Modification of indane-based unusual α-amino acid derivatives via the Suzuki-Miyaura coupling reaction

Article abstract of DOI:10.1055/s-2002-20026

Various highly functionalized indane-based unusual α-amino acid derivatives have been prepared via the Suzuki-Miyaura coupling reaction as a key step.

Full text of DOI:10.1055/s-2002-20026

PAPER
339
Modification of Indane-Based Unusual -Amino Acid Derivatives via the
Suzuki–Miyaura Coupling Reaction
M
odification o
a
f
-Amino
m
Acid Derivatives
v
b
ia the Suzuk
a
C
s
oupling R
i
eactio
v
n
arao Kotha,* Somnath Halder, Kakali Lahiri (née Chakraborty)
Department of Chemistry, Indian Institute of Technology-Bombay, Mumbai, 400 076, India
Fax +91(22)5723480; E-mail: srk@chem.iitb.ac.in
Received 25 October 2001; revised 6 December 2001
I and CO2H; R1, R3, R4 = H) were also prepared in the lit-
erature and showed activity similar to that observed by
treating animals with psychotomimetics.5
Abstract: Various highly functionalized indane-based unusual
amino acid derivatives have been prepared via the Suzuki–Miyaura
coupling reaction as a key step.
-
In this regard, the development of new synthetic methods
for the synthesis of indane-based , -AAs with varied to-
pographical and electronic properties is desirable. To-
wards this goal, a general methodology based on building
block approach may be useful because it can deliver a se-
ries of indane-based , -AAs with varying shape, size and
redox properties within a very short period of time starting
with a common precursor. Herein, we describe our results
regarding the synthesis of various indane-based , -AA
derivatives using the Suzuki–Miyaura coupling reaction6
as a key step (Scheme 1).
Key Words: amino acids, boron, coupling, drugs, heterocycles
, -Dialkylated amino acids ( , -AAs) play an important
role in the design of conformationally restricted peptides.1
Cyclic -amino acids (AAAs) are considered a special
class of , -AAs. The conventional method for the prepa-
ration of cyclic AAA derivatives involving the Bucherer–
Berg (BB) method2 has many limitations. The required
keto precursors are difficult to prepare and the intermedi-
ate hydantoin requires drastic reaction conditions (excess
barium hydroxide at 140 °C or 60% sulfuric acid at
140 °C) for hydrolysis. Many sensitive functional groups
may not survive under these reaction conditions. Due to
non-availability of simple synthetic methods to deliver
complex cyclic AAAs, only simplest members of this
class have been used in the peptide arena. Among the con-
strained analogs of phenylalanine (Phe), indane-based
, -AAs were used extensively in the design and synthe-
sis of a variety of bioactive peptides. Some indane (Ind)
related , -AAs reported in the literature for various bio-
logical reasons are shown in Figure 1.3
Scheme 1
Towards this objective, we initially synthesized indane-
based , -AA derivative 4 from o-xylene in a six-step se-
quence (Scheme 2).7,8 Unfortunately, attempts to func-
tionalize 4 via the Suzuki–Miyaura coupling6 with various
aryl boronic acids using a Pd(0) catalyst such as [PPh3]4Pd
were unsuccessful.
Figure 1
In view of the inherent flexibility of the peptide backbone,
considerable attention was focused to provide the infor-
mation on biologically active conformations and to devel-
op more effective ligands. For example, when the C-
terminal Phe residue in chemotactic agent HCO-Met-Leu-
Phe-OH (FMLP) was replaced with Ind (1; R1, R2, R3,
R4 = H), the resulting modified analog has shown to be
highly active in the superoxide production.4 In this con-
nection 5-substituted Ind derivatives (e.g., 1; R2 = Cl, Br,
Scheme 2
Next, we focused our attention towards the preparation of
the diiodo compound 6. In this regard 4,5-diiodo-1,2-dim-
ethylbenzene (5) was prepared according to the literature
procedure.9 Benzylic bromination of 5 with NBS in pres-
ence of AIBN/CCl4 under reflux conditions gave com-
pound 6, which was alkylated with ethyl isocyanoacetate
under PTC conditions7 to afford the alkylated product 7.
