One-pot three-component access to pyranocyclopentendiones

Article abstract of DOI:10.3184/030823410X12753056300098

An efficient synthesis of dialkyl 2-(alkylamino)-5,6-dioxo-4a,7-diphenyl-4, 4a,5,6-tetrahydrocyclopenta[b]pyran- 3,4-dicarboxylates from one-pot three-component reaction of the zwitterions generated from dialkyl acetylenedicarboxylates and alkyl isocyanid

Full text of DOI:10.3184/030823410X12753056300098

330 RESEARCH PAPER
JUNE, 330–332
JOURNAL OF CHEMICAL RESEARCH 2010
One-pot three-component access to pyranocyclopentendiones
Mohammad Bagher Teimouria* and Farideh Mansourib
aPetrochemical Department, Iran Polymer and Petrochemical Institute, P.O. Box 14965-115, Tehran, Iran
bFaculty of Chemistry, Firouzabad Branch, Islamic Azad University, Firouzabad, Iran
An efficient synthesis of dialkyl 2-(alkylamino)-5,6-dioxo-4a,7-diphenyl-4,4a,5,6-tetrahydrocyclopenta[b]pyran-
3,4-dicarboxylates from one-pot three-component reaction of the zwitterions generated from dialkyl acetylenedicar-
boxylates and alkyl isocyanides with 3,5-diphenylcyclopentane-1,2,4-trione is described.
Keywords: acetylenic ester, CH-acid, Huisgen zwitterions, isocyanide, multicomponent reaction
Multicomponent reactions (MCRs) constitute excellent mani-
folds to generate molecular complexity and have received con-
siderable attention due to their high efficiency in the synthesis
of organic building blocks from the easily available starting
materials.1–4 Unlike the usual stepwise formation of individual
bonds in the target molecule, the most attractive attribute of
MCRs is the inherent formation of several bonds in one opera-
tion without isolating the intermediates, changing the reaction
conditions, or adding further reagents.
The reaction of nucleophiles with activated acetylenes for
C–C bond formation is of great significance in organic synthe-
sis.5 The electron-deficient alkynes are often used as Michael
acceptors for the formation of carbon-carbon bonds and recent
studies on the chemistry of heterocycles via conjugate addition
of C-, N- and P-nucleophiles have uncovered a number of
interesting reactions.6–8 Extensive work has been done by many
groups on the reactivities of Huisgen zwitterions derived from
activated acetylenic compounds and isocyanides.9 Recently,
these highly reactive 1,4-dipolar intermediates have been
captured by suitable CH-,10–12 NH-,13–15 and OH-acid16–18 sub-
strates. These studies have led to a number of interesting
carbon–carbon bond forming reactions and heterocyclic
constructions.
we now report the facile synthesis of some new pyranocyclo-
pentendione heterocycles. 3,5-Diphenylcyclopentane-1,2,4-
trione is a very interesting carbocyclic compound, which
has two rather acidic protons. This was used advantageously in
the formation of polyfunctional pyranocyclopentendione
derivatives incorporating the 4,4a-dihydrocyclopenta[b]
pyran-5,6-dione substructure via a three-component condensa-
tion reaction of isocyanides.
The one-pot, three-component condensation reactions of
alkyl isocyanides 1 with dialkyl acetylenedicarboxylates 2 in
the presence of 3,5-diphenylcyclopentane-1,2,4-trione 3 pro-
ceeded at room temperature in dry acetone and were complete
after 24 hours to afford corresponding dialkyl 2-(alkylamino)-
5,6-dioxo-4a,7-diphenyl-4,4a,5,6-tetrahydrocyclopenta[b]pyr
an-3,4-dicarboxylates 4 in 59–83% yields and the full results
are summarized in Scheme 1. 1H and 13C NMR spectra of the
crude products clearly indicated the formation of fused pyrano-
cyclopentendione 4. Any other products could not be detected
by NMR spectroscopy.
