 °C for 20 min. The dark-
brown reaction mixture was then concentrated under reduced pres-
sure and the crude product obtained was purified by recrystalli-
zation (EtOAc/petroleum ether, 50%). Yield: 20 mg (50%); pale-
yellow solid; Rf = 0.40 (silica gel; EtOAc/petroleum ether, 20%);
1
173.1 ppm. IR (thin film): ν = 739, 1068, 1517, 1654, 1742,
˜
m.p. Ͼ 285 °C. H NMR (400 MHz, CDCl3): δ = 7.88–7.90 (m, 2
3648 cm–1. HRMS (Q-Tof): calcd. for C14H14F4O3N [M + H]
320.0910; found 320.0913.
H, Ar-H ϫ2), 8.41–8.43 (m, 2 H, Ar-H ϫ2), 9.31 (s, 2 H, Ar-H
ϫ2) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 127.3, 127.9, 131.4,
132.3, 134.3, 134.9, 182.1 ppm. IR (KBr): ν = 739, 1265, 1682,
˜
General Procedure for the Synthesis of the DA Adduct with Tetra-
cyanoethylene: To a solution of sultine (1 equiv.) in anhydrous tolu-
ene (10–15 mL) was added tetracyanoethylene 42 (1.5 equiv.) and
the reaction mixture was heated at 110 °C (oil bath temperature).
The reaction mixture was cooled to room temp. and the solvent
was removed under reduced pressure to deliver the crude material,
which was purified by column chromatography or recrystallization
to obtain the desired compound.
2853, 2925, 3054 cm–1. C18H6Br4O2 (569.71): calcd. C 37.67, H
1.05; found C 37.52, H 1.02.
General Procedure for the Synthesis of DA Adduct with Methyl 2-
Acetamidoacrylate: To a solution of the sultine (1 equiv.) in anhy-
drous toluene (10 mL) was added methyl 2-acetamidoacrylate 40
(2 equiv.) and the reaction mixture was heated at 110 °C (oil bath
temperature). The reaction mixture was then cooled to room temp.
and the solvent was removed under reduced pressure to deliver the
crude material, which was purified by column chromatography/
recrystallization to obtain the desired compound.
5,6,7,8-Tetrabromonaphthalenetetracarbonitrile (43): Obtained ac-
cording to the general procedure. To tetrabromo sultine 33 (100 mg,
0.20 mmol) in anhydrous toluene (15 mL) was added tetracyano-
ethylene 42 (38 mg, 0.30 mmol) to give the crude product, which
was purified by washing with EtOAc and recrystallization from
acetone to give the desired product 43 as a white solid (30 mg,
42%); Rf = 0.38 (silica gel; EtOAc/petroleum ether, 10%); m.p.
Ͼ 275 °C. 1H NMR (400 MHz, [D6]acetone): δ = 4.32 (s, 4 H, CH2
ϫ2) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 36.5, 110.9,
Methyl 2-Acetamido-5,6,7,8-tetrabromo-1,2,3,4-tetrahydronaphth-
alene-2-carboxylate (41): Obtained according to the general pro-
cedure; tetrabromo sultine 33 (50 mg, 0.10 mmol) and methyl 2-
acetamidoacrylate 40 (29 mg, 0.21 mmol) in anhydrous toluene
(10 mL) was heated to give the crude product, which was purified
by washing with acetone and recrystallization (EtOAc/petroleum
ether, 50%) to give the desired product 41 as a white solid (30 mg,
51%); Rf = 0.22 (silica gel; EtOAc/petroleum ether, 20%); m.p.
282 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 1.78 (s, 3 H,
–NHCOCH3), 1.91–1.95 (m, 1 H, CH), 2.25–2.29 (m, 1 H, CH),
2.50–2.76 (m, 2 H, CH ϫ2), 3.06 (1/2 ABq, J = 16.4 Hz, 1 H, CH),
3.18 (1/2 ABq, J = 16.4 Hz, 1 H, CH), 3.61 (s, 3 H, CO2CH3), 8.30
(s, 1 H, NHCOCH3) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ =
22.2, 27.8, 52.2, 56.7, 79.1, 125.9, 127.2, 127.8, 136.9, 138.0, 169.9,
127.2, 129.3, 129.6 ppm. IR (KBr): ν = 990, 1109, 1397, 1595, 2257,
˜
2932 cm–1. C14H4Br4N4 (543.71): calcd. C 30.69, H 0.74, N 10.23;
found C 30.56, H 0.69, N 10.18.
