Synthesis of benzocycloheptene-based amino acid derivatives via a [4+2] cycloaddition reaction as a key step

Article abstract of DOI:10.1016/S0040-4020(01)00575-0

The seven-membered diene 5 is prepared from 2-butyne-1,4-diol using double orthoester Claisen rearrangement reaction as a key step. The Diels-Alder reaction of the diene 5 with various dienophiles followed by oxidation delivered the benzocycloheptene-based α-amino acid derivatives in very good yields.

Full text of DOI:10.1016/S0040-4020(01)00575-0

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 6261±6265
Synthesis of benzocycloheptene-based amino acid derivatives
via a [412] cycloaddition reaction as a key step
Sambasivarao Kotha,p Nampally Sreenivasachary and Enugurthi Brahmachary
Department of Chemistry, Indian Institute of TechnologyÐBombay, Mumbai 400 076, India
Received 16 November 2000; revised 1 May 2001; accepted 17 May 2001
AbstractÐThe seven-membered diene 5 is prepared from 2-butyne-1,4-diol using double orthoester Claisen rearrangement reaction as a key
step. The Diels±Alder reaction of the diene 5 with various dienophiles followed by oxidation delivered the benzocycloheptene-based
a-amino acid derivatives in very good yields. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
expected to provide the benzocycloheptene based amino
acid derivatives (Scheme 1).
Cyclic aa-dialkylated amino acids (aa-AAs) are con-
sidered to be a special class of aa-AAs. Surprisingly only
the simplest members of this class have been used in the
peptide arena.1,2 This is probably due to the non-availability
of the general methods for their synthesis in the literature. In
view of these facts we have been engaged in the develop-
ment of new methodologies for the synthesis of unusual
a-amino acids (AAAs) via `building block approach'.3
3. Results and discussion
The key diene 8 was prepared according to the literature
procedure involving a double orthoester Claisen rearrange-
ment as a key step (Scheme 2).8 Thus the microwave9
assisted ortho Claisen rearrangement of 2-butyne-1,4-diol
7 with triethyl orthoacetate in presence of catalytic amount
of propionic acid gave the diethyl 3,4-bismethyleneadipate
8 as a major product. Reduction of compound 8 with LiAlH4
in dry THF gave the corresponding diol 9 in 62% isolated
yield. Initially, when the reaction was quenched with ethyl
acetate, diacetoxy derivative 10 (60%) was obtained as the
sole product. Later on, the diacetoxy derivative 10 was
hydrolyzed to diol 9 (88%) using KOH/MeOH conditions
(Scheme 2).
To expand the building block approach that provides
various unusual AAAs via Diels±Alder strategy, it is
desirable to develop new methods for the preparation of
various dienes containing AAA moiety. During the course
of our investigations, few conjugate dienes (1±4, Fig. 1)
embodying AAA unit appeared in the literature.4±7 Unfortu-
nately there is not much information available about
Diels±Alder chemistry of these dienes. Nevertheless, the
Diels±Alder reaction of these dienes (except 4) will not
provide cyclic aaAAs, however they can be employed for
the synthesis of various phenylalanine (Phe) or phenyl-
glycine (with 3) analogs (Fig. 1).
Attempts to convert the diol 9 to the corresponding di-
bromide under PBr3/ether conditions10 were not successful.
Consequently, the reaction of diol 9 with tosyl chloride in
2. Strategy
In order to extend the Diels±Alder methodology towards the
synthesis of benzocycloheptene derived AAA derivatives,
the seven-membered diene building block 5 synthesis was
undertaken. The [412] cycloaddition reaction of exocyclic
diene 5 with suitable dienophiles followed by oxidation is
Keywords: amino acids and derivatives; cycloadditions; dienes; Diels±
Alder reaction drugs.
p
Corresponding author. Fax: 191-22-572 3480;
e-mail: srk@chem.iitb.ac.in
Figure 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00575-0

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S. Kotha et al. / Tetrahedron 57 (2001) 6261±6265
Scheme 1.
hydrolyzed to the corresponding amino ester 15 using conc.
HCl in absolute ethanol. The amino ester 15 was further
converted to the N-acetyl derivative 5 in 67% yield by
using acetic anhydride in dichloromethane (Scheme 3).