Hydrolysis of 7 with concentrated HCl yielded the amino
ester 8 which, on protection with pivaloyl chloride in pres-
Synthesis 2002, No. 3, 18 02 2002. Article Identifier:
1437-210X,E;2002,0,03,0339,0342,ftx,en;E07401SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

340
S. Kotha et al.
PAPER
Ethyl 5,6-Diiodo-2-isocyanoindane-2-carboxylate (7)
To a solution of ethyl isocyanoacetate (134 mg, 1.18 mmol) in
CH3CN (50 mL) was added finely powdered K2CO3 (818 mg, 5.93
mmol), Bu4NHSO4 (TBAHS) as a PTC (101 mg, 0.3 mmol), and di-
bromide 6 (510 mg, 0.98 mmol). The resulting heterogeneous mix-
ture was heated at 80 °C for 3 h. The reaction mixture was cooled
and filtered through glass crucible to remove the unwanted salts.
Then, the solid material was washed with CH3CN (10 mL) and the
filtrate was evaporated on a rotary evaporator under reduced pres-
sure. The residue obtained was taken in Et2O (100 mL) and washed
with H2O (50 mL), brine (20 mL) and then dried over MgSO4. The
solvent was evaporated and the material obtained was purified using
silica gel column chromatography. Elution with a 2.5% EtOAc–pe-
troleum ether mixture gave 7 (235 mg, 50%) as a white solid.
Mp 80 °C.
IR (KBr): 2139, 1743 cm–1.
1H NMR (300 MHz, CDCl3): = 1.35 (t, J = 7.3 Hz, 3 H, ester
CH3), 3.38 (1/2ABq, J = 16.5 Hz, 2 H, Ha-1,3), 3.62 (1/2ABq,
J = 16.5 Hz, 2 H, Hb-1,3), 4.32 (q, J = 7.3 Hz, 2 H, ester OCH2),
7.78 (s, 2 H, Ar-H).
13C NMR (75 MHz, CDCl3): = 14.0 (ester CH3), 45.3 (C-1,3),
63.5 (ester OCH2), 67.9 (C-2), 106.6(C-5,6), 135.4 (C-4,7), 140.2
(C-8,9), 159.7 (NC), 167.8 (ester CO).
UV (CHCl3): max ( ) = 285 nm (1951).
Anal. Calcd for C13H11I2NO2: C, 33.40; H, 2.35; N, 2.99. Found: C,
33.42; H, 2.31; N, 3.09.
Scheme 3
ence of triethylamine, gave the desired indane-based , -
AA 9 in 29% overall yield (Scheme 3).
Hydrolysis of Ethyl 5,6-Diiodo-2-isocyanoindane-2-carboxylate
(7)
To a solution of coupling product 7 (222 mg, 0.475 mmol) in abso-
lute EtOH (15 mL) were added six drops of concd HCl at 0 °C and
stirred at r.t. for 30 minutes. EtOH was evaporated under reduced
pressure and the remaining hydrochloride salt was dissolved in H2O
(5 mL) and extracted with Et2O (3 10 mL) to remove unwanted
organic residues. Then the ether layers were discarded. The aqueous
layer was brought to pH 9–10 by addition of NH4OH solution and
was then extracted with EtOAc (3 30 mL). The combined EtOAc
was washed with H2O (50 mL), brine (20 mL) and then dried over
MgSO4. Evaporation of the solvent under reduced pressure fur-
nished the pure amino ester 8 (157 mg, 72%) as a sticky solid, which
was directly used in the next step.