5,6,7,8-Tetrachloronaphthalenetetracarbonitrile (52): Obtained ac-
cording to the general procedure; tetrachlorosultine 44 (50 mg,
0.16 mmol) and tetracyanoethylene 42 (31 mg, 0.24 mmol) in anhy-
drous toluene (10 mL) were heated to give the crude product, which
was purified by recrystallization (EtOAc/petroleum ether, 30%) to
give the desired product 52 as needle-shaped crystals (32 mg, 53%);
Rf = 0.56 (silica gel; EtOAc/petroleum ether, 40%); m.p. 258 °C.
1H NMR (400 MHz, CDCl3): δ = 3.88 (s, 4 H, CH2 ϫ2) ppm. 13C
173.1 ppm. IR (KBr): ν = 1060, 1349, 1594, 1724, 3360, 3494 cm–1.
˜
HRMS (Q-Tof): calcd. for C14H14NBr4O3 [M + H] 559.7707; found
559.7690.
Methyl 2-Acetamido-5,6,7,8-tetrachloro-1,2,3,4-tetrahydronaphth- NMR (100.6 MHz, [D6]acetone): δ = 34.2, 39.8, 111.5, 127.7, 133.2,
alene-2 carboxylate (50): Obtained according to the general pro-
cedure; tetrachloro sultine 44 (50 mg, 0.16 mmol) and methyl 2-
acetamidoacrylate 40 (46 mg, 0.32 mmol) in anhydrous toluene
133.9 ppm. IR (KBr): ν = 739, 1265, 2306, 3564 cm–1. C H Cl N
˜
14 4 4 4
(367.91): calcd. C 45.44, H 1.09, N 15.14; found C 45.25, H 1.07,
N 15.08..
Eur. J. Org. Chem. 0000, 0–0
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7

Job/Unit: O20484
/KAP1
Date: 11-06-12 16:00:05
Pages: 12
S. Kotha, S. Misra, V. Srinivas
FULL PAPER
5,6,7,8-Tetrafluoronaphthalenetetracarbonitrile (53): Obtained ac-
cording to the general procedure. To tetrafluoro sultine 45 (50 mg,
0.20 mmol) in anhydrous toluene was added tetracyanoethylene 42
(38 mg, 0.30 mmol) to give the crude product, which was purified
by silica gel column chromatography (EtOAc/petroleum ether,
40%) to give 53 as a white crystalline solid (30 mg, 48%); Rf = 0.38
(silica gel; EtOAc/petroleum ether, 40%); m.p. Ͼ 270 °C. 1H NMR
nitrile (15 mL) was added 29b (100 mg, 0.25 mmol) to give a white
solid (30 mg, 34%); Rf = 0.27 (silica gel; EtOAc/petroleum ether,
10%); m.p. 136 °C. H NMR (400 MHz, CDCl3): δ = 1.38 (t, J =
7.1 Hz, 3 H, OCH2CH3), 3.64 (1/2 ABq, J = 17.0 Hz, 2 H, CH2),
3.79 (1/2 ABq, J = 17.0 Hz, 2 H, CH2), 4.36 (q, J = 7.1 Hz, 2 H,
OCH2CH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 14.1, 47.3,
1
63.9, 65.0, 128.9, 132.4, 137.1, 160.7, 167.5 ppm. IR (KBr): ν =
˜
(400 MHz, [D6]acetone): δ = 3.48 (1/2 ABq, J = 15.0 Hz, 1 H, CH), 911, 1265, 1748, 2354, 2986, 3045, 3155 cm–1. C13H9Cl4NO2
3.74 (t, J = 14.9 Hz, 2 H, CH ϫ2), 4.10 (1/2 ABq, J = 15.0 Hz, 1 (350.93): calcd. C 44.23, H 2.57, N 3.97; found C 44.40, H 2.53, N
H, CH) ppm. 13C NMR (100.6 MHz, [D6]acetone): δ = 49.7, 52.1,
3.95.
