The Diels-Alder approach for the synthesis of tetralin-based α-amino acid derivatives and their modification by the Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.1055/s-2004-815987

Tetralin-based a-amino acid (AAA) is a constrained analogue of phenylalanine (Phe) and is used extensively in the design and synthesis of a variety of bioactive peptides. Due to the nonavailability of simple synthetic methods to deliver complex cyclic AAA

Full text of DOI:10.1055/s-2004-815987

558
PAPER
The Diels–Alder Approach for the Synthesis of Tetralin-Based a-Amino Acid
Derivatives and their Modification by the Suzuki–Miyaura Cross-Coupling
Reaction
Diels–Alder
A
a
pproac
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fo
m
r
the Synthesis of
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etralin-Based
a
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-Amino
A
s
cid
D
eriv
i
atives varao Kotha,* Arun Kumar Ghosh
Department of Chemistry, Indian Institute of Technology-Bombay, Mumbai, 400 076, India
Fax +91(22)5723480; E-mail: srk@chem.iitb.ac.in
Received 13 October 2003; revised 16 December 2003
been incorporated in place of Phe3 into m and d-selective
Abstract: Tetralin-based a-amino acid (AAA) is a constrained an-
alogue of phenylalanine (Phe) and is used extensively in the design
and synthesis of a variety of bioactive peptides. Due to the nonavail-
ability of simple synthetic methods to deliver complex cyclic
opioid peptides.6–9 Also, another unusual AAA derivative
Hat (6-hydroxy-2-aminotetralin-2-carboxylic acid) has
been incorporated for Try1 in leucine enkephalin and re-
AAAs, only simplest members of this class have been used in the lated peptides.10–12
peptide area. In this regard, we have developed a new method to
Narcotic analgesics such as morphine has been used as a
prepare various highly functionalized tetralin-based unusual AAA
derivatives 22, 37–43 by trapping o-xylylene (or o-quino-
dimethane) intermediate with methyl 2-acetamidoacrylate (12). In
addition, we have also modified the diidotetralin derivative 40 by
the Suzuki–Miyaura cross-coupling reaction.
potential drug in the treatment of severe pain therapy.13,14
A dynorphin analog, E-2078 has been studied as a poten-
tial analgesic and also another application in k-selective
compounds as potential neuroprotective and anticovulsant
agents.15–17 Recently, Aldrich et al. have synthesized the
heptadecapeptide dynorphin A (Dyn A) analogs by solid-
phase synthesis using F-moc protected AAA and modi-
fied by incorporating S-Act and R-Act at Phe4 position of
Dyn A.18,19
Key words: amino acids, coupling, Diels–Alder reaction, palladi-
um, peptides
Traditional peptide structure-activity studies employing
proteinogenic amino acids have a limited potential. Many
exciting possibilities are opened up when such studies in-
volve the incorporation of non-proteinogenic amino acids
with sterically demanding side-chains. For example, a
large variety of structural variations are feasible even with
tri- or tetrapeptide by single amino acid replacement with
unusual AAA derivatives.1 The realization of these goals
are aided by the development of new and general synthet-
ic methods2 that can deliver nonproteinogenic (or unusu-
al) AAAs with varying degree of topographical,3 steric
and electronic properties. On several occasions, when
phenylalanine (Phe) (1) is replaced with 2-indanylglycine
2 in peptide modifications, the resulting peptidomemitics
have shown enhanced desirable properties.4 In this regard,
we had demonstrated several methodologies for various
derivatives of 2.5a–f At this juncture, we were also interest-
ed in developing new methodology for the synthesis of
various tetralin-based AAA derivatives (e.g. 3).
In addition to the above-mentioned applications of tetra-
lin-based AAAs, tetralin nucleus is an important structural
element, which can fix the relative position of functional
groups to impart a greater specificity for biological activ-
ity. Daunomycin (4), adriamycine (5) are two important
antitumor antibiotics. In this regard, Ishizumi and co-
workers have reported (+)-9-amino-9-deoxydaunomycin
(6)20 (Figure 2) and its related compounds. In this se-
quence, the key precursor tetralin-based AAA 7 has been
synthesized by Bucherer–Berg method.21,22
Conformationally constrained 2-aminotetralin-2-carbox-
ylic acid (Atc) is a constrained Phe analog, which has
Figure 2 Compounds 4–7
Figure 1 Compounds 1–3
SYNTHESIS 2004, No. 4, pp 0558–0567
x
x
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x
x
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0
0
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Advanced online publication: 26.02.2004
DOI: 10.1055/s-2004-815987; Art ID: Z15103SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Diels–Alder Approach for the Synthesis of Tetralin-Based a-Amino Acid Derivatives
559
Synthesis of cyclic AAAs via Bucherer–Berg23 method
begins with the corresponding carbonyl derivative as the
starting material. Thus, treatment of the ketone 8 with po-
tassium cyanide and ammonium carbonate generates
spirohydantoin 9, which upon hydrolysis gives AAA 10
(Scheme 1).
Equation 1
Denyer et al. have synthesized various amino alkyl substi-
tuted tetralin based AAA derivatives via hydantoin inter-
mediate of the corresponding tetralone in a step-wise
manner.24 Along similar lines, Markquez et al. have re-
ported several amino alkyl substituted tetralin-based
AAA derivatives.25 Recently, Undheim et al. have
prepared26 rigid indacene-bridged bis AAA derivative via
a [2+2+2] cycloaddition reaction using Grubbs catalyst
and Solladie-Cavallo et al. have reported the synthesis of
(+)-(R)-methyl
2-aminotetralin-2-carboxylate27
via
Schollköpf’s bislactim method.28–31
As part of our major program directed towards the synthe-
sis of constrained AAA derivatives via ‘Building Block
Approach’,32 we conceived a new strategy33 for the prep-
aration of 2-aminotetralin-2-carboxylic acid derivatives
13 using the Diels–Alder reaction as a key step.