Having prepared the diiodo compound 9 in good yield, we
then attempted the Suzuki–Miyaura coupling reaction
with several boronic acids using [PPh3]4Pd as catalyst. Al-
though there are several methods available for aryl-aryl
coupling reactions, the Suzuki–Miyaura coupling reaction
seems to tolerate various functional groups compared to
the other methods.10 Typically, 62–99% yield of the coup-
ling product 10 was obtained. All the coupling products
were characterized by appropriate spectral data. Our at-
tempts to prepare unsymmetrical indane-based -amino
acid derivatives of 9 in a step-wise fashion were unsuc-
cessful.6d
1H NMR (300 MHz, CDCl3): = 1.29 (t, J = 7.3 Hz, 3 H, ester
CH3), 1.68 (br s, 2 H, NH2), 2.79 (1/2ABq, J = 16.5 Hz, 2 H, Ha-
1,3), 3.45 (1/2ABq, J = 16.5 Hz, 2 H, Hb-1,3), 4.21 (q, J = 7.3 Hz,
2 H, ester OCH2), 7.74 (s, 2 H, Ar-H).
In conclusion, we have shown that the utility of our build-
ing block approach11 combined with the Suzuki–Miyaura
coupling reaction is a useful strategy to prepare highly
constrained analogs of Phe. Since , -AAs are used as
means of controlling the 2° structure in de novo design of
peptides, the unusual , -AA derivatives prepared here
may find useful applications in therapeutics and peptido-
mimetics.
Ethyl 2-Trimethylacetamido-5,6-diiodoindane-2-carboxylate
(9)
To a solution of amino ester 8 (156 mg, 0.34 mmol) and Et3N (62
mg, 0.68 mmol) in anhyd CH2Cl2 (12 mL) was added pivaloyl chlo-
ride (82 mg, 0.68 mmol). The mixture was stirred at r.t. for 1 h. The
solvent was evaporated and the residue extracted with EtOAc (60
mL), washed with H2O (25 mL), brine (20 mL) and dried over
MgSO4. Evaporation of the solvent and purification of the crude
product by silica gel column chromatography using a 7.5% EtOAc–
petroleum ether mixture as eluent gave 9 (163 mg, 88%) as a white
solid.
Catalyst [PPh3]4Pd was prepared according to the reported proce-
dure.12 Thien-2-yl-, phenyl-, 2-furyl- and 4-methylphenylboronic
acids were prepared according to literature procedures.13 Ethyl iso-
cyanoacetate, 4-methoxyphenylboronic and 4-acetylphenylboronic
acids were purchased from Aldrich and used as received. 1H NMR
and 13C NMR spectral data was recorded on Varian VXR 300 or 500
spectrometers using TMS as internal standard and CDCl3 as sol-
vent. The coupling constants (J) are given in Hertz (Hz). Mass spec-
tral measurements were carried out on a GCD1800 Hewlett-
Packard GC-MS spectrometer. UV spectral data were obtained on
Shimadzu UV-2100 or UV-260 instruments.
Mp 239–240 °C.
IR (KBr): 3368, 1720, 1644 cm–1.
1H NMR (300 MHz, CDCl3): = 1.17 (s, 9 H, CMe3), 1.22 (t,
J = 6.9 Hz, 3 H, ester CH3), 3.20 (1/2ABq, J = 16.8 Hz, 2 H, Ha-
1,3), 3.52 (1/2ABq, J = 16.8 Hz, 2 H, Hb-1,3), 4.19 (q, J = 7.3 Hz,
2 H, ester OCH2), 6.28 (s, 1 H, NH), 7.71 (s, 2 H, Ar-H).
Synthesis 2002, No. 3, 339–342 ISSN 0039-7881 © Thieme Stuttgart · New York

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Modification of -Amino Acid Derivatives via the Suzuki–Miyaura Coupling Reaction
341
13C NMR (75 MHz, CDCl3): = 14.0 (ester CH3), 27.3 (CMe3),
38.5 (CMe3), 42.9 (C-1,3), 61.8 (ester OCH2), 65.1 (C-2), 105.4 (C-
5,6), 135.8 (C-4,7), 142.6 (C-8,9), 172.9 (ester CO), 178.4 (NCO).
HRMS: m/z calcd for C31H35NO3: 469.26169; found: 469.26129.
UV (CDCl3): max ( ) = 246 nm (20234).
MS: m/z (%) = 541 (M+).
Ethyl 2-Trimethylacetamido-5,6-bis(4 -methoxyphenyl)indane-
2-carboxylate (10c)
UV (CHCl3): max ( ) = 285 (1218), 237 nm (2946).
To a solution of 9 (25 mg, 0.046 mmol) in a 1:1 THF–toluene mix-
ture (2 mL) 4-methoxyphenylboronic acid (42 mg, 0.276 mmol),
aqueous Na2CO3 (20 mg in 1 mL H2O) and Pd(PPh3)4 (7.5 mg, 14
mol%) were added and the reaction mixture was refluxed for 6 h.