118.0, 139.2, 143.9, 147.2 ppm. IR (KBr): ν = 748, 1266, 1658,
˜
Ethyl
2-Acetamido-4,5,6,7-tetrabromo-2,3-dihydroindene-2-carb-
1965, 2853, 2924 cm–1. C14H4F4N4 (304.03): calcd. C 55.28, H 1.33,
N 18.42; found C 55.08, H 1.30, N 18.35.
oxylate (55a): Obtained according to the general procedure; the
title compound was obtained in 42% yield (46 mg) as a white
amorphous solid; Rf = 0.42 (silica gel; EtOAc/petroleum ether,
General Procedure for the Dialkylation of Ethyl Isocyanoacetate: To
a stirred suspension of potassium carbonate (5 equiv.), TBAHS
(1 equiv.), and EICA (1 equiv.) in anhydrous acetonitrile (15 mL)
was added dibromide (1 equiv.) after 15 min. The resulting hetero-
geneous reaction mixture was stirred at 75 °C for 12 h under nitro-
gen. At the conclusion of the reaction (TLC monitoring), the reac-
tion mixture was cooled and filtered with the aid of a Celite pad.
The filtrate was evaporated under reduced pressure and the residue
was directly used further without purification. However, in some
of the cases, the isocyanide derivative was purified and then charac-
terized on the basis of its spectroscopic data.
1
50%); m.p. 259 °C (dec.). H NMR (400 MHz, CDCl3): δ = 1.26
(t, J = 7.3 Hz, 3 H, OCH2CH3), 2.01 (s, 3 H, NHCOCH3), 3.51
(1/2 ABq, J = 17.5 Hz, 2 H, CH2), 3.65 (1/2 ABq, J = 15.8 Hz,
2 H, CH2), 4.27 (q, J = 7.1 Hz, 2 H, OCH2CH3), 6.23 (s, 1 H,
NHCOCH3) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 22.2,
29.5, 47.5, 52.2, 56.6, 125.9, 127.2, 127.6, 128.3, 136.8, 137.9, 169.8,
173.1 ppm. IR (KBr): ν = 739, 1265, 1648, 1732, 1956, 2987, 3054,
˜
3425 cm–1. HRMS (Q-Tof): calcd. for C14H14NO3Br4 [M + H]
559.7707; found 559.7695.
Ethyl
2-Acetamido-4,5,6,7-tetrachloro-2,3-dihydroindene-2-carb-
General Procedure for Hydrolysis of the Coupling Product: To a
solution of the isocyanide derivative in absolute ethanol (10 mL)
was added dil. aqueous HCl (1–1.5 mL) dropwise and the reaction
mixture was stirred at room temp. for 6–7 h. Ethanol was evapo-
rated under reduced pressure and the resulting residue was dis-
solved in water (20 mL). The aqueous layer was basified to pH 9–
10 by addition of NH3 solution and then extracted with EtOAc
(3ϫ 15 mL). The combined EtOAc extract was washed with water
and brine and dried with anhydrous Na2SO4. Removal of the sol-
vent under reduced pressure gave the required amino ester.
oxylate (55b): Obtained according to the general procedure; the
title compound was obtained in 36% yield (20 mg) as a yellow so-
lid; Rf = 0.50 (silica gel; EtOAc/petroleum ether, 50%); m.p. 213 °C.
1H NMR (400 MHz, CDCl3): δ = 1.28 (t, J = 7.3 Hz, 3 H,
OCH2CH3), 1.94 (s, 3 H, NHCOCH3), 3.51 (1/2 ABq, J = 17.0 Hz,
2 H, CH2), 3.63 (1/2 ABq, J = 17.4 Hz, 2 H, CH2), 4.27 (q, J =
7.1 Hz, 2 H, OCH2CH3), 6.23 (s, 1 H, NHCOCH3) ppm. 13C NMR
(100.6 MHz, [D6]acetone): δ = 13.8, 22.5, 44.2, 61.8, 63.8, 128.2,
130.7, 139.4, 170.3, 172.0 ppm. IR (KBr): ν = 739, 1370, 1648,
˜
2986, 3055, 3432 cm–1. HRMS (Q-Tof): calcd. for C14H14NO3Cl4
[M + H] 383.9728; found 383.9738.