The structures of the products 4a–h were deduced from
their elemental analyses and IR, 1H NMR and 13C NMR spec-
1
tra. For example, the H NMR spectrum of 4a exhibited four
single sharp lines readily recognised as arising from tert-butyl
(δH 1.35 ppm), two methoxy protons (δH 3.63 and 3.68 ppm),
and allylic methine (δH 4.76 ppm) along with multiplets for
the 10 aromatic protons (δH 7.29–7.80). A fairly broad singlet
In connection with our recent interest aimed at the efficient
preparation of biologically active heterocycles via isocyanide-
basedmulticomponentreactionsinvolvingacidicsubstrates,18,19
Scheme 1
* Correspondent. E-mail: m.teimouri@ippi.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2010 331
(δH 8.90 ppm) was observed for the NH group. The presence of
an amine proton was confirmed by exchange with D2O. The
chemical shift of the NH group indicates that this moiety must
have participated in a six-membered intramolecular hydrogen
bond formation with the vicinal carbonyl group.
nucleophilic attack of the isocyanide on to the acetylenic ester
and subsequent protonation of the highly reactive 1:1 zwitter-
ionic intermediate by CH-acid (3,5-diphenylcyclopentane-
1,2,4-trione) affords the vinylisonitrilium cation 5. Then,
vinylisonitrilium cation 5 could undergo addition reactions
with the conjugate base of the CH-acid 6 at the two possible
electrophilic sites (1,2-addition and 1,4-conjugate addition)
to produce two possible intermediates 7 and 8 in equilibrium
with each other. These intermediates can then cyclise under
the reaction conditions employed to produce the dialkyl 2-
(alkylamino)-5,6-dioxo-4a,7-diphenyl-4,4a,5,6-tetrahydrocy-
clopenta[b]pyran-3,4-dicarboxylates 4.
In summary, the three-component reactions of alkyl isocya-
nides, dialkyl acetylenedicarboxylates and 3,5-diphenylcyclo-
pentane-1,2,4-trione were achieved under mild conditions,
providing a convenient method for the synthesis of dialkyl 2-
(alkylamino)-5,6-dioxo-4a,7-diphenyl-4,4a,5,6-tetrahydrocycl
openta[b]pyran-3,4-dicarboxylates. Using this method, a series
of fused pyranocyclopentendione were synthesized from
commercially easily available starting materials.
1
The H decoupled 13C NMR spectrum of 4a showed 22
distinct resonances, which confirmed the proposed structure.
The characteristic signal due to the allylic methine carbon
was discernible at δC 73.8 ppm and four carbonyl groups were
resonated at δC 192.9, 185.6, 172.3 and 172.1 ppm. Partial
assignment of these resonances is given in the Experimental
section.
The structural assignments made on the basis of the 1H and
13C NMR spectra of compound 4a was supported by measure-
ment of its IR spectra. The IR spectrum of 4a showed strong
absorptions at 1774, 1723, 1668 and 1629 cm−1 due to the
carbonyls and the amino group at 3168 cm−1 as a weak broad
band.
The scope and limitations of this three-component reaction
were explored by using three dialkyl acetylenedicarboxylates
and four alkyl isocyanides. The results show that the three-
component reaction is quite general with dialkyl acetylenedi-
carboxylates affording the expected pyranocyclopentendione 4
in good yields. Note that even moderate yields are syntheti-
cally useful because these reactions form complex structures
and a number of bonds are formed. Also, we examined the
scope of reactive isocyanides in the three-component reaction.
As shown in Scheme 1, a variety of structurally diverse alkyl
isocyanides are used in this protocol with good results.
The mechanism of this reaction has not been established
experimentally, a likely mechanism for the formation of
these heterocycles 4 is shown in Scheme 2. In a first step,
Experimental
Melting points were measured on a Büchi 535 apparatus and are
uncorrected. Elemental analyses were performed using an elementar
vario EL III instrument. FT-IR Spectra were recorded on a Bruker
Equinox-55 spectrometer. 1H and 13C NMR spectra were recorded on
a Bruker DRX-500 Avance spectrometer at 400.13 and 100.77 MHz,
respectively, with CDCl3 as solvents and calibrated using residual
undeuterated solvent as an internal reference. Chemical shifts are
reported in parts per million relative to TMS as internal reference.
