Michael addition approach for the synthesis of novel spiro compounds and 2-substituted malonic acid derivatives from Meldrum's acid

Article abstract of DOI:10.1016/j.tetlet.2005.09.030

Novel routes for the synthesis of spiro derivatives of Meldrum's acid and 2-substituted malonic acid derivatives have been developed. Meldrum's acid was monoalkylated using a Michael addition reaction. Mono-Michael adducts were then alkylated using substituted haloalkanes, which on condensation gave spiro derivatives of Meldrum's acid. Bis Michael addition of Meldrum's acid with 1,5-diaryl-1,4-pentadien-3-one gave directly a spiro derivative of Meldrum's acid. These compounds and bis alkylated Meldrum's acid derivatives, on acidic methanolysis gave 2-substituted malonic acids.

Full text of DOI:10.1016/j.tetlet.2005.09.030

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7787–7792
Michael addition approach for the synthesis of novel
spiro compounds and 2-substituted malonic acid derivatives
from MeldrumÕs acid
Madhukar S. Chande* and Rahul R. Khanwelkar
Department of Chemistry, The Institute of Science, 15 Madam Cama Road, Mumbai 400 032, India
Received 5 March 2005; revised 31 August 2005; accepted 7 September 2005
Available online 22 September 2005
Abstract—Novel routes for the synthesis of spiro derivatives of MeldrumÕs acid and 2-substituted malonic acid derivatives have
been developed. MeldrumÕs acid was monoalkylated using a Michael addition reaction. Mono-Michael adducts were then alkylated
using substituted haloalkanes, which on condensation gave spiro derivatives of MeldrumÕs acid. Bis Michael addition of MeldrumÕs
acid with 1,5-diaryl-1,4-pentadien-3-one gave directly a spiro derivative of MeldrumÕs acid. These compounds and bis alkylated
MeldrumÕs acid derivatives, on acidic methanolysis gave 2-substituted malonic acids.
ꢀ 2005 Elsevier Ltd. All rights reserved.
2,2-Dimethyl-1,3-dioxane-4,6-dione (MeldrumÕs acid) 11
is a versatile organic reagent2 and its derivatives are very
useful building blocks in synthetic organic chemistry.
Because of its acidity (pKa 4.83),2 steric rigidness and
notable tendency to regenerate acetone, MeldrumÕs acid
is often employed with advantage over malonic ester.3
atives of MeldrumÕs acid 1 by Michael addition, and 2-
substituted malonic acid derivatives, which are other-
wise difficult or tedious to synthesize.
5-Monoalkyl derivatives of MeldrumÕs acid 3,6b 8,6a and
126a were prepared in high yields by Michael addition of
1 to methyl acrylate 2, acrylonitrile 7, and methyl vinyl
ketone 11 in the presence of benzyltrimethylammonium
hydroxide (Triton B), using K2CO3 as a base in acetoni-
trile as solvent. Formation of the double adduct was
not observed even with 3 mol equiv of the Michael
acceptor, probably for steric reasons (highly crowded
carbanion).6b
There are several methods for the synthesis of 5-mono
and 5,5-disubstituted MeldrumÕs acids.4 Although the
Michael addition reaction5 is widely recognized as one
of the most important C–C bond forming reactions in
organic chemistry and an important method for alkyl-
ation of active methylene compounds, there are only a
few reports on the Michael addition of MeldrumÕs acid
to electrophilic olefins.6
Compound 310 was prepared by heating anhydrous
K2CO3, MeldrumÕs acid 1, and methyl acrylate 2 in aceto-
nitrile in the presence of Triton B at 50–60 ꢁC. The
presence of a triplet for the methine proton at d 3.91
and a quartet and triplet for the two methylene protons
In continuation of our work on the synthesis of novel
spiro compounds,7 we report here, the utilization of
Michael adducts of MeldrumÕs acid for constructing novel
spiro molecules. Spiro systems are important in bio-
organic chemistry and are present in many natural products
and pharmaceuticals8 and 2-substituted malonic acid
derivatives are very useful reagents in organic synthesis.9
1
at d 2.39 and 2.65, respectively, in the H NMR, clearly
indicated the formation of a monoadduct. Compound 3
was then alkylated with ethyl bromoacetate to give the
5,5-dialkylated MeldrumÕs acid 4.11 Dieckmann cyclisa-
tion of 4 in the presence of sodium hydride in dry DMF
gave the spiro derivative 512 as a dark yellow liquid in
good yield.
This letter focuses on a novel synthetic strategy, which
provides versatile routes for the synthesis of spiro deriv-
Substituted MeldrumÕs acids upon acid catalysed alco-
holysis afford carboxylic esters.13 Heating 5 in methan-
olic hydrochloric acid gave 614 in 70% yield (Scheme 1,
Keywords: Michael addition; MeldrumÕs acid; Spiro compound;
2-Substituted malonic acid derivative; Methanolysis.
