Bakers' yeast catalyzed synthesis of polyhydroquinoline derivatives via an unsymmetrical Hantzsch reaction

Article abstract of DOI:10.1016/j.tetlet.2007.03.130

Bakers' yeast efficiently catalyzes the unsymmetrical Hantzsch reaction through a four-component coupling of aldehydes, β-ketoesters, dimedone and ammonium acetate to form polyhydroquinoline derivatives in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2007.03.130

Tetrahedron Letters 48 (2007) 3887–3890
Bakers’ yeast catalyzed synthesis of polyhydroquinoline
derivatives via an unsymmetrical Hantzsch reaction
Atul Kumar* and Ram Awatar Maurya
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 22 January 2007; revised 14 March 2007; accepted 22 March 2007
Available online 25 March 2007
Abstract—Bakers’ yeast efficiently catalyzes the unsymmetrical Hantzsch reaction through a four-component coupling of aldehydes,
b-ketoesters, dimedone and ammonium acetate to form polyhydroquinoline derivatives in good to excellent yields.
Ó 2007 Elsevier Ltd. All rights reserved.
In recent years, much attention has been directed
towards the synthesis of 1,4-dihydropyridyl compounds
due to the wide range of biological activity associated
with these compounds.1 1,4-Dihydropyridyl compounds
are well known as calcium channel modulators. Cardio-
vascular agents such as nifedipine, nicardipine, amlodip-
ine and other related derivatives are dihydropyridyl
compounds, which are effective in treatment of hyper-
tension.2 1,4-Dihydropyridine derivatives possess a
variety of biological activities such as vasodilator, anti-
tumour, bronchodilator, antiatherosclerotic, geroprotec-
tive and hepatoprotective activity.3 Furthermore, these
compounds have been shown to possess diverse medici-
nal utility such as neuroprotectant, platelet anti-aggre-
gatory activity, cerebral antischaemic activity in the
treatment of Alzheimer’s disease and chemosensitiser
behaviour in tumour therapy.4 These examples clearly
indicate the remarkable potential of novel dihydropyri-
dine derivatives as sources of valuable drug candidates.
Oxidation of these compounds to pyridines has also
been extensively studied.5 Thus, the synthesis of this
heterocyclic nucleus is of importance.
from several drawbacks such as long reaction times,
use of a large quantity of volatile organic solvents, low
yields and harsh reaction conditions. Therefore, it is
necessary to develop an efficient and versatile method
for the synthesis of polyhydroquinoline compounds. Re-
cently, several methods have been reported comprising
the use of microwaves, ionic liquids, TMSCl–NaI, metal
triflates and polymers.7–21 However, the use of high tem-
peratures, expensive metal precursors, catalysts that are
harmful to the environment and longer reaction times
limits the use of these methods. Therefore, the search
for improved catalysts for the synthesis of polyhydro-
quinoline derivatives using less hazardous conditions is
of prime importance.
It is well known that bakers’ yeast catalyzes the reduc-
tion of ketones to optically active alcohols.22 Reduction
of b-ketoesters to b-hydroxy esters provides a represen-
tative example.23 Bakers’ yeast has also been success-
fully used in acyloin type condensations, reduction of
carbon–carbon double bonds and oxidative coupling
of thiols to disulfides.24
Numerous methods have been reported for the synthesis
of polyhydroquinoline derivatives. The classical method
involves three-component coupling of an aldehyde with
ethyl acetoacetate and ammonia in acetic acid or by
refluxing in alcohol.6 However, these methods suffer
More recently, Lee reported the synthesis of dihydropyr-
idyl compounds via Hantzsch reaction using bakers’
yeast as the catalyst.25 Here, the acetaldehyde is gener-
ated in situ from fermenting bakers’ yeast and is con-
densed with ethyl acetoacetate and ammonium acetate
to form Hantzsch esters (Scheme 1).
In our ongoing programme, towards the synthesis of
polyhydroquinoline derivatives,26 we decided to add an
external aryl aldehyde (other than acetaldehyde) and
dimedone to the fermenting yeast conditions (Scheme
Keywords: Bakers’ yeast; Hantzsch reaction; Polyhydroquinoline;
Multi-component reaction.
