Simple and facile synthesis of tetralone-spiro-glutarimides and spiro-bisglutarimides from Baylis-Hillman acetates

Article abstract of DOI:10.1039/b717843c

A simple and convenient synthesis of di(E)-arylidene-tetralone-spiro- glutarimides from Baylis-Hillman acetates via an interesting biscyclization strategy involving facile C-C and C-N bond formation is described. Also, one-pot multistep transformation of the Baylis-Hillman acetates into di(E)-arylidene-spiro-bisglutarimides is presented.

Full text of DOI:10.1039/b717843c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Simple and facile synthesis of tetralone-spiro-glutarimides and
spiro-bisglutarimides from Baylis–Hillman acetates†
Deevi Basavaiah* and Raju Jannapu Reddy
Received 19th November 2007, Accepted 3rd January 2008
First published as an Advance Article on the web 6th February 2008
DOI: 10.1039/b717843c
A simple and convenient synthesis of di(E)-arylidene-tetralone-spiro-glutarimides from Baylis–Hillman
acetates via an interesting biscyclization strategy involving facile C–C and C–N bond formation is
described. Also, one-pot multistep transformation of the Baylis–Hillman acetates into
di(E)-arylidene-spiro-bisglutarimides is presented.
we herein report a convenient synthesis of di(E)-arylidene-
Introduction
tetralone-spiro-glutarimides [di(E)-arylidene alonimids, II] via the
bisalkylation of benzyl cyanide with tert-butyl 3-acetoxy-3-aryl-2-
methylenepropanoates (acetates of Baylis–Hillman adducts) fol-
lowed by an interesting biscyclization strategy involving successive
C–C and C–N bond formation through an intramolecular Friedel–
Crafts reaction and hydrolysis of the nitrile group with subsequent
formation of a glutarimide ring. We also herein report one-
pot multistep transformation of the Baylis–Hillman acetates into
spiro-bisglutarimide derivatives.5
Tetralone and spiro-tetralone derivatives1 continue to occupy an
important place in organic and medicinal chemistry because of
the presence of this moiety in a number of natural products
such as palmarumycins1a–d (possess antifungal, antibacterial, and
herbicidal activites), humicolone1e (possesses cytotoxic activity),
daldinone A,1f and aristelegones A–C1g etc. The glutarimide
framework2 represents yet another important structural orga-
nization present in a number of bioactive molecules such as
thalidomide2a–c (sedative and hypnotic), migrastatin2d (antitumor),
sesbanimide2e (antitumor), aminoglutethimide2f (antineoplastic),
cinperene2g (antipsychotic and neuroleptic) and phenglutarimide2h
(antiparkinsonian and anticholinergic) etc. Recently, certain spiro-
glutarimides2i have been investigated for selective antagonists at
the a1d adrenergic receptor. It occurred to us that the development
of a simple and facile synthesis of an interesting and aestheti-
cally appealing spiro molecular architecture containing both the
tetralone framework and glutarimide structural unit linked by
an appropriate spiro bridge as in the case of alonimid (I), i.e.
[1,2,3,4-tetrahydronaphthalen-1-one]-4-spiro-3ꢀ-[piperidine-2ꢀ, 6ꢀ-
dione] (well known for sedative and hypnotic activities),3 would
certainly provide an easy access to the different derivatives of
alonimid (Fig. 1) and hence represents an attractive and challeng-
ing endeavor in organic and medicinal chemistry. In continuation
of our interest in developing simple and useful methodologies
for the synthesis of spiro and hetero/carbocyclic molecules,4
Results and discussion
In recent years, the Baylis–Hillman reaction6 has become a
powerful atom-economical carbon–carbon bond forming reaction
in organic chemistry because it provides a simple and facile
method for the synthesis of interesting classes of densely func-
tionalized molecules that have been used in a variety of inter-
esting organic transformation methodologies.4,6–8 We have been
working on the applications of Baylis–Hillman adducts4c,e–g,k,n,7s
and acetates4a,h,j,m,7r with a view to developing Baylis–Hillman
chemistry as a useful source for the synthesis of various structural
frameworks that ultimately would lead to the production of
important molecules of medicinal relevance. During our on-
going research program on the synthesis of spiromolecues,4b,d
it occurred to us that the carbon linking phenyl and nitrile
groups in benzyl cyanide would be easily projected as the
spiro-carbon, as the phenyl ring would be converted into the
tetralone moiety while the nitrile group would be transformed
into the glutarimide skeleton (Scheme 1). We also envisaged that
Baylis–Hillman (B–H) acetates i.e. tert-butyl 3-acetoxy-3-aryl-2-
methylenepropanoates, would serve as good alkylating agents for
bisalkylation of benzyl cyanide, as one of the ester groups in the
bisadduct (III) would be used for an intramolecular Friedel–Crafts
reaction while the other ester group would serve in the formation
of the glutarimide framework thus leading to the generation
of the spiro molecule with an appropriate substitution profile
(Scheme 1).