*
Corresponding author. E-mail: chandems@vsnl.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.030

7788
M. S. Chande, R. R. Khanwelkar / Tetrahedron Letters 46 (2005) 7787–7792
COMe
O
O
O
O
O
O
H
O
(c)
MeOOC
MeOOC
(d)
O
O
O
O
O
O
O
OEt
Br
)
0%
(7
15
O
COMe
COMe
13 (94%)
OEt
12 (90%)
COMe
HO
COMe
14 (73%)
Route iii
11
(a)
COOMe
O
O
O
O
2
O
O
(c)
O
O
O
(a)
Route i
O
O
O
O
O
OEt
O
O
O
Br
EtOOC
H
1
O
OEt
4 (90%)
COOMe
COOMe
HO
CN
3
(92
%
)
5 (75%)
7
(a)
Route ii
(d)
O
O
O
O
(c)
EtOOC
HN
O
O
MeOOC
(d)
O
O
O
O
O
OEt
O
H
O
Br
MeOOC
6 (70-73%)
O
CN
OEt
O
CN
8 (94%)
10 (78%)
9 (95%)
Scheme 1. Reagents and conditions: (a) Triton B/K2CO3/CH3CN, 50–60 ꢁC, 8 h; (b) K2CO3/(CH3)2CO, reflux, 4 h; (c) NaH/DMF, 10–15 ꢁC, 5 h;
(d) aq HCl/MeOH, reflux, 5 h.
route i). However, reported procedures15 for the diethyl
analog of 6 have disadvantages like low yield, and long-
er reaction time. The procedure reported above repre-
sents a general method for the synthesis of 6, with
good yield and shorter reaction time, which is an inter-
mediate in the synthesis of (R,S)-3-oxocyclopentane-
carboxylic acid, a key intermediate in the synthesis of
various biologically active products.15b
malonic acid derivatives 1724 by refluxing in acidic meth-
anol in good yields. It was observed that compounds 16a
and 16b gave the same compound, dimethyl 2-allyl-2-
methoxycarbonyl pentanedioate 17a on acidic methan-
olysis, which was confirmed on the basis of IR spectra,
which were superimposable. In contrast, 16c gave com-
pound 17b.25
Monoadducts 3, 8 and 12 were refluxed with equimolar
quantities of ethyl chloroformate and K2CO3 in acetone
in an effort to give 5,5-dialkylated MeldrumÕs acids 18a–
c, but when the reactions were monitored by TLC, they
showed unconsumed starting material along with the
new spot. Hence another mol equivalent of ethyl chloro-
formate was added to the reaction mixture along with
1 mol equiv of K2CO3, and within one hour the starting
materials were fully consumed. The products obtained
were not the expected 5,5-dialkylated MeldrumÕs acids
18a–c, but 2-substituted malonic acids 19a–c,26 probably
because of in situ dehydrohalogenation of the mono-
Michael adducts with ethyl chloroformate followed by
hydrolysis of 18 to 19. Many research groups have pre-
pared 19c27 from diethyl malonate, whereas 19b28 and
19a29 are not as well known as 19c in the literature. 2-
Substituted malonic acids can be synthesized using
diethyl malonate as starting material, but the utility of
this method is often hampered by the undesired addition
of a second acceptor molecule because of the high acid-
ity of the resulting dialkyl alkylmalonates. This side
reaction becomes particularly pronounced with reactive
acceptors such that monofunctionalized products can-
not be obtained in this case.5 Hence, our method can
be a solution for the synthesis of 2-monosubstituted
malonic acid derivatives. 2-Monosubstituted malonic
acid derivatives can be alternatively prepared using the
Michael addition on methanetricarboxylic esters.30
When Michael addition of 1 was extended to acrylnitrile
7, under similar experimental conditions the mono ad-
duct 816 was obtained in excellent yield. The IR spec-
trum displayed a sharp band at 2251 cmÀ1 due to the
nitrile group. Alkylation of 8 with ethyl bromoacetate
gave 917 in excellent yield, which on cyclisation fur-
nished the desired spiro molecule 1018 in good yield.
Compound 10 was easily converted into 1,1-di(methoxy-
carbonyl)cyclopentan-3-one 6 by heating in methanolic
hydrochloric acid (Scheme 1, route ii).
5-Monoalkyl MeldrumÕs acid 1219 was prepared in 90%
yield by Michael addition of 1 to methyl vinyl ketone 11,
which was then alkylated using ethyl bromoacetate to
give 5,5-dialkylated MeldrumÕs acid 13.20 Intramolecu-
lar Claisen condensation of 13 in the presence of sodium
hydride in dry DMF gave 1421 as a dark yellow liquid in
good yield. 3-Acetyl-1,1-di(methoxycarbonyl)cyclopen-
tan-4-one 1522 was produced by heating 14 in methan-
olic hydrochloric acid, in 70% yield (Scheme 1, route iii).