Scheme 2
Generally, synthetic approach to 3 involves (BB) the
method starting from the commercially available 2-tetra-
lone. Hydrolysis of the intermediate spirohydantoin re-
quires drastic reaction conditions and consequently
sensitive substrates are not suitable for this purpose.34
Here, we would like to report our results towards the syn-
thesis of tetralin-based AAA derivatives by trapping vari-
ous transient o-xylylene intermediates35 (e.g. 11) with
methyl 2-acetamidoacrylate (12)36 in a Diels–Alder fash-
ion (Equation 1). The detailed retrosynthetic strategy for
tetralin-based AAA derivative 13 is shown in Scheme 2.
Path a involves the thermal isomerization of the benzocy-
clobutene (BCB) 15 to o-xylylene 11 followed by the Di-
els–Alder reaction with 12. The second route (path b) rely
on chelotropic elimination of sulfur dioxide from sultine
19 leading to the formation of transient intermediate 11
which in turn reacts with 12 to generate AAA derivative
13. Although both these routes involve the same interme-
diate, the method of generation of the intermediate 11 is
crucial in present context. Several other reductive elimi-
nation methods for the generation of 11 that are incompat-
ible with 12 are not considered here.35
ries of tetralin-based aaAAs with varying shape, size and
redox properties within a very short period of time. Also,
we report the extension of the ‘Building Block Approach’
by using the Suzuki–Miyaura cross-coupling reaction37 as
a key step (Scheme 3) for the synthesis of various aryl
functionalized tetralin-based aaAAA derivatives.
Scheme 3
Towards the synthesis of compounds of type 13, initially
benzocyclobutene (BCB) was reacted with 12 at different
temperatures (80–120 °C) and it was found that no Diels–
Alder product was formed. Since the parent BCB under-
goes cyclobutene ring opening at 200 °C,38 BCB 15
(R = H) and 12 was reacted in xylene in a sealed tube at
180–200 °C, which gave several products as indicated by
TLC analysis. At this juncture it occurred to us that a
milder method for the generation of o-xylylene 11 is de-
sirable. Moreover, generation of 11 in the absence of di-
enophile is known to give dimerization and/or
Towards this goal, a general methodology based on
‘Building Block Approach’32 was pursused. ‘Building
Block Approach’ involves generation of several target
molecules of diverse structures starting from a common
precursor. By adopting this strategy one can deliver a se-
Scheme 1
Synthesis 2004, No. 4, 558–567 © Thieme Stuttgart · New York

560
S. Kotha, A. K. Ghosh
PAPER
polymerization to generate unwanted products. A perusal
of literature indicated that generation of o-xylylene39–44
such as 11 by thermal elimination of sulfur dioxide from
the sultine, 1,4-dihydro-2,3-benzoxathiin-3-oxide re-
quires lower temperature.
In this regard, the parent sultine 2145 was prepared accord-
ing to the literature procedure by treating of o-xylene di-
bromide 20 with sodium hydroxymethane sulfinate
(rongalite, 18)46 in presence of tetrabutylammonium bro-
mide (TBAB) in DMF at 0 °C (Scheme 4). Having the
sultine derivative 2147 in hand, it was reacted with methyl
2-acetamidoacrylate (12) at benzene reflux temperature to
give the required product 22 in 66% isolated yield. The
structure of 22 was fully in agreement with its spectral
data (Scheme 5).
Scheme 4
Scheme 5
Having established the conditions for trapping o-xylylene
in the presence of 12, the attention was turned next to ex-
pand this strategy to other related substrates. The synthet-
ic routes adopted for the preparation of various sultine
derivatives are shown in Scheme 6. Various tetralin-based
AAA prepared in this regard are included in Table 1.
Scheme 6
Having prepared the diiodo compound 40 in good yield, it
was treated with p-methylphenylboronic acid in the pres-
ence of Pd(0) catalyst, [Pd(PPh3)4], aqueous Na2CO3 and
THF–toluene to deliver the disubstituted tetralin-based
AAA derivative 44 in 89% yield (Scheme 7). Although
there are several methods for aryl–aryl cross-coupling re-
action, the Suzuki–Miyaura cross-coupling reaction
seems to tolerate various functional groups compared to
the other methods.48
sible by the currently available methods such as BB meth-
od due the presence of keto functionality. Moreover, the
synthesis of starting keto precursor required for BB meth-
od is not trivial exercise. We also modified the diiodote-
tralin derivative 40 by Suzuki–Miyaura coupling reaction
with various functionalized aryl boronic acids under Pd(0)
catalyst and the insertion of various aryl functionalities
into tetralin-based AAA is much easily accessible than
other classical methods. Since constrained AAA deriva-
tives play an important role in the design of biologically
active peptides, our results may be of interest to medicinal
and bioorganic chemists working in these areas.
Then, the Suzuki–Miyaura coupling reaction was attempt-
ed with several boronic acids (4-methoxyphenylboronic
acid, 4-fomylphenylboronic acid, 4-acetylphenylboronic
acid, etc.) using [Pd(PPh3)4] catalyst and the results of the
reactions are outlined in Table 2. Typically, 65–91%
yields of the coupling product were observed. All the cou-
pling products 44–49 were characterized by appropriate
spectral data (IR, UV, 1H NMR, 13C NMR, HRMS).
We have shown that various o-xylylene derivatives de-
rived from sultines have been trapped with methyl 2-acet-
amidoacrylate (12) in a Diels–Alder fashion to generate
various tetralin-based constrained AAA derivatives. It is
worth mentioning that compounds of type 42 are inacces-
Scheme 7
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Diels–Alder Approach for the Synthesis of Tetralin-Based a-Amino Acid Derivatives
561
Table 1 Various Tetralin-Based AAA Derivatives Prepared by the Diels–Alder Strategy
Entry
1
Sultine
2145
Yield (%)
83
Diels–Alder Product
Yield (%)
66
22
37
2
3
90a
57
65
64
24
26
28
38
39
40
4
5
6
49a
60
67a
92
30
32
62
36
41
7
8
20
68
53a
60
34
42
43
3642
a Improved yields were obtained as compared to previously reported results.33
Analytical TLC was performed on (10 × 5 cm) glass plates coated
with Acme’s silica gel G or GF 254 (containing 13% CaSO4 as a
binder). Visualization of the spots on TLC plate was achieved either
by exposure to I2 vapor, or UV light. Flash chromatography was
performed using Acme’s silica gel (100–200 mesh) and the column
was usually eluted with EtOAc and petroleum ether (bp 60–80 °C)
mixture. Melting points are uncorrected. FT-IR spectra were re-
corded as KBr pellets unless otherwise mentioned. UV spectra were
taken in CHCl3 solvent. MeCN and CCl4 were distilled over P2O5.