Fig. 1 Alonimid (I) and di(E)-arylidene alonimids (II).
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India.
E-mail: dbsc@uohyd.ernet.in; Fax: 91-40-23012460
† Electronic supplementary information (ESI) available: Representative
experimental procedures, with all spectral data of 2a–i, 3a–i and 4a–
e, crystal data and ORTEP diagrams of 2e, 3a, 3f and 4d. See DOI:
10.1039/b717843c
Accordingly, we first selected tert-butyl 3-acetoxy-2-methylene-
3-phenylpropanoate (1a) as an alkylating agent for bisalkylation
of benzyl cyanide. The best results were achieved when benzyl
cyanide (2 mmol) was treated with B–H acetate 1a (5 mmol)
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Scheme 1 Schematic representation of a retro-synthetic strategy for di(E)-arylidene alonimids.
Table 1 Synthesis of bisadducts (2a–i)a and di(E)-arylidene-tetralone-spiro-glutarimides (3a–i)b from B–H acetates (1a–i)
Entry
B–H acetate
Ar
Productc
Yieldd (%)
Productc
Yieldd (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
C6H5
2a
2b
2c
2d
2ee
2f
2g
2h
2i
73
81
80
78
72
70
65
66
63
3ae
3b
3c
3d
3e
3fe
3g
3h
3i
80
75
77
78
75
82
67
77
71
2-MeC6H4
4-MeC6H4
4-EtC6H4
4-(i-Pr)C6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
a All reactions were carried out on a 2 mmol scale of benzyl cyanide with 5 mmol of B–H acetate (1a–i) in the presence of excess NaH (10 mmol) in
anhydrous toluene under reflux for 1 h in N2 atm. b All reactions were carried out on a 0.5 mmol scale of bisadducts (2a–i) in 1,2-dichloroethane (DCE,
3 mL) with conc. H2SO4 (2.5 mmol) and TFAA (2.5 mmol) under reflux for 6 h. c All the products (2a–i and 3a–i) were obtained as colorless solids, and
fully characterized (see ESI†). d Isolated yields of the pure products 2a–i (based on benzyl cyanide) and 3a–i (based on bisadducts). e The structures of
these molecules were also established from the single crystal X-ray data (see Fig. 2 and 3 and ESI†,‡).10
in the presence of excess NaH (10 mmol) in anhydrous toluene
under reflux for 1 h to provide the desired bisadduct, di-tert-butyl
2,6-di[(E)-benzylidene]-4-cyano-4-phenyl-1,7-heptanedioate (2a)
in 73% isolated yield after column chromatography (silica gel, 5%
EtOAc in hexanes) followed by crystallization9 (from 3% EtOAc
in hexanes at 0 ◦C) (Scheme 2, Table 1 and entry 1). Subsequent
treatment of this bisadduct 2a (0.5 mmol) with conc. H2SO4
(2.5 mmol)–trifluoroacetic anhydride (TFAA) (2.5 mmol) in 1,2-
dichloroethane (DCE, 3 mL) under reflux for 6 h provided the
desired 2,5ꢀ-di[(E)-benzylidene]-[1,2,3,4-tetrahydronaphthalen-1-
one]-4-spiro-3ꢀ-[piperidine-2ꢀ,6ꢀ-dione] (3a) as a colorless solid in
80% isolated yield after column chromatography using silica gel
(30% EtOAc in hexanes) (Scheme 2, Table 1 and entry 1). This
result is indeed very interesting and encouraging in the sense that
the Baylis–Hillman acetate (1a) is transformed into 2,5ꢀ-di[(E)-
benzylidene] alonimid (3a) in two steps in 58% overall yield. We
then successfully extended this methodology to representative