The reaction sequence shown in Scheme 2 further illus-
trates the usefulness of 5-monoalkylated MeldrumÕs
acids 3, 8 and 12. These monoadducts were allylated
by refluxing with allyl bromide in K2CO3/acetone to ob-
tain 5,5-dialkylated MeldrumÕs acids 1623 in excellent
yields. These were converted into 2,2-disubstituted

M. S. Chande, R. R. Khanwelkar / Tetrahedron Letters 46 (2005) 7787–7792
7789
O
X
O
X
X
O
O
O
O
MeOOC
MeOOC
(b)
H
Br
O
O
16a X = COOMe (85%)
16b X = CN (90%)
16c X = COMe (92%)
O
17a X = COOMe (77%)
17b X = COMe (80%)
3 X = COOMe
8 X = CN
12 X = COMe
Cl
O
OEt
Cl
OEt
O
X
O
O
O
X
EtO
EtO
O
O
OEt
H
18a X = COOMe
18b X = CN
18c X = COMe
O
19a X = COOMe (70%)
19b X = CN (72%)
19c X = COMe (75%)
Scheme 2. Reagents and conditions: (a) K2CO3/(CH3)2CO, reflux, 4 h; (b) aq HCl/MeOH, reflux, 5 h.
The double Michael addition on MeldrumÕs acid 1 is
very rare,31 so we decided to carry out the reaction
of dibenzylideneacetones with MeldrumÕs acid 1. We
tested organic bases such as triethylamine, pyridine,
piperidine and K2CO3 along with Triton B in different
solvent systems, but the attempts were unsuccessful.
When the reaction was carried out using K2CO3 in
dry DMF, it was complete after 24 h. However, the
reaction proceeded smoothly in the presence of an
equimolar amount of sodamide in dry DMF at 10–
15 ꢁC in 3 h. Thus spiro cyclohexanone 2132 was syn-
thesized in a single step by bis Michael addition of
MeldrumÕs acid 1 and 1,5-diaryl-1,4-pentadien-3-one
20 in more than 85% yield (Scheme 3). Cyclohexan-
ones and spirocyclohexanones have been extensively
different positions than the equatorial protons (HX).34
In 21a, HA exhibited a doublet of doublets at d 3.98
(dd, J = 3, 11 Hz), while HM and HX exhibited a trip-
let and a doublet of doublets at d 3.73 (t, J = 11 Hz)
and d 2.65 (dd, J = 3, 11 Hz). The coupling constants
of HA are in agreement with those of axial–axial and
axial–equatorial H–H couplings of a cyclohexane chair
conformation.
This confirmed the axial orientation for HA and that the
aryl substituents are in an equatorial orientation as
shown in I (Fig. 1) and not in an axial–equatorial orien-
tation as shown in II (Fig. 1). This was further con-
firmed by the 13C NMR spectrum which highlighted
the symmetry in the molecule, which could only occur
when the aryl substituents are disposed in equatorial ori-
entations as shown in I (Fig. 1). Hence, only the cis 1,3-
diequatorial isomer of 21 I (Fig. 1) had been produced,
selectively, and in very good yield.
1
studied for their stereochemistry.33 The H NMR spec-
trum of 21 displayed an AMX pattern for the methine
(HA) and methylene (HM and HX) protons of the
cyclohexanone moiety. The axial methylene protons
(HM) at C-8 and C-10 lie in the direction of the p-orbi-
tals of the oxygen of the carbonyl group at C-9,
whereas the equatorial protons (HX) at C-8 and C-10
form an angle of 60ꢁ. Thus, the axial methylene pro-
tons (HM) fall in the deshielding zone of the carbonyl
group at position 9. Hence, they absorb at distinctly
Koher and Dewey35 has synthesized 22 from dimethyl
malonate and benzylidene acetone and the same method
has been used by other groups33a,34b,36 to prepare 22.
Compounds 21 were refluxed in methanolic hydrochlo-
ric acid to give 1,1-di(methoxycarbonyl)2,6-diaryl-
R
R
O
R
O
O
O
MeO
(b)
O
O
O
O
(a)
+
O
O
O
MeO
O
O
1
R
R
R
22a R = H (80%)
20a R = H
21a R = H (90%)
21b R = Cl (85%)
21c R = OMe (87%)
22b R = Cl (80%)
22c R = OMe (82%)
20b R = Cl
20c R = OMe
Scheme 3. Reagents and conditions: (a) NaNH2/DMF, 10–15 ꢁC, 3 h; (b) aq HCl/ MeOH, reflux, 5 h.

7790
M. S. Chande, R. R. Khanwelkar / Tetrahedron Letters 46 (2005) 7787–7792
O
O
O
O
HM
HM
Ph
Ph
HM
HM
O
O
HX
HX
Ph
HA
O
O
O
O
HA
HA
HX
HX
HA
Ph
I
II
Figure 1. Compound 22a.
cyclohexan-4-one 2237 (Scheme 3). So, thus our method
is an alternative method for the synthesis of 22.