Analytical TLC was carried out on pre-coated plates (Merck silica gel
60, F254) and visualised with UV light. All chemical reagents were
Scheme 2

332 JOURNAL OF CHEMICAL RESEARCH 2010
obtained from Aldrich, Merck or Acros and were used without further
purification.
(0.419 g, 77%); m.p. 201–203 °C (dec.); IR (KBr) (νmax, cm−1): 3193
(N–H), 1770, 1726 and 1668 (C=O), 1500 (C=C); 1H NMR (CDCl3):
δH 1.20 and 1.24 (6 H, 2 t, 3JHH = 7.0 Hz, 2 –CH2CH3), 2.01–2.11 (10
H, m, 5 CH2), 3.72 (NHCH), 4.06–4.14 (4 H, m, 2 ABX3 overlapping
systems, 2 OCH2CH3), 4.76 (1 H, s, NCH), 7.14–7.88 (10 H, m,
2 C6H5), 8.84 (1 H, br s, NH…O=C); 13C NMR (CDCl3): 192.9, 184.8,
172.5, 172.3, 169.0, 157.5, 134.6, 129.4, 129.3, 129.0, 128.7, 128.1,
127.7, 126.4, 126.2, 77.4, 72.5, 62.1, 61.7, 51.6, 50.6, 42.8, 34.2, 33.5,
25.3, 24.9, 14.6, 14.1. Anal. Calcd for C32H33NO7 (543.60): C, 70.70;
H, 6.12; N, 2.58. Found: C, 70.58; H, 6.08; N, 2.55%.
Diethyl 2-[(1,1,3,3-tetramethylbutyl)amino]-5,6-dioxo-4a,7-diphenyl-
4,4a,5,6-tetrahydrocyclopenta[b]pyran-3,4-dicarboxylate (4g):
Yellow powder (0.379 g, 66%); m.p. 209–211 °C (dec.); IR (KBr)
(νmax, cm−1): 3367 (N–H), 1759, 1723 and 1680 (C=O), 1492 (C=C);
1H NMR (CDCl3): δH 0.84 (9 H, s, C(CH3)3), 1.19 and 1.26 (6 H, 2 t,
3JHH = 7.0 Hz, 2 -CH2CH3), 1.39 and 1.40 (6 H, 2 s, C(CH3)2), 1.46 and
1.75 (2 H, AB system, 2JHH=14.9 Hz, CH2), 4.10–4.15 (4 H, m, 2ABX3
overlapping systems, 2 OCH2CH3), 4.85 (1 H, s, NCH), 7.26–7.72
(10 H, m, 2 C6H5), 8.90 (1 H, br s, NH…O=C); 13C NMR (CDCl3):
δC 192.5, 185.5, 172.4, 172.1, 168.8, 159.2, 134.0, 129.7, 129.3,
129.0, 128.7, 127.6, 127.1, 126.7, 77.3, 74.0, 62.3, 61.6, 57.2, 53.1,
52.1, 42.6, 31.9, 31.1, 30.9, 14.3, 14.0. Anal. Calcd for C34H39NO7
(573.67): C, 71.18; H, 6.85; N, 2.44. Found: C, 70.97; H, 6.78;
N, 2.41%.