B–H acetates (1b–i) to provide di(E)-arylidene alonimids (3b–
i) in good yields (Scheme 2, Table 1 and entries 2–9). In fact,
we obtained single crystals in the case of bisadduct 2e, di(E)-
arylidene alonimids 3a and 3f, and established the structures of
these molecules by single crystal X-ray data analyses (see Fig. 2
and 3 and ESI†,‡).10
After successfully developing a simple and convenient method-
ology for the synthesis of di(E)-arylidene alonimids, we directed
our attention towards the synthesis of spiro-bisglutarimides via
bisalkylation of malononitrile with tert-butyl 3-acetoxy-3-aryl-2-
methylenepropanoates, followed by the hydrolysis of nitrile groups
and subsequent cyclization in a one-pot operation (Scheme 3). In
this direction, we first selected tert-butyl 3-acetoxy-2-methylene-3-
phenylpropanoate (1a) as a substrate for bisalkylation. Thus, the
treatment of 1a (2 mmol) in acetonitrile (3 mL) with malononitrile
(1 mmol) in the presence of triethylamine (1 mmol) at room
temperature for 1 h provided the bisadduct, which, on subsequent
reaction (after removing acetonitrile and triethylamine under
reduced pressure) with conc. H2SO4 (2 mmol) and TFAA (2 mmol)
(addition at 0 ◦C) at room temperature for 24 h in dichloromethane
‡ CCDC reference numbers 656194–656197. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b717843c
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Fig. 2 ORTEP diagrams (50% probability) of compounds (a) 2e and (b) 3a (hydrogen atoms are omitted for clarity).
Fig. 3 ORTEP diagrams (50% probability) of compounds (a) 3f and (b) 4d (hydrogen atoms are omitted for clarity).
Scheme 2 Synthesis of di(E)-arylidene-tetralone-spiro-glutarimides [di(E)-arylidene alonimids].
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Table 2 One-pot multistep synthesis of di(E)-arylidene-spiro-bisglutarimides (4a–e)a from B–H acetates (1a–d, f)
Entry
B–H acetate
Ar
Productb
Yieldc (%)
1
2
3
4
5
1a
1b
1c
1d
1f
C6H5
4a
4b
4c
75
56
64
59
55
2-MeC6H4
4-MeC6H4
4-EtC6H4
2-ClC6H4
4dd
4e
a All reactions were carried out on a 1 mmol scale of malononitrile with 2 mmol of B–H acetate (1a–d, f) in the presence of Et3N in acetonitrile at room
temperature for 1 h and then subsequent treatment with conc. H2SO4 (2 mmol)–TFAA (2 mmol) in dichloromethane (5 mL) at room temperature for
24 h. b All the pure products 4a–e were obtained as colorless solids [with (E)-stereochemistry as evidenced by the 1H NMR spectral analysis and also in
analogy with that of 4d] and fully characterized (see ESI†). c Yields of the pure products based on B–H acetates. d The structure of this molecule [with
(E)-stereochemistry] was also established from the single crystal X-ray data (see Fig. 3 and ESI†,‡).10
Scheme 3 One-pot multistep synthesis of di(E)-arylidene-spiro-bisglutarimides.
(5 mL) followed by usual work-up, provided the desired 3,3ꢀ-spiro-
bis[5-{(E)-benzylidene}piperidine-2,6-dione] (4a) in 75% yield
(Scheme 3, Table 2 and entry 1).