Anhyd THF and Et2O were obtained by distillation over sodium-
benzophenone ketyl. For all the reactions, anhyd MgSO4 was used
as the drying agent after workup. Palladium catalyst, [Pd(PPh3)4]
was prepared according to the literature procedure.49 4-Methylphe-
nylboronic acid, 2-furylboronic acid, 2-thienylboronic acid were
prepared according to the literature50 procedure and other remaining
boronic acids were purchased from Lancaster Chemical Co (UK)
Sultine Derivatives from the Corresponding o-Xylene Dibro-
mides; General Procedure (Scheme 6)
A mixture of o-xylene dibromide (1 equiv), sodium hydroxy meth-
anesulfinate (18; rongalite, 5–6 equiv), and tetrabutylammonium
bromide (TBAB, ca. 10 mol%) in anhyd DMF was stirred at 0 °C.
Typically the reaction required stirring for 3–4 h at 0 °C and for 2–
3 h at r.t. At the conclusion of the reaction (TLC monitoring), the
mixture was diluted with H2O and extracted with Et2O. The com-
bined organic layers were washed with H2O, brine and dried
(MgSO4). The solvent was evaporated and the crude product was
charged on a silica gel column. Elution of the column with EtOAc–
petroleum ether gave the desired sultine derivative.
1,4-Dihydronaphth[2,3-d][1,2]oxathiin-3-oxide (24)
A suspension of rongalite (18; 460 mg, 3 mmol) in DMF (4 mL) was
added to 2,3-bis(bromomethyl)naphthalene (23;51 96 mg, 0.3
mmol) and TBAB (30 mg, 0.1 mmol) at 0 °C and the resulting sus-
pension was stirred at 0 °C for 6 h. At the conclusion of the reaction
(TLC monitoring), the mixture was worked up according to the gen-
eral procedure. The crude product was purified by a silica gel col-
umn chromatography. Elution of the column with 5% EtOAc–
petroleum ether gave the compound 24 (60 mg, 90%) as a white sol-
id; mp 175–176 °C.
1
and Aldrich Chemical Co (USA). H and 13C NMR samples were
prepared in CDCl3 solvent and the chemical shifts were reported in
d scale using tetramethylsilane as the internal standard. 300 MHz 1H
and 75.4 MHz 13C NMR spectra were recorded on a Bruker spec-
trometer. Coupling constants (J) are reported in Hertz.
Synthesis 2004, No. 4, 558–567 © Thieme Stuttgart · New York

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S. Kotha, A. K. Ghosh
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Table 2 Various Tetralin-Based AAA Derivatives Modified by the
ether gave the compound 26 (28 mg, 57%) as a white solid; mp 118–
Suzuki–Miyaura Cross-Coupling Reaction
119 °C.
IR (KBr): 1480, 1436, 1261, 1108 cm–1.
Entry Boronic Acid
1
Coupling Product
Yield
(%)
1H NMR (300 MHZ, CDCl3): d = 3.62 (d, J = 16.4 Hz, 1 H), 3.78
(s, 6 H), 4.11 (d, J = 16.4 Hz, 1 H), 5.09 (d, J = 15.1 Hz, 1 H), 5.15
(d, J = 15.1 Hz, 1 H), 6.77 (s, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 48.2, 55.9, 56.0, 56.8, 109.1,
109.3, 114.6, 122.0, 149.3, 151.4.
89
91
HRMS: m/z calcd for C10H12SO4 [M + H]: 229.0534; found:
229.0534.
44
45
46
2
3
4
UV (CHCl3): lmax (e) = 246 (1674), 296 nm (4190).
6,7-Dibromo-1,4-dihydro-2,3-benzoxathiin-3-oxide (28)
A suspension of rongalite (18; 3.5 g, 23 mmol) in DMF (3 mL) was
added to 1,2-bis(bromomethyl)-4,5-dibromobenzene (27;53 1 g, 2.3
mmol ) and (TBAB) (200 mg, 0.7 mmol) at 0 °C and the resulting
suspension was stirred at 0 °C for 3 h and then at r.t. for 3 h. At the
conclusion of the reaction (TLC monitoring), the mixture was
worked up according to the general procedure. The crude product
was purified by a silica gel column chromatography. Elution of the
column with 5% EtOAc–petroleum ether gave the compound 28
(356 mg 48%) as a white solid; mp 110 °C.
87
65
IR (neat): 1485, 1406, 1374, 1321, 1196, 1117 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.51 (d, J = 15.5 Hz, 1 H), 4.26 (d,
J = 15.5 Hz, 1 H), 4.89 (d, J = 14.4 Hz, 1 H), 5.22 (d, J = 14.4 Hz,
1 H), 7.49 (s, 1 H), 7.51 (s, 1 H).
13C NMR (75.4 MHz, CDCl3): d = 55.3, 61.3, 124.4, 124.8, 126.8,
130.7, 133.8, 134.8.
47
48
HRMS: m/z Calcd for C8H6Br2SO2 [M + H]: 327.8414; found:
327.8435.
5
6
78
79
UV (CHCl3): lmax (e) = 246 nm (3035).
1,4-Dihydro-6,7-diiodo-2,3-benzoxathiin-3-oxide (30)
A suspension of rongalite (18; 298 mg, 1.9 mmol) in DMF (3 mL)
was added to 1,2-bis(bromomethyl)-4,5-diidobenzene (29;54,5g 100
mg, 0.19 mmol) and (TBAB) (61 mg, 2 mmol ) at 0 °C and the re-
sulting suspension was stirred at 0 °C for 3 h and then at r.t.for 3 h.
At the conclusion of the reaction (TLC monitoring), the mixture
was worked up according to the general procedure. The crude prod-
uct was purified by a silica gel column chromatography. Elution of
the column with 5% EtOAc–petroleum ether gave the compound 30
(45 mg, 60%) as a white solid; mp 90–91 °C.