Preparation of 4a; typical procedure
To a magnetically stirred solution of 3,5-diphenylcyclopentane-
1,2,4-trione (0.264 g, 1.0 mmol) and tert-butyl isocyanide (0.084 g,
1.0 mmol) in dry acetone (20 ml) was added dropwise a mixture
of dimethyl acetylenedicarboxylate (0.142 g, 1.0 mmol) in acetone
(2 ml) at room temperature over 10 min via a syringe. The reaction
mixture was stirred at room temperature for 24 h. The solvent was
removed under reduced pressure and the solid residue was washed
with diethyl ether and crystallised from CH2Cl2: n–hexane (1:5) to
give 4a as a yellow powder (0.368 g, 75%). The dried product thus
obtained showed a single spot on TLC and was pure enough for all
analytical purposes.
Dimethyl 2-(tert-bytylamino)-5,6-dioxo-4a,7-diphenyl-4,4a,5,6-tet
rahydrocyclopenta[b]pyran-3,4-dicarboxylate (4a): M.p. 166–168 °C
(dec.); IR (KBr) (νmax, cm−1): 3168 (N–H), 1774, 1723, 1668 and 1629
(C=O), 1493 (C=C); 1H NMR (CDCl3): δH 1.35 (9 H, s, C(CH3)3), 3.63
and 3.68 (6 H, 2 s, 2 OCH3), 4.76 (1 H, s, NCH), 7.29–7.80 (10 H, m,
2 C6H5), 8.90 (1 H, br s, NH…O=C); 13C NMR (CDCl3): δC 192.9,
185.6, 172.3, 172.1, 169.1, 159,3, 134.1, 129.7, 129.4, 129.0, 128.9,
128.6, 127.5, 127.2, 126.3, 77.3, 73.8, 53.2, 52.8, 51.6, 42.8, 30.4.
Anal. Calcd for C28H27NO7 (489.51): C, 68.70; H, 5.56; N, 2.86.
Found: C, 68.47; H, 5.60; N, 2.88%.
Diethyl 2-(benzylamino)-5,6-dioxo-4a,7-diphenyl-4,4a,5,6-tetrahy-
drocyclopenta[b]pyran-3,4-dicarboxylate (4h):Yellow powder (0.326
g, 59%); m.p. 202–204 °C (dec.); IR (KBr) (νmax, cm−1): 3230 (N–H),
1766, 1721 and 1670 (C=O), 1493 (C=C); 1H NMR (CDCl3): δH 1.21
The synthesis of 4b–h was performed under similar conditions as
for 4a.
Dimethyl 2-(cyclohexylamino)-5,6-dioxo-4a,7-diphenyl-4,4a,5,6-
tetrahydrocyclopenta[b]pyran-3,4-dicarboxylate (4b):Yellow powder
(0.428 g, 83%); m.p. 181–183 °C (dec.); IR (KBr) (νmax, cm−1): 3256
(N–H), 1769, 1719 and 1676 (C=O), 1495 (C=C); 1H NMR (CDCl3):
δH 1.99–2.01 (10 H, m, 5 CH2), 3.62 and 3.84 (6 H, 2 s, 2 OCH3), 3.74
(NHCH), 4.70 (1 H, s, NCH), 7.25–7.97 (10 H, m, 2 C6H5), 8.60 (1 H,
br s, NH…O=C); 13C NMR (CDCl3): 192.7, 185.4, 172.4, 172.3,
168.9, 157.8, 134.4, 129.5, 129.3, 128.9, 128.6, 128.3, 127.7, 126.4,
126.3, 77.2, 72.8, 52.8, 51.5, 51.1, 50.9, 42.8, 34.0, 33.4, 25.3, 24.7.
Anal. Calcd for C30H29NO7 (515.55): C, 69.89; H, 5.67; N, 2.72.
Found: C, 70.24; H, 5.64; N, 2.70%.