With a view to understanding the generality of this method-
ology, we extended this strategy to the Baylis–Hillman acetates
(1b–d, f), which provided the resulting spiro-bisglutarimides (4b–
e) in moderate to good yields in an operationally simple one-pot
procedure (Scheme 3, Table 2 and entries 2–5). In fact, we obtained
a single crystal for compound 4d and established the structure of
this molecule by single crystal X-ray data (see Fig. 3 and ESI‡).10
of di(E)-arylidene-tetralone-spiro-glutarimides [di(E)-arylidene
alonimids] and also described a one-pot multistep synthesis
of di(E)-arylidene-spiro-bisglutarimides from Baylis–Hillman ac-
etates (tert-butyl 3-acetoxy-3-aryl-2-methylenepropanoates).
Experimental
General methods
Melting points were recorded on a Superfit (India) capillary
melting point apparatus and are uncorrected. IR spectra were
recorded on a JASCO-FT-IR model 5300 spectrometer using solid
samples as KBr plates. 1H NMR (400 MHz) and 13C NMR (50/
100 MHz) spectra were recorded in deuterochloroform (CDCl3)
or deuterodimethyl sulfoxide (DMSO-d6) or in deuterochloroform
Conclusions
In conclusion, we have successfully developed a convenient
and operationally simple two-step procedure for the synthesis
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(CDCl3) containing deuterodimethyl sulfoxide (DMSO-d6), on
a Bruker-AVANCE-400 and Bruker-AC-200 spectrometer using
tetramethylsilane (TMS, d = 0) as an internal standard. Elemental
analyses were recorded on a Thermo-Finnigan Flash EA 1112
analyzer. Mass spectra were recorded on a Shimadzu-LCMS-2010
A mass spectrometer. The X-ray diffraction measurements were
carried out at 298 K on a Bruker SMART APEX CCD area
detector system equipped with a graphite monochromator and a
Found: C, 80.27; H, 5.00; N, 3.35%; Crystal data for 3a: empirical
formula, C28H21NO3; formula weight, 419.46; crystal color, habit:
colorless, block; crystal dimensions, 0.44 × 0.28 × 0.22 mm3; crys-
tal system, monoclinic; lattice type, primitive; lattice parameters,
˚
˚
˚
a = 9.0369(18) A, b = 25.751(5) A, c = 9.2740(18) A; a = 90.00;
3
˚
b = 96.108(3); c = 90.00; V = 2145.9(7) A ; space group, P21/n
(International Table No. 14); Z = 4; Dcalcd = 1.298 g cm−3; F000
=
2
˚
880; k(Mo-Ka) = 0.71073 A; R (I ≥ 2r1) = 0.0427; wR = 0.1031.‡
˚
Mo-Ka fine-focus sealed tube (k = 0.71073 A).
3,3ꢀ-Spiro-bis[5-{(E)-benzylidene}piperidine-2,6-dione]
(4a).
Di-tert-butyl 2,6-di[(E)-benzylidene]-4-cyano-4-phenyl-1,7-hep-
tanedioate (2a). To a stirred suspension of oil-free excess NaH
(10 mmol, 0.24 g) in anhydrous toluene were added benzyl
cyanide (2 mmol, 0.234 g) and tert-butyl 3-acetoxy-2-methylene-
3-phenylpropanoate (1a) (5 mmol, 1.38 g) at room temperature,
and the mixture was heated under reflux for 1 h under a N2
atmosphere. Then the reaction mixture was allowed to come
to room temperature and was cooled to 0 ◦C. Excess NaH
was carefully quenched with the very slow addition of water at
0 ◦C. The reaction mixture was extracted with ether (3 × 30 mL).
The combined organic layer was dried over anhydrous Na2SO4
and the solvent was evaporated. The residue, thus obtained, was
purified by column chromatography (5% ethyl acetate in hexanes)
followed by crystallization (from 3% ethyl acetate in hexanes at
To
a stirred solution of tert-butyl 3-acetoxy-2-methylene-
3-phenylpropanoate (1a) (2 mmol, 0.552 g) in acetonitrile
(3 mL) were added malononitrile (1 mmol, 0.066 g, 0.06 mL)
and triethylamine (1 mmol, 0.131 mL). After stirring at room
temperature for 1 h, solvent acetonitrile and Et3N were evaporated
under reduced pressure. The resulting residue was diluted with
◦
dichloromethane (5 mL) and cooled to 0 C. To this solution at
0 ◦C, conc. H2SO4 (2 mmol, 0.192 g, 0.10 mL) and trifluoroacetic
anhydride (TFAA, 2 mmol, 0.42 g, 0.28 mL) were added. Then
the reaction mixture was allowed to warm to room temperature.