Sugadare, V. V.; Ambhaikar, S. B. Indian J. Chem. 1999,
38B, 925–931; (c) Chande, M. S.; Joshi, R. M. Indian J.
Chem. 1999, 38B, 218–220; (d) Chande, M. S.; Bhat, U. B.
Indian J. Chem. 1999, 38B, 932–937; (e) Chande, M. S.;
Balel, S. K. Indian J. Chem. 1996, 35B, 377–380; (f)
Chande, M. S.; Bhandari, J. D.; Karyekar, A. S. Indian J.
Chem. 1995, 34B, 985–989; (g) Chande, M. S.; Paingankar,
N. M. Indian J. Chem. 1995, 34B, 603–606; (h) Chande,
M. S.; Bhandari, J. D.; Joshi, V. R. Indian J. Chem. 1993,
32B, 1218–1228.
In this letter, we have reported a novel synthetic strategy
for the synthesis of spiro derivatives of MeldrumÕs acid
using mono and bis Michael additions as well as a con-
venient route for the synthesis of 2-mono and bis-substi-
tuted malonic acid derivatives.
8. (a) Pesaro, M.; Bechamann, J. P. J. Chem. Soc., Chem.
Commun. 1978, 203; (b) Dauben, W. G.; Hawt, D. J.
J. Am. Chem. Soc. 1977, 99, 7307–7314.
Acknowledgements
9. (a) Stadlbauer, W.; Badawey, S. E.; Hojas, G.; Roschger,
P.; Kappe, T. Molecules 2001, 6, 338–352; (b) Arcadi, A.;
Cacchi, S.; Delmastro, M.; Marinelli, F. Synlett 1991,
407–409; (c) Hin, B.; Majer, P.; Tsukamoto, T. J. Org.
Chem. 2002, 67, 7365–7368.
The authors thank TIFR, Mumbai, for measuring the
NMR spectra of the reported compounds.
References and notes
10. Spectroscopic data for 3: mp 76 ꢁC; IR (KBr): 2995, 2952,
2893 (C–H str.), 1749 (C@O; ester) cmÀ1 1H NMR
;
1. (a) Meldrum, A. N. J. Chem. Soc. 1908, 93, 598–601; (b)
Davidson, D.; Bernhard, S. A. J. Am. Chem. Soc. 1948,
70, 3426–3428.
(500 MHz, CDCl3): d = 1.80 (s, 3H, CH3), 1.82 (s, 3H,
CH3), 2.39 (q, J = 7 Hz, 2H, CH2), 2.65 (t, J = 7 Hz, 2H,
CH2), 3.68 (s, 3H, OCH3), 3.91 (t, J = 5 Hz, 1H, CH); 13
C
2. McNab, H. Chem. Soc. Rev. 1978, 7, 345–358.
3. (a) Oikawa, Y.; Sugano, K.; Yonemitsu, O. J. Org. Chem.
1978, 43, 2087–2088; (b) Somain, D.; Descoins, C.;
Commercon, A. Synthesis 1978, 388–389; (c) Hase, T.
A.; Salonen, K. Synth. Commun. 1980, 10, 221; (d) Pinhey,
J. P.; Rowe, B. A. Tetrahedron Lett. 1980, 21, 965–968; (e)
Celerier, J. P.; Deloisy, E.; Kapron, P.; Lhommet, G.;
Maitte, P. Synthesis 1981, 130–132; (f) Houghton, R. P.;
Lapham, D. J. Synthesis 1982, 451; (g) Jacobs, R. T.;
Wright, A. D.; Smith, P. X. J. Org. Chem. 1982, 47, 3769–
3772.
4. (a) Nutaitis, C. F.; Schultz, R. A.; Obuza, J.; Smith, F. X.
J. Org. Chem. 1980, 45, 4606–4608; (b) Rosowsky, A.;
Forsch, R.; Uren, J.; Wick, M.; Kumar, A. A.; Freisheim,
J. H. J. Med. Chem. 1983, 26, 1719–1724; (c) Smircina, M.;
Majer, P.; Majerova, E.; Guerassina, T. A.; Eissenstat, M.
A. Tetrahedron 1997, 53, 12867–12874; (d) Oikawa, Y.;
Hirasawa, H.; Yonemitsu, O. Tetrahedron Lett. 1978,
1759–1762; (e) Hrubowchak, D. M.; Smith, F. X. Tetra-
hedron Lett. 1983, 24, 4951–4954; (f) Huang, X.; Xie, L.
Synth. Commun. 1986, 16, 1701–1707; (g) List, B.;
Castello, C. Synlett 2001, 1687–1689.
NMR (500 MHz, CDCl3): d = 21.2, 26.4 (2 · CH2), 28.5,
30.0 (2 · CH3), 44.7 (CH), 57.7 (OCH3), 105.1 (quaternary
carbon), 165.1, 173.7 (3 · C@O; esters). Anal. Calcd for
C10H14O6: C, 52.17; H, 6.13; O, 41.70. Found: C, 52.50; H,
6.20; O, 41.30.