The dienes in this series (9, 12, 14, 15 and 5) were found to
be unstable and can be stored in presence of catalytic
amount of hydroquinone at low temperature. Diene 5 was
treated with the various dienophiles in re¯uxing benzene
and the resulting adducts were subjected to DDQ oxidation
to give the benzocycloheptene derived AAAs in good yields
(16±18, Table 1). Since the Diels±Alder adducts in these
cases are contaminated with the corresponding aromatized
products as indicated by the 1H NMR spectral data, we did
not made any special attempts to isolate the adducts (Table
1).
Scheme 2. (i) HCC(OEt)3, AcOH, DMF, mW; (ii) LiAlH4, THF, rt;
(iii) TsCl, pyridine, 08C; (iv) Nal, acetone, 708C; (v) (1) LiAlH4, THF,
(2) EtOAc, rt; (vi) KOH, MeOH, rt.
presence of pyridine gave the ditosylate 11 in 74% yield11
which, upon reaction with NaI in acetone at re¯ux, gave the
corresponding diiodide 12 (Scheme 2). The diiodide 12 can
be puri®ed by silica gel column chromatography and used
within a couple of days. It was usually stored at low
temperature in diethyl ether solvent. Thus, bis-alkylation
of ethyl isocyanoacetate 13 with diiodide 12 under phase
transfer catalysis (PTC) conditions gave the required
coupling product 14 (Scheme 3). Since the isonitrile
derivative 14 was found to be unstable, it was immediately
4. Conclusions
To conclude, a new and general synthetic methodology was
developed for the synthesis of linearly substituted benzo-
cycloheptene-based aaAA derivatives. The aaAA deriva-
tives prepared here may not be accessible by any other
conventional methods such as Bucherer Burg method.12
Scheme 3. (i) K2CO3, Bu4NHSO4, CH3CN, 708C; (ii) HCl, EtOH; (iii) Ac2O, CH2Cl2, rt.
Table 1. Synthesis of benzocycloheptene-based a-amino acid derivatives via [412] cycloaddition strategy using diene 5
a
Yields refers to combined isolated yields for both the Diels±Alder and DDQ products.
Tsˆp-toluene sulfonyl.
b

S. Kotha et al. / Tetrahedron 57 (2001) 6261±6265
6263
5. Experimental
The reaction mixture was stirred at rt for 3 h and then
poured into ice cold water (5 ml). The aqueous solution
was extracted with ethyl acetate and the combined organic
extract was washed with water, brine and dried over MgSO4.
Evaporation of the solvent furnished the ditosylate 11
(1.13 g, 74%) as a crystalline solid. Mp, 99±1008C. Rf
(35% EtOAc/hexane) 0.32. IR: (KBr) nmax 3012,
5.1. General
Dry diethyl ether, tetrahydrofuran, benzene and toluene
were obtained by distilling over benzophenone ketyl.
Chloroform, dichloromethane, and acetonitrile were
distilled over phosporus pentoxide. Ethyl isocyanoacetate
and DDQ were purchased from Aldrich Chemical Co.
LiAlH4 was obtained from Fluka.
1
1598 cm21. H NMR (300 MHz, CDCl3): d 2.45 (s, 6H,),
2.56 (t, Jˆ7.1 Hz, 4H), 4.06 (t, Jˆ7.1 Hz, 4H), 4.96 (s, 2H),
5.08 (s, 2H), 7.34 (d, Jˆ8.4 Hz, 4H), 7.77 (d, Jˆ8.4 Hz,
4H). 13C NMR (75.43 MHz, CDCl3): d 21.1, 32.8, 68.2,
114.8, 127.3, 129.3, 132.5, 140.1, 144.3.
Precaution. Ethyl isocyanoacetate and electrophiles used in
this study are lacrymators and irritants and must be handled
with proper care. Some of them are also potent mutagens.
5.1.4. 3,4-Bismethylene-1,6-diiodohexane (12). To a
stirred solution of ditosylate 11 (1 g, 2.2 mmol) in acetone
(50 ml) was added sodium iodide (1.97 g, 14 mmol) and the
reaction mixture was heated at 708C for 8 h. The reaction
mixture was cooled and the solvent was evaporated on
rotary evaporator at reduced pressure. The residue was
dissolved in water and then extracted with ethyl acetate.