After stirring for 24 h at room temperature, the reaction mixture
was poured into aqueous K2CO3 solution. The solid separated
was filtered and well washed with water followed by ethyl acetate.
Thus the obtained solid was dried in vacuo to provide pure
3,3ꢀ-spiro-bis[5-{(E)-benzylidene}piperidine-2,6-dione] (4a) as a
colorless solid in 75% (0.289 g) yield; mp: 255 ◦C (dec.); IR (KBr):
0
◦C) to afford di-tert-butyl 2,6-di[(E)-benzylidene]-4-cyano-4-
phenyl-1,7-heptaned◦ioate (2a), as a colorless solid in 73% (0.80 g)
yield; mp: 118–120 C; IR (KBr): m 2235, 1711, 1635 cm−1 1H
1
m 3200–2830 (multiple bands), 1711, 1680, 1610 cm−1; H NMR
;
NMR (400 MHz, CDCl3): d 1.44 (s, 18H), 3.09 and 3.34 (ABq,
4H, J = 13.6 Hz), 6.98–7.38 (m, 15H), 7.62 (s, 2H); 13C NMR
(50 MHz, CDCl3): d 28.00, 35.95, 48.28, 81.34, 120.39, 126.53,
127.50, 128.04, 128.16, 128.42, 128.84, 130.27, 135.60, 137.54,
142.01, 166.94; LCMS (m/z): 548 (M − H)−; Anal. Calcd. for
C36H39NO4: C, 78.66; H, 7.15; N, 2.55; Found: C, 78.67; H, 7.11;
N, 2.64%.
(400 MHz, 50% DMSO-d6 in CDCl3): d 2.86 and 3.34 (ABq, 4H,
J = 15.2 Hz), 7.19–7.41 (m, 10H), 7.72 (s, 2H), 11.08 (br s, 2H);
13C NMR (100 MHz, DMSO-d6): d 31.02, 50.84, 125.59, 128.88,
129.34, 129.87, 134.34, 138.90, 165.97, 170.54; LCMS (m/z): 387
(M + H)+; Anal. Calcd. for C23H18N2O4: C, 71.49; H, 4.70; N,
7.25; Found: C, 71.33; H, 4.71; N, 7.17%.
Acknowledgements
2,5ꢀ -Di[(E)-benzylidene]-[1,2,3,4-tetrahydronaphthalen-1-one]-
4-spiro-3ꢀ-[piperidine-2ꢀ,6ꢀ-dione] (3a). To
a stirred solution
We thank DST (New Delhi) for funding this project. We also thank
UGC (New Delhi) for providing some instrumental facilities. RJR
thanks CSIR (New Delhi) for his research fellowship. We also
thank the National Single Crystal X-ray Facility in our School
of Chemistry funded by the DST (New Delhi). We thank Prof.
S. Pal, School of Chemistry, University of Hyderabad for helpful
discussions regarding the X-ray crystal structures.