After the usual work-up, the crude product was purified by column
chromatography. Elution of the column with 15% EtOAc–petro-
leum ether gave compound 10c (22 mg, 95%) as a white solid.
Coupling of Arylboronic Acids with Ethyl 2-Trimethylacetam-
ido-5,6-diiodoindane-2-carboxylate (9); General Procedure
A mixture of 9 (1 equiv), arylboronic acid (3–6 equiv), (PPh3)4Pd (
10 mol%), Na2CO3 (4 equiv) in a mixture of H2O and solvent (THF
and toluene) was heated at 80 °C. At the conclusion of the reaction
(TLC monitoring) the reaction mixture was diluted with H2O (5
mL) and extracted with CH2Cl2. The combined organic layer was
washed with H2O, brine and dried over MgSO4. The solvent was
evaporated and the crude product was purified by silica gel column
chromatography. Elution of with EtOAc–petroleum ether gave the
desired cross-coupling product.
Mp 130–132 °C.
IR (KBr): 3314, 1741, 1635 cm–1.
1H NMR (500 MHz, CDCl3): = 1.20 (s, 9 H, CMe3), 1.25 (t,
J = 7.0 Hz, 3 H, ester CH3), 3.28 (1/2ABq, J = 17.0 Hz, 2 H, Ha-
1,3), 3.74 (1/2ABq, J = 17.0 Hz, 2 H, Hb-1,3), 3.78 (s, 6 H, OMe),
4.23 (q, J = 7.0 Hz, 2 H, ester OCH2), 6.25 (s, 1 H, NH), 6.75 (d,
J = 5.0 Hz, 4 H, Ar-H), 7.03 (d, J = 8.5 Hz, 4 H, Ar-H), 7.20 (s, 2
H, Ar-H).
13C NMR (125 MHz, CDCl3): = 14.6 (ester CH3), 27.9 (CMe3),
39.0 (CMe3), 44.1 (C-1,3), 55.7 (OMe), 62.1 (ester OCH2), 66.0 (C-
2), 113.9, 127.0, 131.4, 134.7, 139.5, 139.6, 158.6 (7 Ar-C), 173.8
(ester CO), 179.0 (NCO).
Ethyl2-Trimethylacetamido-5,6-diphenylindane-2-carboxylate
(10a)
To a solution of 9 (20 mg, 0.037 mmol) in a 1:1 THF–toluene mix-
ture (2 mL) phenylboronic acid (18 mg, 0.15 mmol), aqueous
Na2CO3 (16 mg in 1 mL H2O) and Pd(PPh3)4 (5.1 mg, 12 mol%)
were added and the reaction mixture was refluxed for 17 h. At the
conclusion of the reaction (TLC monitoring) the reaction mixture
was worked up according to the general procedure. The crude prod-
uct was purified by column chromatography. Elution of the column
with 6.5% EtOAc–petroleum ether gave compound 10a (15.5 mg,
95%) as a white crystalline solid.
UV (CHCl3): max ( ) = 252 nm (26983).
Anal. Calcd for C31H35NO5: C, 74.25; H, 6.98; N, 2.79. Found: C,
73.82; H, 6.94; N, 2.46.
Mp 178–180 °C.
IR (KBr): 3355, 1740, 1636 cm–1.
Ethyl 2-Trimethylacetamido-5,6-bis(4 -acetylphenyl)indane-2-
carboxylate (10d)
1H NMR (300 MHz, CDCl3): = 1.27 (s, 9 H, CMe3), 1.32 (t,
J = 7.2 Hz, 3 H, ester CH3), 3.37 (1/2ABq, J = 16.8 Hz, 2 H, Ha-
1,3), 3.82 (1/2ABq, J = 16.8 Hz, 2 H, Hb-1,3), 4.29 (q, J = 6.9 Hz,
2 H, ester OCH2), 6.36 (s, 1 H, NH), 7.16–7.31 (m, 10 H, Ar-H),
7.57 (s, 2 H, Ar-H).
13C NMR (75 MHz, CDCl3): = 14.0 (ester CH3), 27.3 (CMe3),
38.4 (CMe3), 43.7 (C-1,3), 61.5 (ester CH2), 65.3 (C-2), 126.2,
126.4, 127.7, 129.8, 139.3, 139.6, 141.5 (7 Ar-C), 173.2 (ester
CO), 178.4 (NCO).