49
IR (neat): 1654, 1455, 1321, 1105 cm–1.
IR (neat): 1639, 1440, 1116 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.47 (d, J = 15.5 Hz, 1 H), 4.21 (d,
J = 15.5 Hz, 1 H), 4.85 (d, J = 14.4 Hz, 1 H), 5.17 (d, J = 14.4 Hz,
1 H), 7.71 (s, 1 H), 7.73 (s, 1 H).
1H NMR (300 MHz, CDCl3): d = 3.75 (d, J = 15.1 Hz, 1 H), 4.67 (d,
J = 15.1 Hz, 1 H), 5.13 (d, J = 13.1 Hz, 1 H), 5.50 (d, J = 13.1 Hz,
1 H), 7.50–7.55 (m, 2 H), 7.76–7.87 (m, 4 H).
13C NMR (75.4 MHz, CDCl3): d = 58.7, 64.3, 124.8, 125.3, 127.0,
127.08, 127.8, 128.0, 128.9, 131.9, 132.7, 133.4.
HRMS: m/z Calcd for C8H6I2SO2 [M + H]: 420.8256; found:
420.8249.
UV (CHCl3): lmax (e) = 252 nm (19507).
HRMS: m/z calcd for C12H10SO2 [M + H]: 219.0479; found:
219.0480.
1,4-Dihydro-6,7-dimethyl-2,3-benzoxathiin-3-oxide (32)55
A suspension of rongalite (18; 210 mg, 1.37 mmol) in DMF (7 mL)
was added to the dibromo compound 3156 (165 mg, 0.57 mmol) and
TBAB (522 mg, 3.39 mmol) at 0 °C and the resulting suspension
was stirred at 0 °C for 2.5 h and then at r.t. for 3 h. At the conclusion
of the reaction (TLC monitoring), the mixture was worked up ac-
cording to the general procedure. The crude product was purified by
a silica gel column chromatography. Elution of the column with 5%
EtOAc–petroleum ether gave the compound 32 (64 mg, 62%) as a
white solid; mp 51–52 °C.
UV (CHCl3): lmax (e) = 248 (3041), 278 nm (4591).
1,4-Dihydro-5,8-dimethoxy-2,3-benzoxathiin-3-oxide (26)
A suspension of rongalite (18; 332 mg, 2.16 mmol) in DMF (2.5
mL) was added to 1,4-dimethoxy-2,3-dibromoxylylene (25;52 70
mg, 0.21 mmol), TBAB (60 mg, 0.18 mmol) at 0 °C under N2. The
resulting suspension was stirred at 0 °C for 4 h and then the mixture
was stirred at r.t. for 3 h. At the conclusion of the reaction (TLC
monitoring), the mixture was worked up according to the general
procedure. The crude product was purified by a silica gel column
chromatography. Elution of the column with 5% EtOAc–petroleum
IR (neat): 1500, 1453, 1112, 1025 cm–1.
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Diels–Alder Approach for the Synthesis of Tetralin-Based a-Amino Acid Derivatives
563
1H NMR (300 MHz, CDCl3): d = 2.26 (s, 6 H), 3.51 (d, J = 15.3 Hz,
1 H), 4.29 (d, J = 15.3 Hz, 1 H), 4.89 (d, J = 13.5 Hz, 1 H), 5.24 (d,
J = 13.5 Hz, 1 H), 6.98 (s, 1 H), 7.01 (s, 1 H).
tography. Elution of the column with 30% EtOAc–petroleum ether
gave the compound 37 (53 mg, 65%) as a white solid; mp 220–
221 °C.
13C NMR (75.4 MHz, CDCl3): d = 19.52, 19.7, 56.6, 63.2, 123.1,
IR (KBr): 3276 (NH), 1739 (ester C=O), 1654 (NC=O) cm–1.
126.8, 130.8, 130.9, 136.5, 137.2.
1H NMR (300 MHz, CDCl3): d = 1.90 (s, 3 H), 2.22–2.32 (m, 1 H),
2.56–2.61 (m, 1 H), 2.91–3.11 (m, 2 H), 3.21 (d, J = 16.2 Hz, 1 H),
3.42 (d, J = 16.2 Hz, 1 H), 3.78 (s, 3 H), 5.71 (s, 1 H), 7.39–7.40 (m,
2 H), 7.57 (s, 1 H), 7.61 (s, 1 H), 7.72–7.75 (m, 2 H).
FAB-MS: m/z = 197 [M + H].
UV (CHCl3): lmax (e) = 246 (911), 268 nm (912).
1,4-Dihydroanthra[2,3-d][1,2]oxathiin-5,11-dione-3-oxide (34)
A suspension of rongalite (18; 278 mg, 1.8 mmol) in DMF (2 mL)
was added to dibromo compound 3357,5f (71 mg, 0.18 mmol) and
TBAB (100 mg, 0.3 mmol) at 0 °C and the resulting suspension was
stirred at 0 °C for 4 h and then at r.t. for 3 h. At the conclusion of the
reaction (TLC monitoring), the mixture was worked up according to
the general procedure. The crude product was purified by a silica gel
column chromatography. Elution of the column with 5% EtOAc–
petroleum ether gave the compound 34 (11 mg, 20%) as a white sol-
id; mp 183–184 °C.
13C NMR (75.4 MHz, CDCl3): d = 23.0, 25.4, 28.6, 38.3, 52.6, 58.1,
125.4, 125.7, 126.8, 127.0, 127.7, 130.9, 132.1, 132.5, 133.4, 170.1,
173.9.
HRMS: m/z calcd for C18H19NO3: 297.1240; found: 297.1235.
UV (CHCl3): lmax (e) = 323 (434), 285 nm (3828).
2-(Acetylamino)-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphtha-
lenecarboxylic Acid Methyl Ester (38)
A solution of the sultine 26 (25 mg, 0.11 mmol), methyl 2-acetami-
doacrylate (12; 35.5 mg, 0.23 mmol) and toluene (1 mL) was stirred
in a sealed tube at 130 °C for 48 h. At the conclusion of reaction
(TLC monitoring), the mixture was worked up according to the gen-
eral procedure and the crude product was purified by a silica gel col-
umn chromatography. Elution of the column with 30% EtOAc–
petroleum ether gave the compound 38 (21.5 mg, 64%) as a white
solid; mp 168–170 °C.