of di-tert-butyl 2,6-di[(E)-benzylidene]-4-cyano-4-phenyl-1,7-
heptanedioate (2a) (0.5 mmol, 0.275 g) in 1,2-dichloroethane
(DCE, 3 mL) were added conc. H2SO4 (2.5 mmol, 0.245 g,
0.13 mL) and trifluoroacetic anhydride (TFAA, 2.5 mmol, 0.525 g,
0.35 mL) at room temperature. The reaction mixture was heated
under reflux for 6 h and was then allowed to cool to room
temperature. The reaction mixture was poured into aqueous
K2CO3 solution and extracted with EtOAc (3 × 25 mL). The
combined organic layer was dried over anhydrous Na2SO4. The
solvent was evaporated and the residue thus obtained was purified
by column chromatography (30% ethyl acetate in hexanes) to
provide 2,5ꢀ-di[(E)-benzylidene]-[1,2,3,4-tetrahydronaphthalen-1-
one]-4-spiro-3ꢀ-[piperidine-2ꢀ,6ꢀ-dione] (3a) as a colorless solid in
80% (0.168 g) yield; mp: 184–186 ◦C; IR (KBr): m 3300–2800 (mul-
Notes and references
1 (a) P. Jiao, D. C. Swenson, J. B. Gloer, J. Campbell and C. A. Shearer,
J. Nat. Prod., 2006, 69, 1667; (b) A. G. M. Barrett, F. Blaney, A. D.
Campbell, D. Hamprecht, T. Meyer, A. J. P. White, D. Witty and D. J.
Williams, J. Org. Chem., 2002, 67, 2735; (c) P. Wipf, J.-K. Jung, S.
Rodriguez and J. S. Lazo, Tetrahedron, 2001, 57, 283; (d) J. P. Ragot,
M.-L. Alcaraz and R. J. K. Taylor, Tetrahedron Lett., 1998, 39, 4921;
(e) D. Laurent, G. Guella, I. Mancini, M.-F. Roquebert, F. Farinole and
F. Pietra, Tetrahedron, 2002, 58, 9163; (f) D. N. Quang, T. Hashimoto,
M. Tanaka, M. Baumgartner, M. Stadler and Y. Asakawa, J. Nat. Prod.,
2002, 65, 1869; (g) T.-S. Wu, Y.-L. Tsai, A. G. Damu, P.-C. Kuo and
P. -L. Wu, J. Nat. Prod., 2002, 65, 1522.
2 (a) T. Yamada, T. Okada, K. Sakaguchi, Y. Ohfune, H. Ueki and V. A.
Soloshonok, Org. Lett., 2006, 8, 5625; (b) S. M. Capitosti, T. P. Hansen
and M. L. Brown, Org. Lett., 2003, 5, 2865; (c) Z. Xiao, K. Schaefer,
S. Firestine and P.-K. Li, J. Comb. Chem., 2002, 4, 149; (d) C. Gaul,
J. T. Njardarson, D. Shan, D. C. Dorn, K.-D. Wu, W. P. Tong, X.-Y.
Huang, M. A. S. Moore and S. J. Danishefsky, J. Am. Chem. Soc.,
2004, 126, 11326; (e) P. A. Grieco, K. J. Henry, J. J. Nunes and J. E.
1
tiple bands), 1711, 1693, 1651, 1624 cm−1; H NMR (400 MHz,
CDCl3): d 3.08 (s, 2H), 3.38 and 3.48 (ABq, 2H, J = 14.8 Hz), 6.88
(d, 2H, J = 6.6 Hz), 7.13–7.41 (m, 9H), 7.43–7.51 (m, 1H), 7.53–
7.62 (m, 1H), 7.72 (s, 1H), 7.85 (s, 1H), 8.20 (d, 1H, J = 7.2 Hz),
8.68 (s, 1H, D2O exchangeable); 13C NMR (100 MHz, CDCl3): d
35.23, 36.15, 48.25, 124.07, 126.64, 128.64, 128.67, 129.10, 129.17,
129.42, 129.55, 129.74, 129.87, 132.58, 133.63, 133.90, 134.60,
140.29, 142.49, 166.30, 174.45, 185.72; LCMS (m/z): 420 (M +
H)+; Anal. Calcd. for C28H21NO3: C, 80.17; H, 5.05; N, 3.34;
1038 | Org. Biomol. Chem., 2008, 6, 1034–1039
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Matt, Jr, J. Chem. Soc., Chem. Commun., 1992, 368; (f) Dictionary of
Drugs, ed. J. Elks and C. R. Ganellin, Chapman and Hall, London,
1st edn, 1990, p. 70 (A-00305); (g) Dictionary of Drugs, ed. J. Elks
and C. R. Ganellin, Chapman and Hall, London, 1st edn, 1990, p.