11. Spectroscopic data for 4: mp 57 ꢁC; IR (KBr): 3024, 2952
(C–H str.), 1738 (C@O; ester) cmÀ1; 1H NMR (500 MHz,
CDCl3): d = 1.25 (t, J = 7 Hz, 3H, CH3), 1.89 (s, 3H,
CH3), 1.93 (s, 3H, CH3), 2.26 (t, J = 7.5 Hz, 2H, CH2),
2.47 (t, J = 7 Hz, 2H, CH2), 3.08 (s, 2H, CH2), 3.68 (s, 3H,
OCH3), 4.13 (q, J = 7 Hz, 2H, OCH2); 13C NMR
(125 MHz, CDCl3): d = 13.9, 28.5, 28.9 (3 · CH3), 32.7,
39.3, 42.4 (3 · CH2), 49.3 (quaternary carbon), 51.7
(OCH3), 61.6 (OCH2), 107.1 (quaternary carbon), 167.8,
169.0, 170.8, 171.6 (4 · C@O; esters). Anal. Calcd for
C14H20O8: C, 53.16; H, 6.37; O, 40.47. Found: C, 53.10; H,
6.30; O, 40.60.
12. Spectroscopic data for 5: IR (CCl4): 3468 (O–H str.), 2926,
2856 (C–H str.), 1741 (C@O; ester) cmÀ1 1H NMR
;
(500 MHz, CDCl3): d = 1.24 (t, J = 7 Hz, 3H, CH3), 1.79
(s, 3H, CH3), 1.81 (s, 3H, CH3), 2.94 (t, J = 8 Hz, 2H,
CH2), 3.14 (t, J = 8 Hz, 2H, CH2), 4.15 (q, J = 7 Hz, 2H,
OCH2), 5.10 (br, 1H, OH) (D2O exchangeable); 13C NMR
(125 MHz, CDCl3): d = 13.9, 26.7, 28.7 (3 · CH3), 31.2,
42.4 (2 · CH2), 47.3 (quaternary carbon C5), 61.5 (OCH2),
94.6 (@C–COOEt), 105.3 (quaternary carbon C8), 165.1
(C–OH of cyclopentanone), 168.2, 170.8, 171.5 (3 · C@O,
esters). Anal. Calcd for C13H16O7: C, 54.93; H, 5.67; O,
39.40. Found: C, 54.85; H, 5.60; O, 39.55.
5. Bergmann, E. D. Org. React. 1959, 10, 179–555.
6. (a) Chan, C. C.; Huang, X. Synthesis 1984, 224–225; (b)
Mane, R. B.; Rao, G. S. K. Chem. Ind. (London) 1976,
786–787; (c) Siperko, L. G.; Smith, F. X. Synth. Commun.
1979, 9, 383–389.
7. (a) Chande, M. S.; Suryanarayan, V. Tetrahedron Lett.
2002, 43, 5173–5175; (b) Chande, M. S.; Pankhi, A. Md.;

M. S. Chande, R. R. Khanwelkar / Tetrahedron Letters 46 (2005) 7787–7792
7791
13. (a) Toth, G.; Koever, K. E. Synth. Commun. 1995, 25,
3067–3074; (b) Haffmann, G. W.; Ebrahimi, M. Z.
Synthesis 1996, 215–218.
(br, 1H, OH) (D2O exchangeable); 13C NMR (125 MHz,
CDCl3): d = 23.8, 28.2 (3 · CH3), 26.9, 31.3 (2 · CH2),
42.6 (quaternary carbon), 105.3 (quaternary carbon),
120.5 (H3COC@C), 165.0 (C@C–OH, esters), 170.4
(2 · C@O, esters), 199.0 (CO–CH3). Anal. Calcd for
C12H14O6: C, 56.69; H, 5.55; O, 37.76. Found: C, 56.70;
H, 5.58; O, 37.72.
14. Spectroscopic data for 6: IR (CCl4): 3000, 2953, 2852 (C–
H str.), 1744 (C@O; ester) cmÀ1 1H NMR (500 MHz,
;
CDCl3): d = 2.20 (m, 2H, CH2), 2.40 (m, 2H, CH2), 2.65
(s, 2H, CH2), 3.71 (s, 3H, OCH3), 3.77 (s, 3H, OCH3); 13
C
NMR (125 MHz, CDCl3): d = 26.7, 31.4, 32.9 (3 · CH2),
47.4 (quaternary carbon), 52.1, 52.9 (2 · OCH3), 168.7,
171.2 (2 · C@O, esters), 208.0 (C@O, cyclopentanone).
Anal. Calcd C9H12O5: C, 54.00; H, 6.04; O, 39.96. Found:
C, 54.00; H, 6.10; O, 39.90.