General Procedure for Acetylation of the Amino Ester: The amino
ester obtained in the previous experiment was dissolved in anhy-
drous CH2Cl2 (20 mL) together with 4-dimethylaminopyridine
(1 equiv.), and freshly distilled acetic anhydride (0.5 mL) was
added. The reaction mixture was stirred at room temp. for 10–12 h
and then quenched with water (25 mL). The aqueous layer was
extracted with ethyl acetate (3ϫ 15 mL) and the combined EtOAc
extract was washed with water and brine and dried with anhydrous
Na2SO4. The solvent was evaporated and the crude product was
purified by silica gel column chromatography.
Ethyl
2-Acetamido-4,5,6,7-tetrafluoro-2,3-dihydroindene-2-carb-
oxylate (55c): Obtained according to the general procedure; the
title compound was obtained in 32% yield (22 mg) as a white solid;
Rf = 0.21 (silica gel; EtOAc/petroleum ether, 30%); m.p. 142 °C.
1H NMR (400 MHz, CDCl3): δ = 1.24 (t, J = 7.3 Hz, 3 H,
OCH2CH3), 2.01 (s, 3 H, NHCOCH3), 3.46 (ABq, J = 16.6,
16.6 Hz, 4 H, CH2 ϫ2), 4.23 (q, J = 7.1 Hz, 2 H, OCH2CH3), 6.31
(s, 1 H, NHCOCH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
14.1, 23.4, 40.1, 62.6, 65.5, 138.8, 141.3, 143.1, 146.1, 170.2,
172.4 ppm. IR (KBr): ν = 741, 1265, 1684, 1740, 2986, 3054,
˜
Ethyl 4,5,6,7-Tetrabromo-2-isocyano-2,3-dihydroindene-2-carboxyl-
ate (54a): Obtained according to the general procedure. To a stirred
suspension of potassium carbonate (47.6 mg, 0.34 mmol), TBAHS
(23.4 mg, 0.06 mmol), and EICA (7.8 mg, 0.06 mmol) in anhydrous
acetonitrile (15 mL) was added 29a (40 mg, 0.06 mmol) after
15 min to obtain a white solid (38 mg, 38%); Rf = 0.32 (silica gel;
EtOAc/petroleum ether, 10%); m.p. 168–170 °C. 1H NMR
(400 MHz, CDCl3): δ = 1.37 (t, J = 7.1 Hz, 3 H, OCH2CH3), 3.64
(1/2 ABq, J = 17.0 Hz, 2 H, CH2), 3.79 (1/2 ABq, J = 17.0 Hz, 2
H, CH2), 4.35 (q, J = 7.1 Hz, 2 H, OCH2CH3) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 14.1, 50.4, 63.9, 65.5, 122.0, 128.1, 140.1,
3435 cm–1. HRMS (Q-Tof): calcd. for C14H14NO3F4 [M + H]
320.0910; found 320.0894.
Ethyl 2-Acetyl-4,5,6,7-tetrabromoindene-2-carboxylate (56): A solu-
tion of TBAHS (199 mg, 0.58 mmol) in water (1 mL) was neutral-
ized with 4 m aqueous NaOH followed by addition of EAA
(38.1 mg, 0.29 mmol, 0.03 mL), aromatic dibromide 29a (170 mg,
0.29 mmol), and CH2Cl2 (15 mL). To the stirred reaction mixture,
4 m aq NaOH (0.5 mL) was added and the resulting mixture was
heated to reflux at 55 °C for 14 h. At the conclusion of the reaction
(TLC monitoring), the reaction mixture was cooled and diluted
with water (15 mL). The aqueous layer was acidified with 0.1 n
H2SO4 to pH 2–3 and then extracted with diethyl ether (3ϫ
15 mL). The combined ether layer was washed with water, brine,
and dried with anhydrous Na2SO4. Removal of the solvent gave
the crude product, which was purified by silica gel column
chromatography (EtOAc/petroleum ether, 2%) to give 56 as a white
solid (75 mg, 46%). Rf = 0.64 (silica gel; EtOAc/petroleum ether,
160.5, 167.5 ppm. IR (KBr): ν = 896, 1265, 1705, 2305, 2986,
˜
3054 cm–1. C13H9Br4NO2 (526.73): calcd. C 29.61, H 1.71, N 2.64;
found C 29.72, H 1.69, N 2.62.