To a solution of 9 (25 mg, 0.046 mmol) in a 1:1 THF–toluene mix-
ture (2 mL) 4-acetylphenylboronic acid (45 mg, 0.274 mmol), aque-
ous Na2CO3 (20 mg in 1 mL H2O) and Pd(PPh3)4 (7 mg, 13 mol%)
were added and the reaction mixture was refluxed for 6 h. After the
usual work-up, the crude product was purified by column chroma-
tography. Elution of the column with 25% EtOAc–petroleum ether
gave compound 10d (21 mg, 87%) as a white solid.
Mp 198–200 °C.
IR (KBr): 3343, 1739, 1680, 1637 cm–1.
1H NMR (500 MHz, CDCl3): = 1.21 (s, 9 H, CMe3), 1.26 (t,
J = 7.0 Hz, 3 H, ester CH3), 2.56 (s, 6 H, COCH3), 3.37 (1/2ABq,
J = 17.0 Hz, 2 H, Ha-1,3), 3.74 (1/2ABq, J = 17.0 Hz, 2 H, Hb-1,3),
4.24 (q, J = 7.0 Hz, 2 H, ester OCH2), 6.38 (s, 1 H, NH), 7.19 (d,
J = 8.0 Hz, 4 H, Ar-H), 7.26 (s, 2 H, Ar-H), 7.79 (d, J = 8.0 Hz, 4
H, Ar-H).
UV (CHCl3) : max ( ) = 269 nm (6270).
Anal. Calcd for C29H31NO3: C, 78.88; H, 7.07; N, 3.17. Found: C,
78.68; H, 7.08; N, 3.22.
Ethyl 2-Trimethylacetamido-5,6-bis(4 -methylphenyl)indane-
2-carboxylate (10b)
13C NMR (125 MHz, CDCl3): = 14.7 (ester CH3), 27.1 (CMe3),
27.9 (COCH3), 39.2 (CMe3), 44.3 (C-1,3), 62.4 (ester OCH2), 65.7
(C-2), 127.0, 128.7, 130.6, 135.8, 139.1, 141.2, 146.9 (7 Ar-C),
174.0 (ester CO), 179.0 (NCO), 198.4 (COCH3).
To a solution of 9 (25 mg, 0.046 mmol) in a 1:1 THF–toluene mix-
ture (2 mL) 4-methylphenylboronic acid (28 mg, 0.206 mmol),
aqueous Na2CO3 (20 mg in 1 mL H2O) and Pd(PPh3)4 (6 mg, 11
mol%) were added and the reaction mixture was refluxed for 23 h.
After the usual work-up, the crude product was purified by column
chromatography. Elution of the column with 5% EtOAc–petroleum
ether gave compound 10b (21.4 mg, 99%) as a thick liquid.
UV (CHCl3): max ( ) = 274 nm (43895).
Anal. Calcd for C33H35NO5: C, 75.43; H, 6.66; N, 2.66. Found: C,
75.1; H, 6.69; N, 2.62.
IR (neat): 3395, 1737, 1649 cm–1.
1H NMR (300 MHz, CDCl3): = 1.19 (s, 9 H, CMe3), 1.25 (t,
J = 7.3 Hz, 3 H, ester CH3), 2.30 (s, 6 H, Ar-CH3), 3.28 (1/2ABq,
J = 16.8 Hz, 2 H, Ha-1,3), 3.74 (1/2ABq, J = 16.8 Hz, 2 H, Hb-1,3),
4.22 (q, J = 7.1 Hz, 2 H, ester OCH2), 6.25 (s, 1 H, NH), 7.0 (s, 8
H, Ar-H), 7.21 (s, 2 H, Ar-H).
13C NMR (75 MHz, CDCl3): = 14.7 (ester CH3), 21.7 (Ar-CH3),
27.9 (CMe3), 39.1 (CMe3), 44.4 (C-1, 3), 62.1 (ester OCH2), 66.0
(C-2), 127.1, 129.1, 130.3, 134.4, 139.5, 139.7, 140.1 (7 Ar-C),
173.9 (ester CO), 179.0 (NCO).