The combined organic extracts were washed with aq.
sodium thiosulfate solution, water, brine and then dried
over MgSO4. Evaporation of the solvent and puri®cation
of the crude product by a silica gel column using ethyl
acetate/hexane (1:49) as an eluent furnished the diiodide
12 (757 mg, 99%) as a light yellow liquid. IR (neat): nmax
5.1.1. 3,4-Bismethylene-1,6-hexanediol (9). A pre-dried
three-neck RB ¯ask (250 ml) equipped with an additional
funnel was charged with diethyl ester 88 (1.5 g, 6.6 mmol) in
dry THF (10 ml). A stirred suspension of LiAlH4 (1.7 g,
44.8 mmol) in dry THF (40 ml) was transferred to the
additional funnel with the aid of double ended needle
under N2 pressure, then slowly added to a stirred solution
of the reaction mixture over a period of 30 min at rt under N2
atmosphere. The reaction mixture was then stirred at rt for
4 h. The reaction mixture was very cautiously poured into
ice-cold water (40 ml) and extracted with ethyl acetate
(100 ml). The combined organic extract was washed with
2 M HCl, water, brine and then dried over MgSO4. Evapo-
ration of the solvent and puri®cation of the crude product by
a silica gel column using ethyl acetate/hexane (1:3) as an
eluent gave diol 9 (590 mg, 62%) as a colorless liquid. IR
(neat): nmax 3345, 1635 cm21. Rf (50% EtOAc/hexane)
1
3012, 1590, 890 cm21. Rf (10% EtOAc/hexane) 0.58. H
NMR (300 MHz, CDCl3): d 2.81 (t, Jˆ7.8 Hz, 4H), 3.26
(t, Jˆ7.8 Hz, 4H), 5.06 (s 2H), 5.18 (s, 2H). 13C NMR
(75.43 MHz, CDCl3): d 4.06, 38.5, 114.4, 144.6.
5.1.5. Ethyl 4,5-dimethylene-1-isocyanocylohepta-1-car-
boxylate (14). A heterogeneous solution of diiodide 12
(494 mg, 1.365 mmol), ethyl isocyanoacetate 13 (153 mg,
1.36 mmol), potassium carbonate (1.5 g, 10.9 mmol) and
tetrabutylammonium hydrogensulfate (91 mg, 0.2 mmol)
in dry acetonitrile (60 ml) was re¯uxed for 3.5 days. The
reaction mixture was cooled and the solid material was
®ltered off. The ®ltrate was evaporated at reduced pressure
and the residue left was dissolved in ether (120 ml) and
washed with water, brine and then dried over MgSO4.
Evaporation of the solvent and puri®cation of the crude
product by a silica gel column using ethyl acetate/hexane
(1:40) as an eluent gave ®rst unreacted starting material 12
(50 mg). Further elution of the column furnished the iso-
nitrile derivative 14 (107 mg, 36%), as a light brown liquid
(40% based on the recovered starting material).
1
0.301. H NMR (300 MHz, CDCl3): d 2.54 (br s, 2H),
2.56 (t, Jˆ6.2 Hz, 4H) 3.73 (t, Jˆ6.2 Hz, 4H), 5.09 (s,
2H), 5.18 (s, 2H). 13C NMR (75.43 MHz, CDCl3): d 37.6,
61.2, 114.5, 143.8. MS: m/e 142 (M1).
In a separate experiment, when the reaction mixture was
quenched with ethyl acetate, diacetoxy derivative 10 was
obtained in 60% yield as a light yellow liquid, which
was again converted to diol 9 as described in the following
experiment. IR (neat): nmax 1740, 1598, 1456 cm21. Rf (30%
EtOAc/hexane) 0.40 1H NMR (300 MHz, CDCl3): d 2.04 (s,
6H), 2.60 (t, Jˆ7.1 Hz, 4H), 4.16 (t, Jˆ7.1 Hz, 4H), 5.06 (s,
2H) 5.21 (s, 2H). 13C NMR (75.43 MHz, CDCl3): 20.9, 33.3,
63.3, 114.3, 142.8, 171.0. MS: m/e 226 (M1).