Ethyl 4,5,6,7-Tetrachloro-2-isocyano-2,3-dihydroindene-2-carboxyl-
ate (54b): Obtained according to the general procedure. To a stirred
solution of EICA (28 mg, 0.25 mmol), TBAHS (85 mg, 0.25 mmol)
and potassium carbonate (172 mg, 1.23 mmol) in anhydrous aceto-
8
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Job/Unit: O20484
/KAP1
Date: 11-06-12 16:00:05
Pages: 12
Diversity Oriented Approach to Polycycles
1
10%); m.p. 142 °C. H NMR (400 MHz, CDCl3): δ = 1.31 (t, J =
thick liquid (30 mg, 54%); Rf = 0.25 (silica gel; EtOAc/petroleum
7.1 Hz, 3 H, OCH2CH3), 2.04 (s, 3 H, COCH3), 3.61 (s, 4 H, CH2 ether, 30%). 1H NMR (400 MHz, CDCl3): δ = 1.23 (t, J = 7.13 Hz,
ϫ2), 4.21 (q, J = 7.1 Hz, 2 H, OCH2CH3) ppm. 13C NMR 6 H, OCH2CH3 ϫ2), 2.30 (s, 3 H, COCH3), 3.47 (s, 2 H, CH2),
(100.6 MHz, CDCl3): δ = 14.1, 26.0, 43.3, 62.6, 64.4, 121.8, 127.0, 4.19–4.22 (m, 4 H, OCH2CH3 ϫ2), 4.68 (s, 2 H, CH2) ppm. 13C
142.0, 171.5, 200.9 ppm. IR (KBr): ν = 763, 1252, 1606, 1712, 2849,
NMR (100.6 MHz, CDCl3): δ = 14.0, 22.2, 28.4, 62.6, 64.1, 66.5,
˜
2918 cm–1. HRMS (Q-Tof): calcd. for C14H13NO3Br4Na [M + Na]
581.7526; found 581.7500.
140.1, 143.0, 143.1, 144.6, 167.0, 171.3 ppm. IR (thin film): ν =
˜
1199, 1265, 1681, 1750, 2858, 2987, 3054 cm–1. HRMS (Q-Tof):
calcd. for C17H18F4NO5 [M + H] 392.1121; found 392.1123.
Ethyl 2-Acetamido-4,5,6,7-tetrabromoindene-2 carboxylate (55a):
To a stirred solution of β-keto ester 56 (25 mg, 0.04 mmol) in
CHCl3 (10 mL) was added methanesulfonic acid (MSA) (0.04 mL)
while maintaining the temperature of the reaction mixture at 0 °C,
followed by addition of freshly activated sodium azide (14 mg,
0.22 mmol) under vigorous stirring. The resulting reaction mixture
was heated to reflux for 48 h. At the conclusion of the reaction
(TLC monitoring), the reaction mixture was cooled, poured into
cold water (20 mL) and the aqueous layer was acidified with 0.1 m
H2SO4 to pH 2–3. The aqueous layer was extracted with diethyl
ether (3ϫ 15 mL) and the combined ether layer was washed with
water, brine and dried with anhydrous Na2SO4. The crude product
was purified by column chromatography (silica gel; EtOAc/petro-
leum ether, 30%) to afford 55a as a white solid (12 mg, 47%).