22. Spectroscopic data for 15: IR (CCl4): 3001, 2953, 2849 (C–
H str.), 1745 (C@O; ester) cmÀ1 1H NMR (500 MHz,
;
CDCl3): d = 2.14 (s, 3H, COCH3), 2.62 (s, 2H, CH2), 2.92
(m, 2H, CH2), 3.69 (s, 3H, OCH3), 3.75 (s, 3H, OCH3),
8.95 (m, 1H, CH); 13C NMR (125 MHz, CDCl3): d = 22.1
(CH3), 29.2, 32.8 (2 · CH2), 36.6 (CH), 47.4 (quaternary
carbon), 52.1, 52.8 (2 · OCH3), 168.7, 171.2 (2 · C@O,
esters), 207.2, 208.2 (2 · C@O). Anal. Calcd for C11H14O6:
C, 54.54; H, 5.83; O, 39.63. Found: C, 54.50; H, 5.87; O,
39.63.
15. (a) Westerlund, A.; Gras, J. L.; Carlson, R. Tetrahedron
2001, 57, 5879–5883; (b) Sung, S. Y.; Bisel, P.; Frahm, A.
W. Pharmazie 1998, 8, 521–524.
16. Spectroscopic data for 8: mp 124 ꢁC; IR (KBr): 3005,
2946, 2899 (C–H str.), 2251 (CN str.), 1740 (C@O; ester)
cmÀ1; 1H NMR (60 MHz, CDCl3): d = 1.74 (s, 3H, CH3),
1.82 (s, 3H, CH3), 2.41 (q, J = 7 Hz, 2H, CH2), 2.71 (t,
J = 7 Hz, 2H, CH2), 3.61 (t, J = 5 Hz, 1H, CH). Anal.
Calcd C9H11NO4: C, 54.82; H, 5.62; N, 7.10; O, 32.46.
Found: C, 54.70; H, 5.73; N, 7.16; O, 32.47.
23. Spectroscopic data for 16c: mp 75 ꢁC; IR (CCl4): 3089,
1
3006, 2944 (C–H str.), 1774, 1737 (C@O; ester) cmÀ1; H
NMR (500 MHz, CDCl3) d = 1.71 (s, 3H, CH3), 1.79 (s,
3H, CH3), 2.14 (s, 3H, CH3), 2.29 (t, J = 7.5 Hz, 2H,
CH2), 2.56 (t, J = 7.5 Hz, 2H, CH2), 2.73 (d, J = 7.5 Hz,
2H, CH2), 5.21 (dd, J = 9, 7.5 Hz, 2H, @CH2), 5.67 (m,
1H, @CH); 13C NMR (125 MHz, CDCl3): d = 24.5, 26.7
(3 · CH3), 24.1, 33.0, 36.6 (3 · CH2), 48.0 (tetrahedral
carbon), 100.5 (tetrahedral carbon), 116.2 (HC@CH2),
125.5 (HC@CH2), 163.2 (2 · C@O; esters), 200.6 (C@O,
ketone). Anal. Calcd for C13H18O5: C, 61.40; H, 7.14; O,
31.46. Found: C, 61.45; H, 7.15; O, 31.4.
17. Spectroscopic data for 9: mp 133 ꢁC; IR (KBr): 2986 (C–H
1
str.), 2253 (CN str.), 1739 (C@O; ester) cmÀ1; H NMR
(500 MHz, CDCl3) d = 1.23 (t, J = 7.5 Hz, 3H, CH3), 1.82
(s, 3H, CH3), 1.86 (s, 3H, CH3), 2.28 (t, J = 7.5 Hz, 2H,
CH2), 2.49 (t, J = 7 Hz, 2H, CH2), 3.18 (s, 2H, CH2), 4.13
(q, J = 7.5 Hz, 2H, OCH2); 13C NMR (125 MHz, CDCl3):
d = 13.9 (CH2CN), 13.1, 28.7, 29.2 (3 · CH3), 33.1, 38.7
(2 · CH2), 49.3 (quaternary carbon), 61.7 (OCH2), 107.5
(quaternary carbon), 117.5 (CN), 167.0, 170.6 (3 · C@O;
esters). Anal. Calcd C13H17NO6: C, 55.12; H, 6.05;
N, 4.94; O, 33.89. Found: C, 55.10; H, 6.07; N, 4.93; O,
33.90.
24. Spectroscopic data for 17b: IR (CCl4): 3080, 2950 (C–H
str.), 1719 (C@O) cmÀ1 1H NMR (500 MHz, CDCl3)
;
d = 2.00 (s, 3H, CH3), 2.25 (t, J = 7.5 Hz, 2H, CH2), 2.48
(t, J = 7.5 Hz, 2H, CH2), 2.70 (d, J = 7.5 Hz, 2H, CH2),
3.69 (s, 6H, 2 · OCH3), 5.51 (dd, J = 9, 7.5 Hz, 2H, @CH2),
5.73 (m, 1H, @CH). Anal. Calcd for C12H18O5: C, 59.49;
H, 7.49; O, 33.02. Found: C, 59.45; H, 7.45; O, 33.1.