5.1.2. Hydrolysis of diacetoxy derivative (10) to diol (9).
To a solution of 10 (55 mg, 0.24 mmol) in methanol (5 ml)
was added ®nely grounded KOH (32 mg, 0.6 mmol) at rt.
The reaction mixture was allowed to stir at rt for 30 min.
The solvent was evaporated at reduced pressure and the
residue was dissolved in water and extracted with ether.
The combined ether extract was washed with water, brine
and then dried over MgSO4 Evaporation of the solvent gave
IR (neat): nmax, 2137, 1735, 3105 cm21 Rf (10% EtOAc/
1
hexane) 0.50. H NMR (300 MHz, CDCl3): d 1.29 (t, Jˆ
7.2 Hz, 3H), 1.92 (m, 2H), 2.16 (dd, Jˆ6.8, 14.0 Hz, 2H)
2.40 (dd, Jˆ6.8, 14.0 Hz, 2H), 2.60 (m, 2H), 4.23 (q, Jˆ
7.2 Hz 2H), 4.81 (s, 2H), 5.22 (s, 2H). 13C NMR
(75.43 MHz, CDCl3): d 13.9, 29.5, 37.7, 62.7, 67.7, 111.7,
131.2, 148.3, 162.3.
1
diol 9 as a colorless liquid (30 mg, 88%) whose IR and H
5.1.6. Hydrolysis of the isonitrile derivative (14) to amino
ester (15). A solution of 14 (80 mg, 0.36 mmol) in absolute
ethanol (5 ml) was added conc. HCl (5 drops) at 08C and the
reaction mixture was stirred at rt for 1 h. Then the solvent
was evaporated and the residue was dissolved in water
(5 ml). The acidic aq. solution was basi®ed by addition of
ammonia solution. Then it was extracted with ethyl acetate.
NMR spectral data were found to be identical to that of the
material obtained in the experiment where the LiAlH4
reaction was quenched carefully with water.
5.1.3. Conversion of the diol (9) to ditosylate (11). To a
stirred solution of 9 (490 mg, 4.6 mmol) in pyridine (5 ml)
was added TsCl (1.21 g, 6.9 mmol) in ®ve portions at 08C.

6264
S. Kotha et al. / Tetrahedron 57 (2001) 6261±6265
The combined organic extract was washed with water, brine
and then dried over MgSO4. Evaporation of the solvent gave
pure amino ester 15 (72 mg, 95%) as a colorless liquid
which was used in subsequent protection step without
further puri®cation. Rf (40% EtOAc/hexane) 0.50.
7.63±7.68 (m, 2H), 7.81 (1/2 ABq, Jˆ8.0 Hz, 2H). FAB-
MS: m/e 431 (M1). HRMS (EI) m/z for C20H18SO5
(M2C2H5NO) Calcd: 346.1205; Found: 346.1195.
5.1.10. Ethyl 4-acetamido-2,3,6,5-tetrahydro-8H-cyclo-
hepta[b]-8,13-anthroquinone-4-carboxylate (18).
A
solution of diene 5 (8.5 mg, 0.03 mmol) and 1,4-naphtho-
quinone (5.3 mg, 0.03 mmol) in dry benzene (5 ml) was
re¯uxed for 5 days. Then, the solvent was evaporated and
the crude product was puri®ed by a silica gel column using
ethyl acetate/hexane (2:3) as an eluent to furnish cyclo-
adduct (13.7 mg, 99%) as a light yellow solid. Mp, 258±
2608C. The above Diels±Alder adduct (11 mg, 0.02 mmol)
and DDQ (12.2 mg, 0.05 mmol) was re¯uxed in dry ben-
zene for 48 h. Evaporation of the solvent and puri®cation of
the crude product by a neutral alumina column using ethyl
acetate/hexane (2:3) as an eluent gave aromatized product
18 (8.1 mg, 75%) as a yellow solid. Mp, 255±2578C. UV
(CHCl3): lmax ([M21 cm21) 261 (15,000) nm. IR (KBr):
nmax 3305, 1736, 1671 cm21. Rf (80% EtOAc/hexane) 0.38
1H NMR (300 MHz, CDCl3): d 1.25 (t, Jˆ7.3 Hz, 3H), 2.08
(s, 3H), 2.01±2.17 (m, 2H), 2.28±2.40 (m, 2H), 2.95±3.12
(m, 4H), 4.19 (q, Jˆ7.1 Hz, 2H), 5.72 (s, 1H), 7.79 (dd, Jˆ
5.6, 3.3 Hz, 2H), 8.04 (s, 2H), 8.29 (dd, Jˆ5.6, 3.4 Hz, 2H).