General Procedure for SM Cross-Coupling Reaction in the Presence
of [Pd(PPh3)4]: A mixture of tetrabromo Tic derivative 57a
(1 equiv.), appropriate boronic acid (4.5 equiv.), [Pd(PPh3)4] (5–
10 mol-%), and Na2CO3 (5 equiv.) in water/THF/toluene (1:1:1)
was heated at 80 °C. The reaction mixture was degassed with nitro-
gen for 20 min prior to the addition of the catalyst. At the conclu-
sion of the reaction (TLC monitoring), the reaction mixture was
diluted with water, extracted with EtOAc, and the combined or-
ganic layer was washed with water, brine, and dried with Na2SO4.
The solvent was evaporated and the crude product was loaded onto
a silica gel column. Elution of the column with EtOAc/petroleum
ether gave the desired cross-coupling product.
Diethyl 2-Acetyl-5,6,7,8-tetraphenyl-1,2-dihydroisoquinoline-3,3-di-
carboxylate (59a): Obtained according to the general procedure;
phenylboronic acid 58a (60 mg, 0.49 mmol) and aqueous Na2CO3
(58 mg, 0.55 mmol) were added to a solution of 57a (70 mg,
0.11 mmol) in THF/toluene/water (1:1:1, 9 mL), and the resulting
reaction mixture was degassed for 15 min. [Pd(PPh3)4] (6.3 mg,
5 mol-%) was then added to obtain a white solid (30 mg, 51%); Rf
= 0.50 (silica gel; EtOAc/petroleum ether, 50%); m.p. 204 °C. 1H
NMR (400 MHz, CDCl3): δ = 1.26 (t, J = 6.93 Hz, 6 H, OCH2CH3
ϫ2), 1.96 (s, 3 H, COCH3), 3.35 (s, 2 H, CH2), 4.02–4.07 (m, 2 H,
OCH2CH3), 4.22–4.26 (m, 2 H, OCH2CH3), 4.49 (s, 2 H, CH2),
6.69–6.82 (m, 10 H, Ar-H ϫ10), 6.997.18 (m, 10 H, Ar-H
ϫ10) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 14.0, 22.1, 35.6,
46.0, 62.0, 68.0, 125.6, 125.7, 126.8, 126.9, 127.1, 127.7, 128.0,
130.2, 130.6, 131.2, 131.3, 131.6, 138.3, 138.7, 138.9, 139.8, 139.9,
General Procedure for the Synthesis of Tic Derivatives: To a stirred
suspension of potassium carbonate (6 equiv.) and DEAM (1 equiv.)
in anhydrous acetonitrile (15 mL) was added aromatic dibromide
(1 equiv.) after 15 min. The resulting heterogeneous reaction mix-
ture was stirred at 75 °C for 24 h under nitrogen. At the conclusion
of the reaction (TLC monitoring), the reaction mixture was cooled
and filtered with the aid of a Celite pad. The filtrate was evaporated
under reduced pressure.
Diethyl 2-Acetyl-5,6,7,8-tetrabromo-1,2-dihydroisoquinoline-3,3-di-
carboxylate (57a): Obtained according to the general procedure. To
a stirred suspension of potassium carbonate (595 mg, 4.31 mmol)
and DEAM (187 mg, 0.86 mmol) in anhydrous acetonitrile (10 mL)
was added dibromo compound 29a (500 mg, 0.86 mmol) to give a
white solid (320 mg, 58%); Rf = 0.32 (silica gel; EtOAc/petroleum
ether, 50%); m.p. 168 °C. 1H NMR (400 MHz, CDCl3): δ = 1.24
(t, J = 7.13 Hz, 6 H, OCH2CH3 ϫ2), 2.31 (s, 3 H, COCH3), 3.66
(s, 2 H, CH2), 4.19–4.24 (m, 4 H, OCH2CH3 ϫ2), 4.73 (s, 2 H,
CH2) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 14.0, 22.5, 39.0,
50.0, 62.6, 67.4, 124.4, 126.8, 128.4, 128.8, 134.2, 134.7, 167.2,
140.0, 140.1, 140.7, 168.2, 170.6 ppm. IR (KBr): ν = 1019, 1266,
˜
1659, 1730, 2930, 3543 cm–1. HRMS (Q-Tof): calcd. for
C41H38NO5 [M + H] 624.2750; found 624.2776.