IR (KBr): 1678, 1592, 1402, 1342, 1293, 1120, 1093 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.79 (d, J = 15.7 Hz, 1 H), 4.48 (d,
J = 15.7 Hz, 1 H), 5.7 (d, J = 14.8 Hz, 1 H), 5.46 (d, J = 14.8 Hz, 1
H), 7.81–7.85 (m, 2 H), 8.18 (s, 2 H), 8.31–8.36 (m, 2 H).
MS-ES+: m/z calcd for C25H16O2S: 298.0299; found: 298.0231.
Tetralin-Based AAA Derivatives by the Diels–Alder Reaction
with Various Sultine Derivatives and Methyl 2-Acetamidoacry-
late (12) General Procedure (Table 1)
A solution of sultine (1 equiv) and methyl 2-acetamidoacrylate (12;
1.5–2 equiv) in benzene or toluene was refluxed until the starting
materials had disappeared. At the conclusion of the reaction (TLC
monitoring), the solvent was removed at reduced pressure and the
crude product was purified by silica gel column chromatography.
Elution of the column with EtOAc–petroleum ether mixture gave
the required tetralin-based AAA derivative (Table 1).
IR (KBr): 3285 (NH), 1742 (ester C=O), 1661 (NC=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.92 (s, 3 H), 1.98–2.04 (m, 1 H),
2.40–2.67 (m, 2 H), 2.89 (d, J = 17.2 Hz, 2 H), 3.08 (d, J = 17.2 Hz,
1 H), 3.76 (s, 6 H), 3.79 (s, 3 H), 5.60 (s, 1 H), 6.65 (s, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 19.6, 23.0, 26.2, 32.6, 52.5, 55.5,
56.9, 107.0, 107.3, 122.0, 125.5, 151.0, 151.5, 169.9, 174.2.
HRMS: m/z calcd for C16H21NO3: 307.1419; found: 307.1416.
UV (CHCl3): lmax (e) = 289 (5228), 243 nm (3742).
2-(Acetylamino)-6,7-dibromo-1,2,3,4-tetrahydro-2-naphthale-
necarboxylic Acid Methyl Ester (39)
2-(Acetylamino)-1,2,3,4-tetrahydro-2-naphthalenecarboxylic
Acid Methyl Ester (22)
A solution of the sultine 28 (50 mg, 0.12 mmol), methyl 2-acetami-
doacrylate (12; 36 mg, 0.24 mmol) and toluene (1.5 mL) was stirred
in a sealed tube at 120 °C for 48 h. At the conclusion of reaction
(TLC monitoring), the mixture was worked up according to the gen-
eral procedure and the crude product was purified by a silica gel col-
umn chromatography. Elution of the column with 35% EtOAc–
petroleum ether gave the compound 39 (41 mg, 67%) as a white sol-
id; mp 267–268 °C.
A solution of the sultine 21 (24 mg, 0.18 mmol), methyl 2-acetami-
doacrylate (12; 26 mg, 0.14 mmol) and distilled benzene (1.5 mL)
was stirred at 85 °C for 20 h. At the conclusion of reaction (TLC
monitoring), the mixture was worked up according to the general
procedure and the crude product was purified by a silica gel column
chromatography. Elution of the column with 30% EtOAc–petro-
leum ether gave the compound 22 (20 mg, 66%) as a white solid;
mp 127–128 °C.
IR (KBr): 3344 (NH), 1721 (ester C=O), 1670 (NC=O) cm–1.
IR (KBr): 3296 (NH), 1731 (ester C=O), 1650 (NC=O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.77 (s, 3 H), 1.75–1.89 (m, 1
H), 2.21–2.25 (m, 1 H), 2.55–2.68 (m, 2 H), 2.89 (d, J = 17.0 Hz, 1
H), 3.13 (d, J = 17.0 Hz, 1 H), 3.57 (s, 3 H), 5.75 (s, 1 H), 7.81 (s, 2
H), 8.1 (s, 1 H).
13C NMR (75.4 MHz, DMSO-d6): d = 22.2, 24.0, 27.8, 35.7, 52.0,
56.3, 120.4, 120.5, 133.1, 133.8, 135.6, 136.7, 169.6, 173.5.
1H NMR (300 MHz, CDCl3): d = 1.92 (s, 3 H), 2.09–2.18 (m, 1 H),
2.55–2.6 (m, 1 H), 2.78–2.84 (m, 2 H), 2.98 (d, J = 16.5 Hz, 1 H),
3.27 (d, J = 16.5 Hz, 1 H), 3.76 (s, 3 H), 5.75 (s, 1 H), 7.06–7.26 (m,
4 H).
13C NMR (75.4 MHz, CDCl3): d = 23.0, 25.1, 27.7, 37.8, 52.5, 57.7,
126.1, 126.5, 128.8, 129.5, 131.9, 134.9, 170.1, 173.9.
HRMS: m/z calcd for C14H15Br2NO3: 402.9418; found: 402.9419.
UV (CHCl3): lmax (e) = 242 (3272), 280 (1579) 288 nm (1573).
HRMS: m/z calcd for C14H17NO3 [M + H]: 248.1286; found:
248.1284.
UV (CHCl3): lmax (e) = 274 (460), 266 nm (546).
2-(Acetylamino)-1,2,3,4-tetrahydro)-6,7-diiodo-2-naphthalene-
carboxylic Acid Methyl Ester (40)
2-(Acetylamino)-1,2,3,4-tetrahydro-2-anthracenecarboxylic
Acid Methyl Ester (37)
A solution of the sultine 30 (90 mg, 0.21 mmol), methyl 2-acetami-
doacrylate (12; 61 mg, 0.42 mmol) and toluene (3.5 mL) was stirred
in a sealed tube at 130 °C for 72 h. At the conclusion of reaction
(TLC monitoring), the mixture was worked up according to the gen-
eral procedure and the crude product was purified by a silica gel col-
umn chromatography. Elution of the column with 35% EtOAc–
A solution of the sultine 24 (60 mg, 0.27 mmol), methyl 2-acetami-
doacrylate (12; 75 mg, 0.54 mmol) and toluene (2.5 mL) was stirred
at 130 °C for 40 h. At the conclusion of the reaction (TLC monitor-
ing), the mixture was worked up according to the general procedure
and the crude product was purified by a silica gel column chroma-
Synthesis 2004, No. 4, 558–567 © Thieme Stuttgart · New York

564
S. Kotha, A. K. Ghosh
PAPER
petroleum ether gave the compound 40 (98 mg, 92%) as a white sol-
id; mp 272–273 °C.