FAB-MS: m/e 409 (M1). HRMS (EI) m/z for C21H15O5
(M2C2H5NO) Calcd: 346.1195; Found: 346.1205.
5.1.7. Ethyl 1-acetamido-3,4-dimethylenecyclohepta-1-
carboxylate (5). A solution of the amino ester 15 (50 mg,
0.24 mmol), acetic anhydride (50 mg, 0.5 mmol) and
DMAP (10 mg) in dichloromethane (5 ml) was stirred at rt
for 1 h. The solvent was evaporated and the crude material
was directly charged on a silica gel column. Elution of the
column with ethyl acetate/hexane (1:9) mixture gave the
acetyl derivative 5 (40 mg, 67%) as a white crystalline
solid. Mp, 68±698C. IR (neat): nmax 1740, 1648 cm21. Rf
1
(50% EtOAc/hexane) 0.50. H NMR (300 MHz, CDCl3):
d 1.24 (t, Jˆ7.1 Hz, 3H), 2.01 (s, 3H), 1.86±2.05 (m,
2H), 2.17±2.31 (s, 2H), 2.31±2.39 (m, 4H), 4.15 (q, Jˆ
7.1 Hz, 2H), 4.78 (d, Jˆ1.5 Hz, 2H), 5.18 (d, Jˆ1.5 Hz,
2H), 5.61 (s, 1H). 13C NMR (75.43 MHz, CDCl3): d 14.2,
23.4, 29.7, 35.8, 61.3, 61.8, 111.0, 149.5, 169.8, 173.8.
5.1.8. Ethyl 3-acetamido-7,8-dicarbomethoxybenzo-
cycloheptane-3-carboxylate (16). A solution of diene 5
(10 mg, 0.04 mmol) and DMAD (5.6 mg, 0.06 mmol) in
dry benzene (2 ml) was re¯uxed for 4 days. Then the solvent
was evaporated and the crude product was puri®ed by a
silica gel column using ethyl acetate/hexane (2:3) as an
eluent to give cycloadduct (15.6 mg, 99.9%) as a white
solid. Mp, 144±1458C. Subsequently the cycloadduct
(12 mg, 0.03 mmol) and DDQ (7 mg, 0.03 mmol) in dry
benzene (3 ml) was re¯uxed for 48 h. Then, the solvent
was evaporated and the crude product was puri®ed by a
neutral alumina column using ethyl acetate/hexane (2:3)
mixture as an eluent to give 16 (11.8 mg, 99%) as a white
sticky solid. UV (CHCl3): lmax ([M21 cm21) 248 (2500)
nm. IR (KBr): nmax 3296, 1730, 1660 cm21. Rf (75%
Acknowledgements
We thank the DST, New Delhi for the ®nancial support.
N. S. and E. B. thank CSIR, New Delhi for the award of
Fellowships. We also thank RSIC-Mumbai for recording the
spectral data.
References
1
EtOAc/hexane) 0.43. H NMR (300 MHz, CDCl3): d 1.24
(t, Jˆ7.1 Hz, 3H), 2.06 (s, 3H), 1.99±2.11 (m, 2H), 2.26±
2.33 (m, 2H), 2.77±3.00 (m, 4H), 3.89 (s, 6H), 4.15 (q, Jˆ
7.1 Hz, 2H), 5.72 (s, 1H), 7.47 (s, 2H). FAB-MS: m/e 391
(M1). HRMS (EI) m/z for C20H25NO7 Calcd: 391.1631;
Found: 391.1617.
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