*
Corresponding author. Tel.: +91 522 2612411; fax: +91 522
2623405; e-mail: dratulsax@gmail.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.130

3888
A. Kumar, R. A. Maurya / Tetrahedron Letters 48 (2007) 3887–3890
method provides a versatile approach for the synthesis
of aryl substituted polyhydroquinoline derivatives.
ROOC
COOR
O
O
i
+
NH4OAc
Bakers’ yeast (200 mg) and D-glucose (300 mg) were
taken in 5 ml phosphate buffer (pH 7.0) and stirred
overnight. Dimedone (140 mg, 1 mmol), benzaldehyde
(106 mg, 1 mmol), ethyl acetoacetate (130 mg, 1 mmol)
and ammonium acetate (75 mg, 1 mmol) were added
to the fermenting yeast and the reaction mixture was
stirred for a further 24 h, then diluted with water and ex-
tracted with ethyl acetate. The organic layer was dried
over sodium sulfate and concentrated to give a crude
product. The pure polyhydroquinoline derivative 4a
was obtained by crystallization from methanol (79%
yield).
OR
N
H
Scheme 1. Reagents and conditions: (i) baker’s yeast, D-glucose,
phosphate buffer (pH 7.0).
O
R
O
O
RCHO
+
COOR1
OR1
i
N
H
O
O
NH4OAc
(4a-4l)
Scheme 2. Reagents and conditions: (i) bakers’ yeast, D-glucose,
In order to study the catalytic efficiency of bakers’ yeast,
we carried out control reactions without bakers’ yeast
using an identical procedure to that described above
(Scheme 3).
phosphate buffer (pH 7.0), rt, 24 h.
2). Due to the presence of more reactive aryl aldehydes
we exclusively obtained the aryl substituted polyhydro-
quinoline derivatives. Under our reaction conditions
no product corresponding to acetaldehyde was gener-
ated in situ from fermenting bakers’ yeast. The present
Only trace amounts of the desired polyhydroquinolines
derivativea 4a–f were observed on TLC and the major
product isolated was a dimedone–aldehyde adduct. We
also carried out control reactions with a series of alde-
hydes 1a–f and in all cases the dimedone–aldehyde
O
R
O
O
RCHO
COOR1
OR1
+
i
Table 1. Control reactions:a formation of the dimedone–aldehyde
adduct
N
H
+
O
O
traces
4a-4f
Entry
R
Yield 4a–f
Yieldb 5a–f (%)
NH4OAc
R
O
R
O
O
1
2
3
4
5
6
C6H5
4-HO–C6H4
4-HO-3-CH3O–C6H3
4-C2H5O-3-HO–C6H3
3-O2N–C6H4
Trace
Trace
Trace
Trace
Trace
Trace
95
94
97
94
95
93
COOR1
ii
OH HO
5a-5f Major product isolated
N
H
2-CH3O–C6H4
4a-4f
low yield
a
D-Glucose (300 mg), phosphate buffer (pH 7.0, 5 ml), aldehyde
(1 mmol), dimedone (1 mmol), ethyl acetoacetate (1 mmol ), ammo-
nium acetate (1 mmol), stir, 24 h.
b Isolated yields.
Scheme 3. Reagents and conditions: (i) D-glucose, phosphate buffer
(pH 7.0), rt, 24 h; (ii) bakers’ yeast, D-glucose, phosphate buffer
(pH 7.0), ammonium acetate, ethyl acetoacetate, rt, 24 h.
Table 2. Synthesis of polyhydroquinoline derivatives via unsymmetrical Hantzsch reaction catalyzed by bakers’ yeasta
Entry
R
R1
Productb
Yieldsc (%)
Mpd (°C)
1
2
3
4
5
6
7
8
9
C6H5
4-HO–C6H4
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
4a
4b
4c
4d
4e
4f
79
81
72
73
68
67
82
71
75
78
65
62
188–190
234–235
225–227
196–197
177–178
193–195
261–262
222–223
>270
4-HO-3-CH3O–C6H3
4-C2H5O-3-HO–C6H3
3-O2N–C6H4
2-CH3O–C6H4
4-CH3–C6H4
(CH3)2N–C6H4
4-CH3–C6H4
3,4-Cl2–C6H3
3-CH3O–C6H4
C6H5
4g
4h
4i
10
11
12
CH3
t-Bu
t-Bu
4j
198–200
190–191
222–223
4k
4l
a Reaction conditions: bakers’ yeast (200 mg), D-glucose (300 mg), phosphate buffer (pH 7.0, 5 ml), aldehyde (1 mmol), dimedone (1 mmol), b-keto
ester (1 mmol) and ammonium acetate (1 mmol), stir, room temperature, 24 h.