IR (KBr): 3305 (NH), 1735 (ester C=O), 1651 (NC=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.95 (s, 3 H), 2.03–2.13 (m, 1 H),
2.46–2.51 (m, 1 H), 2.68–2.76 (m, 2 H), 2.91 (d, J = 17.0 Hz, 1 H),
3.21 (d, J = 17.0 Hz, 1 H), 3.75 (s, 3 H), 5.56 (s, 1 H), 7.57 (s, 1 H),
7.63 (s, 1 H).
13C NMR (75.4 MHz, DMSO-d6): d = 22.2, 23.8, 27.7, 35.6, 51.9,
56.3, 104.6, 104.8, 135.9, 137.1, 138.6, 139.3, 169.6, 173.5.
in sealed tube at 120 °C for 24 h. At the conclusion of reaction (TLC
monitoring), the mixture was worked up according to the general
procedure and the crude product was purified by a silica gel column
chromatography. Elution of the column with 50% EtOAc–petro-
leum ether gave the compound 43 (41 mg, 60%) as a white solid;
mp 168–170 °C.
IR (KBr): 3305 (NH), 1735 (ester C=O), 1651 (NC=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.97 (s, 3 H), 2.32 (br s, 1 H), 2.57
(br s, 1 H), 3.13 (s, 2 H), 3.33 (d, J = 16.5 Hz, 1 H), 3.56 (d, J = 16.5
Hz, 1 H), 3.78 (s, 3 H), 6.03 (s, 1 H), 7.78 (s, 1 H), 7.84 (s, 1 H),
8.76 (s, 2 H).
MS: m/z = 499 (M+).
13C NMR (75.4 MHz, CDCl3): d = 23.1, 25.7, 28.7, 38.0, 52.8, 57.8,
UV (CHCl3): lmax (e) = 293 nm (1245).
127.9, 128.7, 136.5, 138.5, 141.5, 141.7, 144.5, 144.6, 170.3, 173.6.
Anal. Calcd for C14H15I2NO3: C, 33.67; H, 3.03; N, 2.80. Found: C,
33.71; H, 3.04; N, 2.62.
HRMS: m/z calcd for C16H17N3O3: 299.1269; found: 299.1266.
UV (CHCl3): lmax (e) = 324 (9880), 245 nm (18952).
2-(Acetylamino)-1,2,3,4-tetrahydro)-6,7-dimethyl-2-naphthal-
enecarboxylic Acid Methyl Ester (41)
SM Cross-Coupling of Arylboronic Acids with 2-(Acetylami-
no)-1,2,3,4-tetrahydro-6,7-diido-2-naphthalenecarboxylic Acid
Methyl Ester (40); General Procedure (Table 2)
A solution of the sultine 32 (16 mg, 0.08 mmol), methyl 2-acetami-
doacrylate (12; 17 mg, 0.12 mmol) and toluene (1 mL) was stirred
in a sealed tube at 130 °C for 6 h. At the conclusion of the reaction
(TLC monitoring), the mixture was worked up according to the gen-
eral procedure and the crude product was purified by a silica gel col-
umn chromatography. Elution of the column with 35% EtOAc–
petroleum ether gave the compound 41 (8 mg, 36%) as a pale yel-
low solid; mp 188–190 °C.
A mixture of the diiodocompound 40 (1 equiv), arylboronic acid (3–
4 equiv), (PPh3)4Pd (ca. 5–10 mol%), Na2CO3 (4 equiv) in H2O,
THF, and toluene was heated at 80 °C under N2. At the conclusion
of the reaction, (TLC monitoring) the mixture was diluted with H2O
(5 mL) and extracted with CH2Cl2. The combined organic layers
were washed with H2O, brine and dried (MgSO4). The solvent was
evaporated and the crude product left was charged on a silica gel
column. Elution of the column with EtOAc–petroleum ether gave
the desired cross-coupling product (Table 2).
IR (neat): 3354 (NH), 1722 (ester C=O), 1663 (NC=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.92 (s, 3 H), 2.03–2.14 (m, 1 H),
2.21 (s, 6 H), 2.56–2.82 (m, 3 H), 2.88 (d, J = 16.8 Hz, 1 H), 3.17
(d, J = 16.8 Hz, 1 H), 3.76 (s, 3 H), 5.62 (s, 1 H), 6.84 (s, 1 H), 6.91
(s, 1 H).
13C NMR (75.4 MHz, CDCl3): d = 19.2, 23.0, 24.5, 27.5, 29.6, 37.7,
52.5, 57.8, 128.9, 129.9, 130.5, 132.2, 134.5, 135.0, 170.0, 174.0.
2-(Acetylamino)-1,2,3,4-tetrahydro-6,7-bis(4¢-methylphenyl)-2-
naphthalenecarboxylic Acid Methyl Ester (44)
A mixture of 40 (25 mg, 0.05 mmol), 4-methylphenylboronic acid
(41 mg, 0.3 mmol), (PPh3)4Pd (12 mg, 0.01 mmol), Na2CO3 (32 mg,
0.3 mmol), H2O (1 mL), THF (2 mL), and toluene (2 mL) was re-
fluxed at 80 °C for 7 h. At the conclusion of the reaction (TLC mon-
itoring), the mixture was worked up according to the general
procedure. The crude product was purified by a silica gel column
chromatography. Elution of the column with 25% EtOAc–petro-
leum ether gave the compound 44 (19 mg, 89%) as a white crystal-
line solid; mp 232–234 °C.
HRMS: m/z calcd for C16H21NO3: 275.1521; found: 275.1521.
UV (CHCl3): lmax (e) = 280 (1116), 272 nm (1102).