Diethyl 2-Acetyl-5,6,7,8-tetrakis(4-methoxyphenyl)-1,2-dihydroiso-
quinoline-3,3-dicarboxylate (59b): Obtained according to the gene-
ral procedure; 4-methoxyphenylboronic acid 58b (107 mg,
0.70 mmol) and aqueous Na2CO3 (83 mg, 0.78 mmol) were added
to a solution of 57a (100 mg, 0.157 mmol) in THF/toluene/water
(1:1:1, 12 mL), and the resulting reaction mixture was degassed for
15 min. [Pd(PPh3)4] (9 mg, 5 mol-%) was then added to obtain a
white solid (43 mg, 42%); Rf = 0.21 (silica gel; EtOAc/petroleum
171.1 ppm. IR (KBr): ν = 1062, 1265, 1671, 1744, 2853, 2986,
˜
3054 cm–1. HRMS (Q-Tof): calcd. for C17H18NO5Br4 [M + H]
631.7918; found 632.7946.
Diethyl 2-Acetyl-5,6,7,8-tetrachloro-1,2-dihydroisoquinoline-3,3-di-
carboxylate (57b): Obtained according to the general procedure. To
a stirred suspension of potassium carbonate (255 mg, 1.85 mmol)
and DEAM (80 mg, 0.37 mmol) in anhydrous acetonitrile (10 mL)
was added dibromo compound 29b (150 mg, 0.37 mmol) to give a
white solid (55 mg, 47%); Rf = 0.42 (silica gel; EtOAc/petroleum
ether, 30%); m.p. 153 °C. 1H NMR (400 MHz, CDCl3): δ = 1.22
(t, J = 7.13 Hz, 6 H, OCH2CH3 ϫ2), 2.30 (s, 3 H, COCH3), 3.61
(s, 2 H, CH2), 4.17–4.19 (m, 4 H, OCH2CH3 ϫ2), 4.71 (s, 2 H,
CH2) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 14.0, 22.5, 34.9,
46.1, 62.6, 67.0, 129.7, 131.2, 131.6, 131.8, 132.1, 132.5, 167.2,
1
ether, 50%); m.p. 96 °C. H NMR (400 MHz, CDCl3): δ = 1.71 (t,
J = 7.13 Hz, 6 H, OCH2CH3 ϫ2), 1.99 (s, 3 H, COCH3), 3.33 (s,
2 H, CH2), 3.61 (s, 6 H, OCH3 ϫ2), 3.77 (s, 6 H, OCH3 ϫ2), 4.02–
4.11 (m, 2 H, OCH2CH3), 4.21–4.25 (m, 2 H, OCH2CH3), 4.48 (s,
2 H, CH2), 6.38–6.41 (m, 4 H, Ar-H ϫ4), 6.55–6.60 (m, 4 H, Ar-
H ϫ4), 6.70–6.74 (m, 4 H, Ar-H ϫ4), 6.85 (d, J = 8.72 Hz, 2 H,
Ar-H ϫ2), 6.93 (d, J = 8.71 Hz, 2 H, Ar-H ϫ2) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 14.0, 22.2, 35.7, 46.0, 55.0, 55.2, 61.9,
68.0, 112.4, 113.2, 113.4, 130.7, 131.3, 131.6, 131.7, 132.2, 132.3,
132.6, 132.7, 138.1, 139.7, 140.3, 140.8, 157.1, 158.1, 158.3, 168.3,
171.4 ppm. IR (KBr): ν = 1062, 1265, 1673, 1745, 2854, 2986,
˜
3054 cm–1. HRMS (Q-Tof): calcd. for C17H18Cl4NO5 [M + H]
455.9939; found 455.9941.
170.6 ppm. IR (KBr): ν = 1176, 1266, 1743, 2986, 3045 cm–1.
˜
HRMS (Q-Tof): calcd. for C45H46NO9 [M + H] 744.3173; found
744.3159.
