Adenine as aminocatalyst for green synthesis of diastereoselective Mannich products in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2009.02.218

The three-component organocatalysed Mannich type reaction is carried out in a green co-solvent of ethanol and water at room temperature using adenine as catalyst and hydrogen peroxide as additive. The Mannich products are obtained in considerably good diastereoselectivity depending on the effects of substituents on aniline.

Full text of DOI:10.1016/j.tetlet.2009.02.218

Tetrahedron Letters 50 (2009) 2384–2388
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Adenine as aminocatalyst for green synthesis of diastereoselective Mannich
products in aqueous medium
*
Papori Goswami , Babulal Das
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The three-component organocatalysed Mannich type reaction is carried out in a green co-solvent of eth-
anol and water at room temperature using adenine as catalyst and hydrogen peroxide as additive. The
Mannich products are obtained in considerably good diastereoselectivity depending on the effects of sub-
stituents on aniline.
Received 18 November 2008
Revised 18 February 2009
Accepted 28 February 2009
Available online 5 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Aminocatalysed
Mannich
Hydrogen peroxide
Adenine
Diastereoselective
The organocatalysis has come a long way in the field of syn-
thetic organic chemistry, motivated by the stereoselective enzy-
matic processes. The secondary amine has been exploited
extensively as enantioselective organocatalysts, which generally
acts through either electrophilic iminium or nucleophilic enamine
pathway.1 Although the primary amine has been used by natural
enzymes such as type I aldolases, decarboxylases and dehydrata-
ses, containing the catalytically active lysine residues,2 very little
progress has taken place in this field with chiral primary amines till
date3 partly due to the unfavourable imine-secondary enamine
equilibria.4
in situ formation of imines, has gained considerable importance
as it allows structural variations.
Accordingly, several recent reports of organocatalysed asym-
metric Mannich reaction in polar solvents such as DMSO and
NMP are found in the literature.10,11 A few recent reports reveal
that the reaction is carried out in aqueous medium catalysed by or-
ganic molecules.12
We wish to report a modified version of environmentally be-
nign Mannich reaction with different aldehydes, ketones and
amines for the synthesis of b-amino carbonyl compounds in a
green solvent (ethanol–water 4:1) in presence of adenine as cata-
Amongst the innumerable synthesis of chiral compounds, the
Mannich reaction has so far been exploited for the synthesis of chi-
ral nitrogen-containing compounds, and by far the most important
carbon–carbon bond-forming reactions.5 The vital importance of
the Mannich products as important precursors of pharmaceutical
and natural products6 has always boosted researchers to find out
better process for their synthesis. The limitations7 associated with
the classical Mannich type reaction such as drastic reaction condi-
tions, long reaction time with low yields and formation of un-
wanted side products, have induced numerous modern versions8
of the reaction. These improved methodologies are mainly based
on two-component reactions where the imine as electrophile is
pre-formed and reacted with stable nucleophiles such as enolates,
enol ethers and enamines.9 Recently, three-component approach
for this reaction using organocatalyst and other catalysts, with
lyst and 40 ll of 30% H2O2 as additive as shown in Scheme 1.
Adenine, belonging to the class of purine derivatives was chosen
as the catalyst, since we envisaged that the primary amine present in
adenine would take active participation in the formation of enamine
intermediate with cyclohexanone. The resulting enamine can easily
attack the Mannich acceptor (imine formed by aldehydes and
amine), thereby assisting in the formation of Mannich products.
To start with, the reaction was screened with varying amounts
of the catalyst. The model reaction of benzaldehyde, aniline and
cyclohexanone was carried out with 5 mol % to 20 mol % of catalyst
in ethanol and water mixture, among which 20 mol % was found to
be the most effective as shown in Table 1. Consequently, ethanol
and water in the ratio of 4:1 were found to be the best possible sol-
vent to furnish the desired adduct in good yield with a comparative
diastereoselective ratio.
In an attempt to obtain good diastereoselectivity of the Man-
nich products, we examined the reaction by adding 30% hydrogen
peroxide in presence of 20 mol % of adenine. To our delight, intro-
* Corresponding author. Tel.: +91 3612583000; fax: +91 3612690762.
E-mail address: papori@iitg.ernet.in (P. Goswami).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.218

P. Goswami, B. Das / Tetrahedron Letters 50 (2009) 2384–2388
2385
R
R
R
NH2
O
Adenine(20 mol%)/H2O2
O
HN
O
HN
CHO
rt
R
R
R
anti
syn
R = H, Me, OMe, Br------
Scheme 1. Direct Mannich reaction catalysed by adenine and hydrogen peroxide.
Table 1
duction of 30% hydrogen peroxide induced a relatively better dia-
stereoselectivity along with increased yield. The reaction was final-
Adenine catalysed three-component Mannich type reaction of benzaldehyde, cyclo-
hexanone and aniline in the presence of varying amounts of catalyst
Entry
Catalyst (mol %)
Time (h)
Yielda (%)
1
2
3
4
5
—
5
10
15
20
24
24
24
12
8
10
50
65
79
85
a
Isolated yield.
Table 2
Adenine catalysed three-component Mannich type reaction of benzaldehyde, cyclo-
hexanone and aniline in the presence of varying amounts of 30% H2O2
Entry
H2O2 (ml)
Time (h)
Yielda (%)
syn:antib
1
2
3
4
5
—
8
6
6
6
6
85
91
93
95
95
40:50
22:78
20:80
17:83
18:82
.02
.03
.04
.05
a
Yields refer to isolated yields.
b
Diastereomeric ratio was determined by 1H NMR analysis at 400 MHz.
Figure 1. ORTEP plot of compound 4a.
Table 3
Adenine catalysed three-component Mannich type reaction of benzaldehyde, cyclohexanone and various amines
R1
R2
R2
R1
R2
R1
NH2
3
+
Adenine/ H2O2
rt
O
O
HN
O
HN
+
CHO
2
syn
anti
1a
4a - 4f
Entry
Amine (3)
Time (h)
Yielda,b (%)
syn:antic
a
b
c
d
e
f
R1 = R2 = H
6
4
8
10
4
5
95
90
80
82
92
84
17:83
71:29
26:73
23:77
70:30
82:18d
R
1 = Br, R2 = H
R1 = Me, R2 = H
R1 = OMe, R2 = H
R1 = I,R2 = H
R1 = NO2, R2 = H
a
Yields refer to isolated yields.
b
c
Compounds were analysed by 1H NMR, 13C NMR and elemental analysis.
Diastereomeric ratio was determined by 1H NMR analysis at 400 MHz.
Compounds were purified by column chromatography.
d