25. Yamazaki, T.; Kasatkin, A.; Kawanaka, Y.; Sato, F. J.
Org. Chem. 1996, 61, 2266–2267.
18. Spectroscopic data for 10: IR (CCl4): 2938, 2931 (C–H
str.), 1740 (C@O; ester) cmÀ1 1H NMR (500 MHz,
;
CDCl3): d = 1.21 (t, J = 7 Hz, 3H, CH3), 1.79 (s, 3H,
CH3), 1.81 (s, 3H, CH3), 2.88 (t, J = 7 Hz, 2H, CH2), 2.97
(t, J = 7 Hz, 2H, CH2), 3.14 (m, 1H, CH), 4.14 (q,
J = 7 Hz, 2H, OCH2), 6.97 (br, 1H, NH) (D2O exchange-
able); 13C NMR (125 MHz, CDCl3): d = 13.2, 27.1, 28.1
(3 · CH3), 31.0, 37.0 (2 · CH2), 42.6 (CH), 46.9 (quater-
nary carbon C5), 61.1 (OCH2), 105.3 (quaternary carbon
C8), 163.7 (C@NH), 170.5, 171.1, 172.8 (3 · C@O, esters).
Anal. Calcd for C13H17NO6: C, 55.12; H, 6.05; N, 4.94; O,
33.89. Found: C, 55.10; H, 6.03; N, 4.90; O, 33.97.
26. Spectroscopic data for 19c: IR (CCl4): 2983, 2905 (C–H
str.), 1734 (C@O str.) cmÀ1; 1H NMR (500 MHz, CDCl3):
d = 1.12 (t, J = 7 Hz, 6H, 2 · CH3), 1.99 (m, 5H, CH2 &
CH3), 2.41 (t, J = 7 Hz, 2H, CH2), 3.24 (t, J = 7 Hz, 1H,
CH), 4.05 (q, J = 7 Hz, 4H, 2 · OCH2); 13C NMR
(125 MHz, CDCl3): d = 8.0 (2 · COOCH2CH3), 16.9
(COCH3) 24.3, 34.8 (2 · CH2), 45.1 (CH), 55.8
(2 · OCH2), 163.6, 164.1 (2 · C@O; esters), 201.8 (C@O,
ketone). Anal. Calcd for C11H18O5: C, 57.38; H, 7.88; O,
34.74. Found: C, 57.40; H, 7.84; O, 34.76.
27. (a) Bergmann, E. D.; Corett, Ruth J. Org. Chem. 1956, 21,
107–110; (b) Ross, N. C.; Levine, R. J. Org. Chem. 1964,
29, 2346–2350; (c) Rao, Y. V. S.; Vos, D. E. D.; Jacobs, P.
A. Angew. Chem., Int. Ed. 1997, 36, 2261–2263; (d)
Mastrorilli, P.; Nobile, C. F.; Suranna, G. P. J. Mol.
Catal. A: Chem. 2003, 195, 263–274; (e) Climent, M. J.;
Corma, A.; Iborra, S.; Velty, A. J. Mol. Catal. A: Chem.
2002, 182–183, 327–342; (f) Boruah, A.; Baruah, M.;
Prajapati, D.; Sandhu, J. S. Synth. Commun. 1998, 28,
653–658; (g) Lee, P. H.; Seomoon, D.; Lee, K.; Heo, Y. J.
Org. Chem. 2003, 68, 2510–2513; (h) Nelson, J. H.;
Howells, P. N.; Delullo, G. C.; Landen, G. L. J. Org.
Chem. 1980, 45, 1246–1249.
19. Spectroscopic data for 12: mp 120 ꢁC; 3004, 2955, 2893
(C–H str.), 1788, 1747 (C@O; ester), 1708 (C@O; ketone)
cmÀ1; 1H NMR (60 MHz, CDCl3): d = 1.76 (s, 3H, CH3),
1.83 (s, 3H, CH3), 2.16 (s, 3H, CH3), 2.30 (q, J = 7 Hz,
2H, CH2), 2.73 (t, J = 7 Hz, 2H, CH2), 3.86 (t, J = 5 Hz,
1H, CH). Anal. Calcd for C10H14O5: C, 56.07; H, 6.59; O,
37.34. Found: C, 56.00; H, 6.60; O, 37.40.
20. Spectroscopic data for 13: mp 110 ꢁC; IR (KBr): 2928 (C–
H str.), 1740 (C@O; ester) cmÀ1 1H NMR (500 MHz,
;
CDCl3): d = 1.28 (t, J = 7 Hz, 3H, CH3), 1.89 (s, 3H,
CH3), 1.90 (s, 3H, CH3), 2.16 (s, 3H, CH3), 2.22 (t,
J = 7.5 Hz, 2H, CH2), 2.61 (t, J = 7 Hz, 2H, CH2), 3.13 (s,
2H, CH2), 4.12 (q, J = 7 Hz, 2H, OCH2); 13C NMR
(125 MHz, CDCl3): d = 8.7, 23.7, 24.7, 25.7 (4 · CH3),
20.6, 32.5, 34.1 (3 · CH2), 43.7 (quaternary carbon), 56.3
(OCH2), 101.8 (quaternary carbon), 162.8, 165.6
(3 · C@O; esters) 200.1 (CO-CH3). Anal. Calcd for
C14H20O7: C, 55.99; H, 6.71; O, 37.29. Found: C, 56.00;
H, 6.70; O, 37.30.