Ethyl 2-Trimethylacetamido-5,6-dithien-2 -ylindane-2-car-
boxylate (10e)
To a solution of 9 (25 mg, 0.046 mmol) in a 1:1 THF–toluene mix-
ture (2 mL) thien-2-ylboronic acid (24 mg, 0.184 mmol), aqueous
Na2CO3 (20 mg in 1 mL H2O) and Pd(PPh3)4 (6 mg, 11 mol%) were
added and the reaction mixture was refluxed for 6 h. After the usual
work-up, the crude product was purified by column chromatogra-
phy. Elution of the column with 10% EtOAc–petroleum ether gave
compound 10e (12.8 mg, 62%) as a thick liquid.
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S. Kotha et al.
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IR (neat): 3391, 1733, 1658, 1510, 1433, 698 cm–1.
55, 585. (h) Cativiela, C.; Diaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 2000, 11, 645.
(2) Trigalo, F.; Buisson, D.; Azerad, R. Tetrahedron Lett. 1988,
29, 6109.
1H NMR (300 MHz, CDCl3): = 1.21 (s, 9 H, CMe3), 1.27 (t,
J = 7.3 Hz, 3 H, ester CH3), 3.31 (1/2ABq, J = 17.2 Hz, 2 H, Ha-
1,3), 3.71 (1/2ABq, J = 17.2 Hz, 2 H, Hb-1,3), 4.24 (q, J = 7.3 Hz,
2 H, ester OCH2), 6.31 (s, 1 H, NH), 6.86 (dd, J = 1.4, 1.9 Hz, 2 H,
thiophene-H), 6.95 (dd, J = 3.6, 3.6 Hz, 2 H, thiophene-H), 7.26
(dd, J = 1.4, 4.9 Hz, 2 H, thiophene-H), 7.34 (s, 2 H, Ar-H).
13C NMR (75 MHz, CDCl3): = 14.7 (ester CH3), 27.9 (CMe3),
39.2 (CMe3), 44.2 (C-1,3), 62.3 (ester OCH2), 66.0 (C-2), 126.3,
127.5, 128.3, 133.4, 135.8, 140.8, 143.5 (7 Ar-C), 173.8 (ester
CO), 179.0 (NCO).
(3) (a) Schiffmann, E.; Corcoran, B.; Wahl, S. Proc. Natl. Acad.
Sci. U.S.A. 1975, 72, 1059. (b) Bhandari, A.; Jones, D. G.;
Schullek, J. R.; Vo, K.; Schunk, C. A.; Tamanaha, L. L.;
Chen, D.; Yuan, Z.; Needels, M. C.; Gallop, M. A. Bioorg.
Med. Chem. Lett. 1998, 8, 2303. (c) Ma, D.; Tian, H.; Sun,
H.; Kozikowski, A. P.; Pshenichkin, S.; Wroblewski, J. T.
Bioorg. Med. Chem. Lett. 1997, 7, 1195. (d) For references
related to indane chemistry see: Ganellin, C. R. Adv. Drug
Res. 1967, 4, 163. (e) See also: Hong, B. C.; Sarshar, S.
Org. Prep. Proced. Int. 1999, 31, 1.
(4) (a) Torrini, I.; Zecchini, G. P.; Paradisi, M. P.; Lucente, G.;
Gavuzzo, E.; Mazza, F.; Pochetti, G.; Spisani, S.; Giuliani,
A. L. Int. J. Pept. Protein Res. 1991, 38, 495. (b) Gavuzzo,
E.; Lucente, G.; Mazza, F.; Zecchini, G. P.; Paradisi, M. P.;
Pochetti, G.; Torrini, I. Int. J. Pept. Protein Res. 1991, 37,
268.
HRMS: m/z calcd for C25H27NO3S2: 453.14324; found: 453.14309.
UV (CHCl3): max ( ) = 258 nm (55350).
Ethyl 2-Trimethylacetamido-5,6-di-2 -furylindane-2-carboxy-
late (10f)
To a solution of 9 (25 mg, 0.046 mmol) in a 1:1 THF–toluene mix-
ture (2 mL) 2-furylboronic acid (29 mg, 0.26 mmol), aqueous
Na2CO3 (20 mg in 1 mL H2O) and Pd(PPh3)4 (6 mg, 11 mol%) were
added and the reaction mixture was refluxed for 7 h. After the usual
work-up, the crude product was purified by silica gel column chro-
matography. Elution of the column with 10% EtOAc–petroleum
ether gave compound 10f (14 mg, 72%) as a thick liquid.