3
and 1.24 (6 H, 2 t, JHH = 7.0 Hz, 2 -CH2CH3), 4.09–4.15 (4 H, m,
2 ABX3 overlapping systems, 2 OCH2CH3), 4.33 and 4.38 (2 H, AB
2
system, JHH = 15.0 Hz, NHCH2Ph), 4.72 (1 H, s, NCH), 7.23–8.10
(10 H, m, 3 C6H5), 9.01 (1 H, br s, NH…O=C); 13C NMR (CDCl3):
δC 190.2, 186.0, 172.9, 172.5, 169.9, 159.9, 137.7, 134.3, 129.5,
129.2, 129.1, 128.9, 128.6, 128.5, 128.0, 127.4, 127.0, 126.6, 126.5,
77.4, 73.6, 62.3, 62.0, 48.5, 43.2, 14.3, 13.9.Anal. Calcd for C33H29NO7
(551.58): C, 71.86; H, 5.30; N, 2.54. Found: C, 71.57; H, 5.27;
N, 2.56%.
Dimethyl 2-[(1,1,3,3-tetramethylbutyl)amino]-5,6-dioxo-4a,7-
diphenyl-4,4a,5,6-tetrahydrocyclopenta[b]pyran-3,4-dicarboxylate
(4c): Yellow powder (0.426 g, 78%); m.p. 196–198 °C (dec.); IR
(KBr) (νmax, cm−1): 3437 (N–H), 1763, 1726 and 1673 (C=O), 1495
We would like to thank Iran Polymer and Petrochemical
Institute (IPPI) Research Council for the financial support.
1
(C=C); H NMR (CDCl3): δH 0.82 (9 H, s, C(CH3)3), 1.36 and 1.37
2
(6 H, 2 s, C(CH3)2), 1.48 and 1.78 (2 H, AB system, JHH = 15.0 Hz,
Received 3 May 2010; accepted 18 May 2010
Paper 1000101 doi: 10.3184/030823410X12753056300098
Published online: 2 July 2010
CH2), 3.63 and 3.69 (6 H, 2 s, 2 OCH3), 4.77 (1 H, s, NCH), 7.31–7.74
(10 H, m, 2 C6H5), 8.95 (1 H, br s, NH…O=C); 13C NMR (CDCl3):
δC 192.9, 185.6, 172.3, 172.2, 169.1, 159.0, 134.1, 129.5, 129.3,
128.9, 128.6, 127.9, 127.2, 126.4, 77.4, 73.5, 56.9, 53.0, 52.8, 51.6,
50.9, 42.4, 31.5, 31.1, 30.9. Anal. Calcd for C32H35NO7 (545.62):
C, 70.44; H, 6.47; N, 2.57. Found: C, 70.21; H, 6.51; N, 2.55%.
Dimethyl 2-(benzylamino)-5,6-dioxo-4a,7-diphenyl-4,4a,5,6-tetra-
hydrocyclopenta[b]pyran-3,4-dicarboxylate (4d): Yellow powder
(0.367 g, 70%); m.p. 160–162 °C (dec.); IR (KBr) (νmax, cm−1): 3155
(N–H), 1770, 1727 and 1666 (C=O), 1500 (C=C); 1H NMR (CDCl3):
δH 3.66 and 3.71 (6 H, 2 s, 2 OCH3), 4.36 and 4.40 (2 H, AB system,
2JHH = 14.8 Hz, NHCH2Ph), 4.80 (1 H, s, NCH), 7.20–8.07 (10 H, m,
3 C6H5), 8.96 (1 H, br s, NH…O=C); 13C NMR (CDCl3): δC 190.1,
185.3, 173.1, 172.5, 169.8, 159.7, 138.6, 134.5, 129.5, 129.2, 129.0,
128.9, 128.7, 128.5, 127.9, 127.8, 127.1, 126.8, 126.5, 77.5, 74.3,
53.1, 52.8, 48.5, 43.2. Anal. Calcd for C31H25NO7 (523.53): C, 71.12;
H, 4.81; N, 2.68. Found: C, 70.91; H, 4.78; N, 2.70%.
References
1
2
3
4
5
J.D. Sunderhaus and S.F. Martin, Chem. Eur. J., 2009, 15, 1300.