28. (a) Liebman, A. A.; Malarek, D. H.; Dorsky, A. M.;
Kaegi, H. H. J. Heterocycl. Chem. 1974, 11, 1105–1107;
(b) Albertson, N. F.; Fillman, J. L. J. Am. Chem. Soc.
1949, 71, 2818–2820; (c) Volcho, K. P.; Kurbakova, S. Y.;
Korchagina, D. V.; Suslov, E. V.; Salakhutdinov, N. F.;
Toktarev, A. V.; Echevskii, G. V.; Barkhash, V. A. J. Mol.
Catal. A: Chem. 2003, 195, 263–274; (d) Koelsch, C. F. J.
Am. Chem. Soc. 1943, 65, 2458–2459.
21. Spectroscopic data for 14: IR (CCl4): 3425 (O–H str.),
2986 (C–H str.), 1721 (C@O; ester) cmÀ1 1H NMR
;
(500 MHz, CDCl3): d = 1.81 (s, 6H, 2 · CH3), 1.82 (s, 3H,
COCH3), 3.17 (s, 2H, CH2), 3.79 (s, 2H, CH2), 6.00–7.00

7792
M. S. Chande, R. R. Khanwelkar / Tetrahedron Letters 46 (2005) 7787–7792
29. Ito, K.; Nakanishi, S.; Otsuji, Y. Chem. Lett. 1988, 473–
476.
T. W.; Wynberg, H. J. Org. Chem. 1979, 44, 1508–1514;
(c) De Jongh, H. A. P.; Wynberg, H. Tetrahedron 1965, 21,
515–533; (d) Risistano, F.; Grassi, G.; Foti, F.; Romeo, R.
Synthesis 2002, 1, 116–120.
30. Skarzewski, J. Synthesis 1990, 1125–1127.
31. Bengoa, G. E.; Cuerva, J. M.; Matio, C.; Echavarren, A.
M. J. Am. Chem. Soc. 1996, 118, 8553–8565.
32. Spectroscopic data for 21a: mp 184 ꢁC; IR (KBr): 3065,
34. (a) Reddy, D. B.; Reddy, M. M.; Padmavathi, V. Indian J.
Chem. 1992, 31B, 407–410; (b) Reddy, D. B.; Padmavathi,
V.; Seenaiah, B.; Reddy, M. V. R. Org. Prep. Proced. Int.
1992, 24, 21–26.
35. Koher, E. P.; Dewey, C. S. J. Am. Chem. Soc. 1924, 46,
1267–1278.
3035, 2999, 2928 (C–H), 1762, 1730 (C@O) cmÀ1 1H
;
NMR (300 MHz, CDCl3): d = 0.58 (s, 6H, 2 · CH3), 2.65
(dd, J = 3, 11 Hz, 2HX), 3.75 (t, J = 11 Hz, 2HM), 3.98
(dd, J = 3, 11 Hz, 2HA), 7.15–7.38 (m, 10H, aromatic
protons); 13C NMR (75 MHz, CDCl3): d = 28.4, 28.7
(2 · CH3), 42.9 (2 · CH2), 50.1 (2 · CH), 60.6 (quaternary
carbon), 106.3 (quaternary carbon), 128.4–136.9 (aromatic
carbons) 165.4, 168.2 (2 · C@O; esters), 207.4 (C@O,
ketone). Anal. Calcd for C23H22O5: C, 73.00; H, 5.86; O,
21.14. Found: C, 73.10; H, 5.87; O, 21.03.
36. Otto, H. H. Monatsh. Chem. 1973, 104, 526–537.
37. Spectroscopic data for 22a: mp 135 ꢁC; IR (KBr): 1740
1
(C@O; ester) cmÀ1; H NMR (60 MHz, CDCl3): d = 2.92
(dd, J = 3, 11 Hz, 2HX), 3.40 (s, 6H, –OCH3), 3.12 (t,
J = 11 Hz, 2HM), 4.47 (dd, J = 3, 11 Hz, 2HA), 7.15–7.38
(m, 10H, aromatic protons). Anal. Calcd for C22H22O5: C,
72.12; H, 6.05; O, 21.83. Found: C, 72.10; H, 6.02; O,
21.88.
33. (a) Rowland, A. T.; Hohneker, J. A.; McDaniel, K. F.;
Moore, D. S. J. Org. Chem. 1982, 47, 301–306; (b) Hoeve,