(5) Pinder, R. M.; Butcher, B. H.; Buxton, D. A.; Howells, D. J.
J. Med. Chem. 1971, 14, 893.
(6) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Martin, A. R.; Yang, Y. Acta Chem. Scand. 1993, 47,
221. (c) Miyaura, N. In Advances in Metal-Organic
Chemistry, Vol. 6; Jai Press: Connecticut, 1998, 187–243.
(d) For references related to bis- and multi-Suzuki–Miyaura
coupling reaction see: Liu, Y.; Gribble, G. W. Tetrahedron
Lett. 2000, 41, 8717. (e) See also: Tellenbröker, J.; Kuck, D.
Eur. J. Org. Chem. 2001, 1483. (f) See also: Xu, G.; Sygula,
A.; Marcinow, Z.; Rabideau, P. W. Tetrahedron Lett. 2000,
41, 9931. (g) For references related to Suzuki–Miyaura
coupling reaction from our group see: Kotha, S.;
Chakraborty, K.; Brahmachary, E. Synlett 1999, 1621.
(h) See also: Kotha, S.; Lahiri, K.; Sreenivasachary, N.
Synthesis 2001, 1932. (i) See also: Kotha, S.; Lahiri, K.
Bioorg. Med. Chem. Lett. 2001, 11, 2887. (j) See also:
Kotha, S.; Behera, M.; Vinod Kumar, R. Bioorg. Med.
Chem. Lett. 2002, 12, 105.
IR (neat): 3398, 1735, 1663, 1512, 1479, 737 cm–1.
1H NMR (300 MHz, CDCl3): = 1.18 (s, 9 H, CMe3), 1.24 (t,
J = 7.1 Hz, 3 H, ester CH3), 3.28 (1/2ABq, J = 16.8 Hz, 2 H, Ha-
1,3), 3.69 (1/2ABq, J = 16.8 Hz, 2 H, Hb-1,3), 4.21 (q, J = 7.1 Hz,
2 H, ester OCH2), 5.98 (dd, J = 0.9, 3.3 Hz, 2 H, furan-H), 6.24 (s,
1 H), 6.41 (dd, J = 2.0, 3.2 Hz, 2 H, furan-H), 7.43 (dd, J = 0.7, 1.8
Hz, 2 H, furan-H), 7.45 (s, 2 H, Ar-H).
13C NMR (75 MHz, CDCl3): = 14.6 (ester CH3), 27.9 (CMe3),
39.1 (CMe3), 44.1 (C-1,3), 62.2 (ester OCH2), 66.0 (C-2), 99.5,
108.5, 112.0, 125.5, 128.8, 140.8, 142.1 (7 Ar-C), 173.7 (ester
CO), 179.0 (NCO).
HRMS: m/z calcd for C25H27NO5: 421.18892; found: 421.18858.
UV (CHCl3): max ( ) = 262 nm (9970).
(7) Kotha, S.; Brahmachary, E. J. Org. Chem. 2000, 65, 1359.
(8) We found that the pivaloyl group is helpful to increase the
solubility in nonpolar organic solvents. This aspect is also
useful to increase the lipophilicity of indane-based AAA
derivatives. See: Brahmachary, E. PhD Thesis; IIT,
Bombay: India, 1999.
Acknowledgements
We would like to thank DST-New Delhi for the financial support.
We are grateful to RSIC-Mumbai and TIFR for providing the spec-
tral data. SH and KL thank IIT, Bombay for the award of research
fellowships. We would like to thank the referees for their valuable
suggestions.
(9) Suzuki, H.; Nakamura, K.; Goto, R. Bull. Chem. Soc. Jpn.
1966, 39, 128.
(10) Stanforth, S. P. Tetrahedron 1998, 54, 263.
(11) (a) Kotha, S.; Brahmachary, E. Tetrahedron Lett. 1997, 38,
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Tetrahedron Lett. 1998, 39, 2805. (c) Kotha, S.;
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Application of Transition Metal Catalyst in Organic
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Synthesis 2002, No. 3, 339–342 ISSN 0039-7881 © Thieme Stuttgart · New York