b Products were characterized by MS, IR, 1H NMR and 13C NMR spectroscopy.27
c Isolated yield.
d Melting points are uncorrected.

A. Kumar, R. A. Maurya / Tetrahedron Letters 48 (2007) 3887–3890
3889
4. (a) Klusa, V. Drugs Future 1995, 20, 135–138; (b) Bretzel,
R. G.; Bollen, C. C.; Maester, E.; Federlin, K. F. Am. J.
Kidney. Dis. 1993, 21, 54–63; (c) Bretzel, R. G.; Bollen, C.
C.; Maester, E.; Federlin, K. F. Drugs Future 1992, 17,
465–468; (d) Boer, R.; Gekeler, V. Drugs Future 1995, 20,
499–509.
5. (a) Zhang, D.; Wu, L. Z.; Zhou, L.; Han, X.; Yang, Q. Z.;
Zhang, L. P.; Tung, C. H. J. Am. Chem. Soc. 2004, 126,
3440–3441; (b) Eynde, J. J. V.; Delfosse, F.; Mayence, A.;
Haverbeke, Y. V. Tetrahedron 1995, 51, 6511–6516; (c)
Anniyappan, M.; Muralidharan, D.; Perumal, P. T.
Tetrahedron 2002, 58, 5069–5073; (d) Heravi, M. M.;
Behbahani, F. K.; Oskooie, H. A.; Shoar, R. H. Tetra-
hedron Lett. 2005, 46, 2775–2777; (e) Esfahani, M. N.;
Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.;
Momeni, A. R. Bioorg. Med. Chem. 2006, 14, 2720–2724.
6. Loev, B.; Snader, K. M. J. Org. Chem. 1965, 30, 1914–
1916.
7. Tu, S.-J.; Zhou, J.-F.; Deng, X.; Cai, P.-J.; Wang, H.;
Feng, J.-C. Chin. J. Org. Chem. 2001, 21, 313–316.
8. Sabita, G.; Reddy, G. S. K. K.; Reddy, C. S.; Yadav, J. S.
Tetrahedron Lett. 2003, 44, 4129–4131.
9. Ji, S. J.; Jiang, Z. Q.; Lu, J.; Loh, T. P. Synlett 2004, 831–
835.
10. Breitenbucher, J. G.; Figliozzi, G. Tetrahedron Lett. 2000,
41, 4311–4315.
11. Dondoni, A.; Massi, A.; Minghini, E.; Bertolasi, V.
Tetrahedron 2004, 60, 2311–2326.
12. Wang, L. M.; Sheng, J.; Zhang, L.; Han, J. W.; Fan, Z. Y.;
Tian, H.; Qian, C. T. Tetrahedron 2005, 61, 1539–1543.
13. Ko, S.; Yao, C.-F. Tetrahedron 2006, 62, 7293–7299.
14. Maheswara, M.; Siddaiah, V.; Damu, G. L. V.; Rao, C. V.
Arkivoc 2006, 201–206.
15. (a) Chandrasekhar, S.; Reddy, N. S.; Sultana, S. S.;
Narsihmulu, C.; Reddy, K. V. Tetrahedron 2006, 62, 338–
345; (b) Li, H.; Wang, B.; Deng, L. J. Am. Chem. Soc.
2006, 128, 732–733; (c) Poulsen, T. B.; Bernardy, L.; Bell,
M.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2006, 45, 1–5.