2-(Acetylamino)-1,2,3,4,6,11-hexahydro-6,11-dioxo-2-naphtha-
cenecarboxylic Acid Methyl Ester (42)
A solution of the sultine 34 (24 mg, 0.08 mmol), methyl 2-acetami-
doacrylate (12; 17 mg, 0.12 mmol) and toluene (1 mL) was stirred
at 110 °C for 9 h. At the conclusion of reaction (TLC monitoring),
the mixture was worked up according to the general procedure and
the crude product was purified by a silica gel column chromatogra-
phy. Elution of the column with 50% EtOAc–petroleum ether gave
the compound 42 (16 mg, 53%) as a yellow solid; mp 230–232 °C.
IR (KBr): 3329 (NH), 1739 (ester C=O), 1675 (NC=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.98 (s, 3 H), 2.14–2.22 (m, 1 H),
2.31 (s, 6 H), 2.62–2.68 (m, 1 H), 2.83–2.89 (m, 2 H), 3.02 (d,
J = 17.2 Hz, 1 H), 3.32 (d, J = 17.2 Hz, 1 H), 3.78 (s, 3 H), 5.71 (s,
1 H), 7.01 (s, 8 H), 7.11 (s, 1 H), 7.16 (s, 1 H).
13C NMR (75.4 MHz, CDCl3): d = 21.3, 23.3, 25.0, 27.8, 37.9, 52.8,
58.0, 128.8, 128.9, 129.7, 131.1, 131.8, 134.2, 136.3, 138.3, 138.7,
170.4, 174.1.
IR (neat): 3358 (NH), 1731 (ester C=O), 1674 (NC=O), 1589 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.01 (s, 3 H), 2.15–2.25 (m, 1 H),
2.58–2.63 (m, 1 H), 2.96–3.01 (m, 2 H), 3.21 (d, J = 17.1 Hz, 1 H),
3.46 (d, J = 17.1 Hz, 1 H), 3.78 (s, 3 H), 6.03 (s, 1 H), 7.80 (d,
J = 3.8 Hz, 2 H), 7.91 (s, 1 H), 7.93 (s, 1 H), 8.24 (d, J = 3.6 Hz, 2
H).
13C NMR (75.4 MHz, CDCl3): d = 23.11, 25.8, 28.0, 37.9, 52.8,
57.5, 127.1,127.6, 128.2, 131.5, 131.6, 133.4, 134.1, 139.9, 142.1,
170.4, 173.4, 182.7, 182.9.
MS: m/z = 427 (M+).
HRMS: m/z calcd for C28H29NO5 [M + H]: 428.2225; found:
428.2222.
UV (CHCl3): lmax (e) = 252 nm (19507).
2-(Acetylamino)-1,2,3,4-tetrahydro-6,7-bis(4¢-methoxyphenyl)-
2-naphthalenecarboxylic Acid Methyl Ester (45)
FAB-MS: m/z = 400 [M + Na].
HRMS: m/z calcd for C22H19NO5 [M + Na]: 400.1160; found:
400.1156.
A mixture of 40 (15 mg, 0.03 mmol), 4-methoxyphenylboronic acid
(27 mg, 0.18 mmol), (PPh3)4Pd (12 mg, 0.01 mmol), Na2CO3 (19
mg, 0.18 mmol), H2O (1 mL), THF (2 mL), and toluene (2 mL) was
refluxed 80 °C for 9 h. At the conclusion of the reaction (TLC mon-
itoring), the mixture was worked up according to the general proce-
dure. The crude product was purified by a silica gel column
chromatography. Elution of the column with 25% EtOAc–petro-
UV (CHCl3): lmax (e) = 331 (5660), 263 nm (54764).
2-(Acetylamino)-1,2,3,4-tetrahydro)-2-benzo[g]quinoxalinecar-
boxylic Acid Methyl Ester (43)
A solution of the sultine 36 (50 mg, 0.23 mmol), methyl 2-acetami-
doacrylate (12; 66.8 mg, 0.47 mmol) and toluene (2 mL) was stirred
Synthesis 2004, No. 4, 558–567 © Thieme Stuttgart · New York

PAPER
Diels–Alder Approach for the Synthesis of Tetralin-Based a-Amino Acid Derivatives
565
leum ether gave the compound 45 (12.5 mg, 91%) as a yellow crys-
talline solid; mp 178–179 °C.
UV (CHCl3): lmax (e) = 270 nm (22197).
2-(Acetylamino)-1,2,3,4-tetrahydro-6,7-bis(5¢-acetylthienylphe-
nyl)-2-naphthalenecarboxylic Acid Methyl Ester (48)
IR (KBr): 3341 (NH), 1733 (ester C=O), 1674 (NC=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.98 (s, 3 H), 2.04–2.22 (m, 1 H),
2.63–2.68 (m, 1 H), 2.83–2.89 (m, 2 H), 3.02 (d, J = 17.0 Hz, 1 H),
3.32 (d, J = 17.0 Hz, 1 H), 3.78 (s, 9 H), 5.7 (s, 1 H), 6.76 (d, J = 8.7
Hz, 4 H), 7.01–7.06 (m, 4 H), 7.09 (s, 1 H), 7.15 (s, 1 H).
13C NMR (75.4 MHz, CDCl3): d = 23.4, 25.0, 27.9, 37.9, 52.9, 55.4,
58.1, 113.5, 113.6, 130.9, 131.2, 131.7, 133.7, 134.0, 138.4, 138.7,
158.4, 170.4, 174.1.
A mixture of 40 (30 mg, 0.06 mmol), 5¢-acetylthienylboronic acid
(35 mg, 0.2 mmol), (PPh3)4Pd (7 mg, 0.006 mmol), Na2CO3 (16 mg,
0.36 mmol), H2O (1 mL), THF (2.5 mL), and toluene (2.5 mL) was
refluxed at 80 °C for 12 h. At the conclusion of the reaction (TLC
monitoring), the mixture was worked up according to the general
procedure. The crude product was purified by a silica gel column
chromatography. Elution of the column with 30% EtOAc–petrol-
eum ether gave the compound 48 (23.5 mg, 78%) as a semi-solid.