L. El Kaim and L. Grimaud, Tetrahedron, 2009, 65, 2153.
M. Syamala, Org. Prep. Proc. Int., 2009, 41, 1.
I. Akritopoulou-Zanze, Curr. Opin. Chem. Biol., 2008, 12, 324.
J.I. Dickstein and S.I. Miller, The chemistry of functional groups. the
chemistry of carbon-carbon triple bond, Part 2, S. Patai, ed.; Wiley:
Chichester, 1978; Chap. 19, p. 813.
6
A. Ramazani, A.R. Kazemizadeh, E. Ahmadi, N. Noshiranzadeh and
A. Souldozi, Curr. Org. Chem., 2008, 12, 59.
7
8
V. Nair, S. Devipriya and E. Suresh, Tetrahedron, 2008, 64, 3567.
V. Nair, R.S. Menon, A.R. Sreekanth, N. Abhilash and A.T. Biju, Acc.
Chem. Res., 2006, 39, 520.
9
V. Nair, A.U. Vinod, N. Abhilash, R.S. Menon, V. Santhi, R.L. Varma,
S. Viji, S. Mathew and R. Srinivas, Tetrahedron, 2003, 59, 10279.
Diethyl2-(tert-butylamino)-5,6-dioxo-4a,7-diphenyl-4,4a,5,6-tetra-
hydrocyclopenta[b]pyran-3,4-dicarboxylate (4e): Yellow powder
(0.373 g, 72%); m.p. 178–180 °C (dec.); IR (KBr) (νmax, cm−1): 3210
(N–H), 1769, 1721 and 1670 (C=O), 1498 (C=C); 1H NMR (CDCl3):
10 I. Yavari and M.T. Maghsoodlou, J. Chem. Res.(S), 1998, 386.
11 I. Yavari, M. Adib and M.H. Sayahi, J. Chem. Soc., Perkin Trans. 1, 2002,
2343.
12 M.B. Teimouri, R. Bazhrang, V. Eslamimanesh and A. Nouri, Tetrahedron,
2006, 62, 3016.
13 A. Shaabani, M.B. Teimouri, P. Mirzaei and H.R. Bijanzadeh, J. Chem.
Res.(S), 2003, 82.
14 M.B. Teimouri, Tetrahedron, 2006, 62, 10849.
15 M.B. Teimouri, F. Mansouri and R. Bazhrang, Tetrahedron, 2010, 66,
259.
16 I.Yavari, M.Anary-Abbasinejad,A.Alizadeh and Z. Hossaini, Tetrahedron,
2003, 59, 1289.
17 A. Alizadeh, S. Rostamnia, L.-G. Zhu, Tetrahedron, 2006, 62, 5641.
18 M.B. Teimouri and R. Bazhrang, Monatsh. Chem., 2009, 140, 513.
19 M.B. Teimouri and F. Mansouri, J. Comb. Chem., 2008, 10, 507.
3
δH 1.19 and 1.22 (6 H, 2 t, JHH = 7.0 Hz, 2 -CH2CH3), 1.33 (9 H,
s, C(CH3)3), 4.08–4.19 (4 H, m, 2 ABX3 overlapping systems,
2 OCH2CH3), 4.81 (1 H, s, NCH), 7.30–8.02 (10 H, m, 2 C6H5), 8.86
(1 H, br s, NH…O=C); 13C NMR (CDCl3): δC 192.1, 184.7, 172.2,
172.0, 169.6, 159,1, 134.2, 129.5, 129.2, 129.1, 128.7, 128.3, 127.8,
127.1, 125.9, 77.3, 74.1, 62.0, 60.7, 52.2, 42.7, 30.6, 14.1, 13.9. Anal.
Calcd for C30H31NO7 (517.56): C, 69.62; H, 6.04; N, 2.71. Found:
C, 69.91; H, 6.10; N, 2.68%.
Diethyl2-(cyclohexylamino)-5,6-dioxo-4a,7-diphenyl-4,4a,5,6-tetra-
hydrocyclopenta[b]pyran-3,4-dicarboxylate (4f): Yellow powder

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.