16. (a) Rasalkar, M. S.; Potdar, M. K.; Mohile, S. S.;
Salunkhe, M. M. J. Mol. Catal. A: Chem. 2005, 235,
267–270; (b) Alcaide, B.; Almendros, P.; Luna, A.; Torres,
M. S. J. Org. Chem. 2006, 71, 4818–4822.
adducts were the major products isolated. The results of
this study are shown in Table 1.
We also carried out a reaction in which the bakers’ yeast
(200 mg) and D-glucose (300 mg) were taken in 5 ml
phosphate buffer (pH 7.0) and stirred overnight. Then
dimedone–aldehyde adduct (5a, 1 mmol), ethyl aceto-
acetate (130 mg, 1 mmol) and ammonium acetate
(75 mg, 1 mmol) were added to the reaction mixture.
The reaction was stirred for 24 h leading to polyhydro-
quinoline derivative 4a, which was isolated by column
chromatography in 24% yield (Scheme 3).
We proceeded to synthesize a series of polyhydroquino-
line derivatives via unsymmetrical Hantzsch reaction
catalyzed by bakers’ yeast.27 Various functionalized aryl
aldehydes reacted smoothly to give polyhydroquinoline
derivatives in high yields. Hydroxy, methoxy, ethoxy,
nitro and chloro substituted aldehydes were tolerated.
We also carried out the reaction with other b-keto esters
(methyl acetoacetate and t-butyl acetoacetate). The
results of this study are shown in Table 2.
In conclusion, we have successfully developed an easy,
efficient and versatile method for the synthesis of poly-
hydroquinoline derivatives from the reaction of alde-
hydes, b-keto esters, dimedone and ammonium acetate
catalyzed by bakers’ yeast at room temperature. The
process does not require the use of any volatile organic
solvent, harmful metal catalyst and thus, is a simple,
environmentally friendly, and high yielding reaction
for the synthesis of polyhydroquinolines via unsymmet-
rical Hantzsch reaction.
Acknowledgement
R.A.M. is thankful to the CSIR, New Delhi for financial
support in the form of a junior research fellowship.
17. Janey, J. M.; Hsiano, Y.; Armstrong, J. D., III. J. Org.
Chem. 2006, 71, 390–392.
18. (a) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bogevig,
A.; Jorgensen, K. A. J. Am. Chem. Soc. 2002, 124, 827–
833; (b) Kotrusz, P.; Toma, S. Molecules 2006, 11, 197–
205.
Supplementary data
19. (a) Ramachary, D. B.; Chodari, N. S.; Barbas, C. F., III.
Angew. Chem. 2003, 115, 4365–4369; (b) Kotrusz, P.;
Toma, S. Arkivoc 2006, 100–109.
20. Hossein, A. O.; Elham, R.; Majid, M. H. J. Chem. Res.
2006, 246–247.
The NMR spectra and details are attached as Supple-
mentary data. Supplementary data associated with this
article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.03.130.
21. (a) Yadav, J. S.; Kumar, S. P.; Kondaji, G.; Rao, R. S.;
Nagaiah, K. Chem. Lett. 2004, 33, 1168–1169; (b) Mabry,
J.; Ganem, B. Tetrahedron Lett. 2006, 47, 55–56.
22. Sih, C. J.; Chen, C.-S. Angew. Chem., Int. Ed. Engl. 1984,
23, 570.
References and notes
23. Csuk, R.; Glanzer, B. I. Chem. Rev. 1991, 91, 49–97.
24. (a) Fuganti, C.; Grasselli, P.; Servi, S.; Speafico, F.;
Ziroty, C. J. Org. Chem. 1984, 49, 4087–4089; (b) Fuganti,
C. Pure Appl. Chem. 1990, 62, 1449–1452; (c) Utaka, M.;
Konisi, S.; Tkeda, A. Tetrahedron Lett. 1986, 27, 4737–
4740; (d) Ohta, H.; Kobavashi, N.; Ozaki, K. J. Org
Chem. 1989, 54, 1802–1804; (e) Rao, K. R.; Kumar, H. M.
S. Bioorg. Med. Chem. Lett. 1991, 10, 507–508.
25. Lee, J. H. Tetrahedron Lett. 2005, 46, 7329–7330.
26. Kumar, A.; Maurya, R. A. Tetrahedron 2007, 63, 1952–
1956.