MS: m/z = 459 (M+).
IR (KBr): 3348 (NH), 1738 (ester C=O), 1677 (NC=O), 1604, 1551
cm–1.
HRMS: m/z calcd for C28H29NO5 [M + H]: 460.2123; found:
460.2116.
1H NMR (300 MHz, CDCl3): d = 1.99 (s, 3 H), 2.15–2.20 (m, 1 H),
2.25–2.35 (m, 1 H), 2.52 (s, 6 H), 2.71–2.75 (m, 1 H), 2.88–2.91 (m,
1 H), 3.06 (d, J = 17.4 Hz, 1 H), 3.39 (d, J = 17.4 Hz, 1 H), 3.77 (s,
3 H), 5.76 (s, 1 H), 6.79 (d, J = 3.6 Hz, 2 H), 7.20 (s, 2 H), 7.49 (d,
J = 3.6 Hz, 2 H).
UV (CHCl3): lmax (e) = 252 nm (18502).
2-(Acetylamino)-1,2,3,4-tetrahydro-6,7-bis(4¢-formylphenyl)-2-
naphthalenecarboxylic Acid Methyl Ester (46)
A mixture of 40 (30 mg, 0.06 mmol), 4-formylphenylboronic acid
(23 mg, 0.15 mmol), (PPh3)4Pd (7 mg, 0.006 mmol), Na2CO3 (16
mg, 0.15 mmol), H2O (1 mL), THF (2.5 mL), and toluene (2.5 mL)
was refluxed 80 °C at for 8 h. At the conclusion of the reaction
(TLC monitoring), the mixture was worked up according to the gen-
eral procedure. The crude product was purified by a silica gel col-
umn chromatography. Elution of the column with 25% EtOAc–
petroleum ether gave the compound 46 (24 mg, 87%) as a yellow
crystalline solid; mp 218–220 °C.
HRMS: m/z calcd for C26H25NO5S2 [M + H]: 496.1252; found:
496.1249.
UV (CHCl3): lmax (e) = 242 (5164), 306 nm (7168).
2-(Acetylamino)-1,2,3,4-tetrahydro-6,7-bis(2¢-benzothienylphe-
nyl)-2-naphthalenecarboxylic Acid Methyl Ester (49)
A mixture of 40 (30 mg, 0.07 mmol), 2-benzothienylphenylboronic
acid (32 mg, 0.18 mmol), (PPh3)4Pd (8 mg, 0.006 mmol), Na2CO3
(16 mg, 0.36 mmol), H2O (1 mL) THF (2.5 mL), and toluene (2.5
mL) was refluxed at 80 °C for 12 h. At the conclusion of the reac-
tion (TLC monitoring), the mixture was worked up according to the
general procedure. The crude product was purified by a silica gel
column chromatography. Elution of the column with 30% EtOAc–
petroleum ether gave the compound 49 (28.5 mg, 79%) as a white
solid; mp 173–174 °C.
IR (KBr): 3342 (NH), 1730 (ester C=O), 1702 (CHO), 1665
(NC=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 2.0 (s, 3 H), 2.04–2.26 (m, 1 H),
2.58–2.63 (m, 1 H), 2.90–2.97 (m, 2 H), 3.12 (d, J = 17.2 Hz, 1 H),
3.45 (d, J = 17.2 Hz, 1 H), 3.79 (s, 3 H), 5.73 (s, 1 H), 7.19–7.28 (m,
6 H), 7.73 (d, J = 8.4 Hz, 4 H), 9.96 (s, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 23.4, 25.2, 28.4, 37.6, 52.9, 57.9,
129.7, 130.5, 131.2, 131.7, 133.7, 134.9, 135.6, 147.0, 147.1, 170.5,
173.9, 192.0.
IR (KBr): 3334 (NH), 1731 (ester C=O), 1657 (NC=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 2.00 (s, 3 H), 2.14–2.34 (m, 2 H),
2.61–2.65 (m, 1 H), 2.86–2.92 (m, 1 H), 3.08 (d, J = 16.9 Hz, 1 H),
3.38 (d, J = 16.9 Hz, 1 H), 3.79 (s, 3 H), 5.76 (s, 1 H), 7.15–7.74 (m,
12 H).
HRMS: m/z calcd for C28H27NO5 [M + H]: 457.1888; found:
457.1883.
UV (CHCl3): lmax (e) = 274 nm (21113).
HRMS: m/z calcd for C30H25NO3S2 [M + H]: 512.1353; found:
512.1344.
2-(Acetylamino)-1,2,3,4-tetrahydro-6,7-bis(4¢-acetylphenyl)-2-
naphthalenecarboxylic Acid Methyl Ester (47)
UV (CHCl3): lmax (e) = 248 (28045), 300 (19281), 314 nm (20799).
A mixture of 40 (30 mg, 0.06 mmol), 4-acetylphenylboronic acid
(60 mg, 0.36 mmol), (PPh3)4Pd (14 mg, 0.01 mmol), Na2CO3 (39
mg, 0.36 mmol), H2O (1 mL), THF (2.5 mL), and toluene (2.5 mL)
was refluxed 80 °C at for 8 h. At the conclusion of the reaction
(TLC monitoring), the mixture was worked up according to the gen-
eral procedure. The crude product was purified by a silica gel col-
umn chromatography. Elution of the column with 25% EtOAc–
petroleum ether gave the compound 47 (19 mg, 65%) as a white
crystalline solid; mp 188–190 °C.
Acknowledgment
We gratefully acknowledge the CSIR, New Delhi for the financial
support and RSIC Mumbai Prof. A. Srikrishna, IISc for recording
the spectral data. AG thanks the IIT-Bombay for the award of a re-
search fellowship.
References
IR (KBr): 3348 (NH), 1738 (ester C=O), 1677 (NC=O), 1604, 1551
cm–1.
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58.0, 128.4, 130.1, 131.2, 131.7, 132.9, 135.3, 135.6, 137.7, 138.0,
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HRMS: m/z calcd for C30H31NO5 [M + H]: 485.2280; found:
485.2252.
Synthesis 2004, No. 4, 558–567 © Thieme Stuttgart · New York

566
S. Kotha, A. K. Ghosh
PAPER
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