281 (C-00380); (h) Dictionary of Drugs, ed. J. Elks and C. R. Ganellin,
Chapman and Hall, London, 1st edn, 1990, p. 960 (P-00155); (i) A.
Leonardi, D. Barlocco, F. Montesano, G. Cignarella, G. Motta, R.
Testa, E. Poggesi, M. Seeber, P. G. De Benedetti and F. Fanelli, J. Med.
Chem., 2004, 47, 1900.
3 (a) Dictionary of Drugs, ed., J. Elks and C. R. Ganellin, Chapman
and Hall, London, 1st edn, 1990, p. 32 (A-00142); (b) A. A. Carr and
D. R. Meyer, Ger. Pat. 1971, 2,035,636, Chem. Abstr. 1971, 74, 99895h;
(c) For synthesis of alonimid from c-cyano-c-phenylpimelonitrile: C. F.
Koelsch, J. Org. Chem., 1960, 25, 164.
4 (a) D. Basavaiah and K. Aravindu, Org. Lett., 2007, 9, 2453; (b) D.
Basavaiah and K. R. Reddy, Org. Lett., 2007, 9, 57; (c) D. Basavaiah,
R. J. Reddy and J. Srivardhana Rao, Tetrahedron Lett., 2006, 47, 73;
(d) D. Basavaiah, J. Srivardhana Rao, R. J. Reddy and A. J. Rao, Chem.
Commun., 2005, 2621; (e) D. Basavaiah, J. Srivardhana Rao and R. J.
Reddy, J. Org. Chem., 2004, 69, 7379; (f) D. Basavaiah, D. S. Sharada
and A. Veerendhar, Tetrahedron Lett., 2004, 45, 3081; (g) D. Basavaiah
and T. Satyanarayana, Chem. Commun., 2004, 32; (h) D. Basavaiah and
J. Srivardhana Rao, Tetrahedron Lett., 2004, 45, 1621; (i) D. Basavaiah
and A. J. Rao, Chem. Commun., 2003, 604; (j) D. Basavaiah and T.
Satyanarayana, Tetrahedron Lett., 2002, 43, 4301; (k) D. Basavaiah,
R. M. Reddy, N. Kumaragurubaran and D. S. Sharada, Tetrahedron,
2002, 58, 3693; (l) D. Basavaiah, B. Sreenivasulu and J. Srivardhana
Rao, Tetrahedron Lett., 2001, 42, 1147; (m) D. Basavaiah and T.
Satyanarayana, Org. Lett., 2001, 3, 3619; (n) D. Basavaiah and R. M.
Reddy, Tetrahedron Lett., 2001, 42, 3025.
5 Spiro-bisglutarimides are known in the literature. They are prepared
via the reaction of N-phenethylacrylamide with dimethyl malonate
followed by cyclization: J. B. Popovic-Dordevic, M. D. Ivanovic
and V. D. Kiricojevic, Tetrahedron Lett., 2005, 46, 2611; and also via
the reaction of malononitrile with ethyl acrylate or methyl methacrylate
followed by cyclization: P. Victory and D. Jose, Afinidad, 1978, 35, 161;
Chem. Abstr., 1978, 89, 179515j. The Baylis–Hillman acetates were
used for the preparation of glutarimides:(a) V. Singh, G. P. Yadav,
P. R. Maulik and S. Batra, Tetrahedron, 2006, 62, 8731; (b) C.-Y. Chen,
M.-Y. Chang, R.-T. Hsu, S.-T. Chen and N.-C. Chang, Tetrahedron
Lett., 2003, 44, 8627. However, applications of the Baylis–Hillman
adducts/acetates for the preparation of spiro-bisglutarimides are not
known in the literature.
Rev., 2003, 103, 811; (c) E. Ciganek, Org. React., 1997, 51, 201; (d) D.
Basavaiah, P. Dharmarao and R. Suguna Hyma, Tetrahedron, 1996,
52, 8001; (e) S. E. Drewes and G. H. P. Roos, Tetrahedron, 1988, 44,
4653.
7 (a) N. Utsumi, H. Zhang, F. Tanaka and C. F. Barbas III, Angew.