Diethyl 2-Acetyl-5,6,7,8-tetrafluoro-1,2-dihydroisoquinoline-3,3-di-
carboxylate (57c): Obtained according to the general procedure. To
a stirred suspension of potassium carbonate (97 mg, 0.70 mmol)
and DEAM (30 mg, 0.14 mmol) in anhydrous acetonitrile (10 mL)
was added dibromo compound 29c (50 mg, 0.14 mmol) to give a
Diethyl 2-Acetyl-5,6,7,8-tetrakis(4-acetylphenyl)-1,2-dihydroisoquin-
oline-3,3-dicarboxylate (59c): Obtained according to the general
procedure; 4-acetylphenylboronic acid 58c (115 mg, 0.70 mmol)
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Pages: 12
S. Kotha, S. Misra, V. Srinivas
FULL PAPER
422; c) J. Zon, N. Amrhein, R. Gancarz, Phytochemistry 2002,
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and aqueous Na2CO3 (83 mg, 0.78 mmol) were added to a solution
of 57a (100 mg, 0.157 mmol) in THF/toluene/water (1:1:1, 9 mL),
and the resulting reaction mixture was degassed for 15 min.
[Pd(PPh3)4] (9 mg, 5 mol-%) was then added to obtain a white solid
(62 mg, 52%); Rf = 0.25 (silica gel; EtOAc/petroleum ether, 60%);
m.p. 214 °C. 1H NMR (400 MHz, CDCl3): δ = 1.25 (t, J = 7.13 Hz,
6 H, OCH2CH3 ϫ2), 1.94 (s, 3 H, COCH3), 2.56 (s, 6 H, COCH3
ϫ2), 2.57 (s, 6 H, COCH3 ϫ2), 3.29 (s, 2 H, CH2), 4.04–4.09 (m,
2 H, OCH2CH3), 4.10–4.27 (m, 2 H, OCH2CH3), 4.45 (s, 2 H,
CH2), 6.82 (t, J = 8.52 Hz, 4 H, Ar-H ϫ4), 7.09 (d, J = 8.32 Hz,
2 H, Ar-H ϫ2), 7.16 (d, J = 8.32 Hz, 2 H, Ar-H ϫ2), 7.44–7.47
(m, 4 H, Ar-H ϫ4), 7.78–7.85 (dd, J = 7.92, 8.32 Hz, 4 H, Ar-H
ϫ4) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 14.0, 22.2, 26.5,
26.7, 35.4, 45.8, 62.4, 67.6, 127.4, 128.1, 128.4, 130.3, 130.5, 131.1,
131.2, 131.5, 132.2, 134.9, 135.9, 136.1, 136.4, 137.6, 138.7, 139.2,
139.4, 142.9, 143.9, 144.0, 167.9, 170.4, 197.5, 197.7, 197.8 ppm.
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IR (KBr): ν = 1016, 1266, 1360, 1606, 1682, 1746, 2853, 2985 cm–1.
˜
[12]
[13]
HRMS (Q-Tof): calcd. for C49H46NO9 [M + H] 792.3173; found
792.3153.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra of the new com-
pounds.
Acknowledgments
[14]
We thank the Council of Scientific and Industrial Research, New
Delhi and the Department of Science and Technology, New Delhi
for financial support, and the Sophisticated Analytical Instrument
Facility, IIT-Bombay for recording spectroscopic data. S. K. thanks
the Department of Science and Technology for the award of a J. C.
Bose fellowship. S. M. thanks the Council of Scientific and Indus-
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Received: April 14, 2012
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Job/Unit: O20484
/KAP1
Date: 11-06-12 16:00:05
Pages: 12
S. Kotha, S. Misra, V. Srinivas
FULL PAPER
Polycycles and Amino Acids
Small “drug like” molecules are obtained
by using alkylation, Diels–Alder reaction,
and Suzuki–Miyaura cross-coupling as key
steps. This methodology allows a wide
range of molecules to be assembled using
simple scaffolds such as indanes, tetralins,
and tetrahydroisoquinolines, which can en-
hance the chemical space for potential
therapeutic molecules.
S. Kotha,* S. Misra, V. Srinivas ...... 1–12
Diversity Oriented Approach to Polycyclic
Compounds through the Diels–Alder Re-
action and the Suzuki Coupling
Keywords: Synthesis design / Medicinal
chemistry / Drug discovery / Template syn-
thesis / Cross-coupling
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