1. (a) Bossert, F.; Meyer, H.; Wehinger, E. Angew. Chem.,
Int. Ed. Engl. 1981, 20, 762–769; (b) Nakayama, H.;
Kasoaka, Y. Heterocycles 1996, 42, 901–909.
2. (a) Buhler, F. R.; Kiowski, W. J. Hypertens. 1987, 5, S3;
(b) Reid, J. L.; Meredith, P. A.; Pasanisi, F. J. Cardiovasc.
Pharmacol. 1985, 7, S18.
3. (a) Godfaid, T.; Miller, R.; Wibo, M. Pharmacol. Rev.
1986, 38, 321–327; (b) Sausins, A.; Duburs, G. Hetero-
cycles 1988, 7, 269–289; (c) Mannhold, R.; Jablonka, B.;
Voigdt, W.; Schoenafinger, K.; Schravan, K. Eur. J. Med.
Chem. 1992, 27, 229–235.

3890
A. Kumar, R. A. Maurya / Tetrahedron Letters 48 (2007) 3887–3890
27. Data for selected compounds: Compound 4b: 1H NMR
(CD3OD, 200 MHz) d: 0.75 (s, 3H), 0.92 (s, 3H), 0.99 (t,
J = 7.1 Hz, 3H), 1.86–2.31 (m, 7H), 3.82 (d, J = 7.1 Hz,
2H), 3.93 (s, 1H), 4.20 (s, 1H), 4.80 (s, 1H), 6.40 (m, 2H),
6.86 (m, 2H). 13C NMR (DMSO-d6, 75 MHz) d: 25.69,
28.34, 31.28, 34.00, 49.52, 58.13, 103.36, 109.54, 113.63,
127.51, 137.61, 143.53, 148.33, 154.42, 166.21, 193.50. IR
(KBr, cmÀ1): 3439, 3280, 3075, 2964, 1679, 1611, 1483. MS
(ESI): m/z = 356 (M+H). Compound 4k: 1H NMR
(CDCl3, 300 MHz) d 0.96 (s, 3H), 1.08 (s, 3H), 1.38 (s,
9H), 2.14–2.35 (m, 7H), 3.78 (s, 3H), 4.98 (s, 1H), 5.86 (s,
1H), 6.65 (m, 1H), 6.88 (m, 2H), 7.10 (m, 1H). 13C NMR
(CDCl3, 75 MHz) d: 17.73, 26.90, 26.99, 28.10, 31.30,
35.82, 39.42, 49.58, 53.75, 78.55, 105.98, 109.58, 110.06,
112.95, 119.43, 127.32, 141.57, 147.66, 148.31, 157.94,
165.71, 194.57. IR (KBr, cmÀ1): 3292, 3224, 3087, 2958,
1699, 1605, 1491. MS (ESI): m/z = 398.0 (M+H). Anal.
Calcd for C24H32NO4: 398.2, Found: 398.0. Anal. Calcd
for C24H31NO4: C, 72.52; H, 7.86; N, 3.52. Found: C,
1
72.38; H, 7.76; N, 3.41. Compound 4l: H NMR (CDCl3,
300 MHz) d 0.93 (s, 3H), 1.07 (s, 3H), 1.37 (s, 9H,), 2.11–
2.27 (m, 4H), 2.32 (s, 3H), 4.99 (s, 1H), 6.43 (s, 1H), 7.07
(t, J = 7.1 Hz, 1H), 7.18–7.23 (m, 2H), 7.28–7.32 (m, 2H).
13C NMR (CDCl3, 75 MHz) d: 17.84, 25.92, 26.91, 28.05,
31.36, 35.90, 39.74, 49.53, 78.60, 106.34, 110.60, 124.59,
126.45, 126.85, 141.14, 145.92, 147.29, 165.62, 194.32.
IR (KBr, cmÀ1): 3280, 3216, 3084, 2965, 1678, 1608, 1491.
MS (ESI): m/z = 368 (M+H). Anal. Calcd for
C23H29NO3: C, 75.17; H, 7.95; N, 3.81. Found: C, 75.14;
H, 7.89; N, 3.72.