Chem., Int. Ed., 2007, 46, 1878; (b) E. L. Myers, J. G. de Vries and V. K.
Aggarwal, Angew. Chem., Int. Ed., 2007, 46, 1; (c) F. Douelle, A. S.
Capes and M. F. Greaney, Org. Lett., 2007, 9, 1931; (d) A. Nakano,
K. Takahashi, J. Ishihara and S. Hatakeyama, Org. Lett., 2006, 8,
5357; (e) I. Deb, M. Dadwal, S. M. Mobin and I. N. N. Namboothiri,
Org. Lett., 2006, 8, 1201; (f) M. E. Krafft and J. A. Wright, Chem.
Commun., 2006, 2977; (g) L. Navarre, S. Darses and J.-P. Genet, Adv.
Synth. Catal., 2006, 348, 317; (h) S. A. Rodgen and S. E. Schaus, Angew.
Chem., Int. Ed., 2006, 45, 4929; (i) J. Srivardhana Rao, J.-F. Briere, P.
Metzner and D. Basavaiah, Tetrahedron Lett., 2006, 47, 3553; (j) M.
Shi, L.-H. Chen and C.-Q. Li, J. Am. Chem. Soc., 2005, 127, 3790;
(k) K. Matsui, S. Takizawa and H. Sasai, J. Am. Chem. Soc., 2005, 127,
3680; (l) T. Turki, J. Villieras and H. Amri, Tetrahedron Lett., 2005, 46,
3071; (m) T. Kataoka and H. Kinoshita, Eur. J. Org. Chem., 2005, 45;
(n) L. S. Santos, C. H. Pavam, W. P. Almeida, F. Coelho and M. N.
Eberlin, Angew. Chem., Int. Ed., 2004, 43, 4330; (o) S. Luo, X. Mi,
H. Xu, P. G. Wang and J.-P. Cheng, J. Org. Chem., 2004, 69, 8413;
(p) D. Basavaiah, B. Sreenivasulu and A. J. Rao, J. Org. Chem., 2003,
68, 5983; (q) C. Yu and L. Hu, J. Org. Chem., 2002, 67, 219; (r) D.
Basavaiah, K. Muthukumaran and B. Sreenivasulu, Synthesis, 2000,
545; (s) D. Basavaiah and S. Pandiaraju, Tetrahedron Lett., 1995, 36,
757.
8 For recent applications of B–H acetates, see: (a) Z. Shafiq, L. Liu,
D. Wang and Y. J. Chen, Org. Lett., 2007, 9, 2525; (b) S. J. Kim,
H. S. Lee and J. N. Kim, Tetrahedron Lett., 2007, 48, 1069; (c) P. V.
Ramachandran, S. Madhi, L. Bland-Berry, M. V. R. Reddy and M. J.
O’Donnell, J. Am. Chem. Soc., 2005, 127, 13450; (d) G. W. Kabalka,
G. Dong, B. Venkataiah and C. Chen, J. Org. Chem., 2005, 70, 9207;
(e) W. P. Hong, H. N. Lim, H. W. Park and K.-J. Lee, Bull. Korean
Chem. Soc., 2005, 26, 655; (f) C.-W. Cho and M. J. Krische, Angew.
Chem., Int. Ed., 2004, 43, 6689.
9 The crude product 2a contains 8% (Z)-isomer, as indicated by the 1H
NMR spectral analysis. In the case of 2c–i, crude compounds show the
presence of 5–14% (Z)-isomer. However, crystallization provides pure
(E)-isomers. In the case of 2b, 1H NMR of the crude product did not
show the presence of any (Z)-isomer (see ESI†).
10 Detailed X-ray crystallogaphic data is available from the CCDC, 12
Union Road, Cambridge CB2, 1EZ, UK for compounds 2e (CCDC #
656194), 3a (CCDC # 656195), 3f (CCDC # 656196) and 4d (CCDC #
656197).
6 (a) D. Basavaiah, K. V. Rao and R. J. Reddy, Chem. Soc. Rev., 2007,
36, 1581; (b) D. Basavaiah, A. J. Rao and T. Satyanarayana, Chem.
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