2386
P. Goswami, B. Das / Tetrahedron Letters 50 (2009) 2384–2388
ly optimised with 40
l
l of 30% H2O2 which gave excellent yield and
stituents gave anti-form as the chief products as evident from 1H
NMR results. These observations indicate that diastereoselectivity
of the Mannich products is governed by the nature of substituents
in aniline with our protocol.
Secondly, we tried to examine our protocol with a diverse
range of aldehydes 1g–l. The annotations indicate that both elec-
tron-donating and electron-withdrawing substituents on alde-
hydes undergo the reaction with good to excellent yields. In
contrast to aniline, the anti-products were invariably formed in
a major scale, independent of the nature of substituents on the
aldehyde as depicted in Table 4. It is worth mentioning that
the aliphatic aldehydes were inactive and failed to furnish the
desired products with this protocol.
better diastereoselectivity as presented in Table 2. The Mannich
product is precipitated out after the completion of the reaction.
The reaction mixture was added to water and the product was iso-
lated by simple filtration and further purified by recrystallisation
from chloroform.
These significant results encouraged us to examine the general-
ity and scope of our protocol with a variety of anilines and alde-
hydes substituted by both electron-withdrawing and electron-
donating groups. Thus a variety of amines 3a–f were examined
by the reaction with benzaldehyde 1a and cyclohexanone 2.13 Ta-
ble 3 points out to the fact that the substituents play a vital role in
directing the diastereoselectivity of the b-amino ketones. The pres-
ence of electron-withdrawing substituents on amine leads to the
major formation of syn products while the electron-donating sub-
The structure of 4a was further confirmed by recording a single-
crystal XRD and the ORTEP plot is shown in Figure 1.
Table 4
Adenine catalysed three-component Mannich type reaction of cyclohexanone, aniline and various aldehydes in the presence of 30% H2O2
NH2
O
HN
R2
O
Adenine/ H2O2
rt
O
HN
R2
3a
R3
R1
+
R3
R2
CHO
R1
2
R1
R3
1
4g - 4l
Entry
Aldehyde (1)
Time (h)
Yielda,b (%)
syn:antic
g
h
i
j
k
l
R1 = OMe, R2 = R3 = H
R1 = Cl, R2 = R3 = H
R1 = Br, R2 = R3 = H
R1 = OH, R2 = R3 = H
8
6
6
7
10
9
88
93
89
91
75
78
29:71d
41:59
35:65
31:69
39:61d
34:76
R
1 = R3 = H, R2 = NO2
R1 = R2 = H, R3 = Br
a
Yields refer to isolated yields.
b
c
Compounds were analysed by 1H NMR, 13C NMR and elemental analysis.
Diastereomeric ratio was determined by 1H NMR analysis at 400 MHz.
Compounds were purified by column chromatography.
d
Table 5
Adenine catalysed three-component Mannich type reaction of amines, 2-butanone and various aldehydes
NH2
3a
HN
O
HN
O
O
5
Adenine/H2O2
rt
CHO
R1
R1
R1
6a, 6g - 6j
7a, 7g - 7j
1
Entry
Aldehyde (1)
Time (h)
Yielda,b (%)
Regioisomer (6:7)c
syn:anti (7)d
a
g
h
i
R1 = H
6
4
8
4
7
95
90
79
91
75
56:44
70:30
53:47
72:27
75:25
17:83
29:71
26:74
31:69
49:51
R
1 = OMe
R1 = Cl
R1 = Br
R1 = OH
j
a
Yields refer to isolated yields.
Compounds were analysed by 1H NMR, 13C NMR and elemental analysis.
b
c,d
Diastereomeric and regioisomeric ratios were determined by 1H NMR analysis at 400 MHz.

P. Goswami, B. Das / Tetrahedron Letters 50 (2009) 2384–2388
2387
In order to broaden the generality of our protocol further, we
tried to extend our application to an acyclic ketone which was cho-
sen to be 2-butanone 5. A set of reactions were carried out with dif-
ferent aldehydes 1a and 1g–j with compounds 5 and 3a as shown
in Table 5. Although the reaction proceeded smoothly, it was not
ity is due to the more basic nature of nitrogen as compared to that
of oxygen.
Taking mechanism into consideration, the reaction proceeds
through the initial formation of imine 11 between the aldehyde
and the amine. Simultaneously, the catalyst 8 forms an imine 9
with the cyclohexanone moiety which tautomerises to form enam-
ine intermediate 10. Although both the E and Z enamines can be
formed, the formation of E enamine is thermodynamically more
favourable, leading to the formation of the diastereoselective Man-
nich products.14 Consequently the imine 11 comes in close proxim-
ity to 10 due to the hydrogen bonding and forms a six-membered
transition state 12 in due course. The proton transfer takes place to
form 13 which is further hydrolysed to 14 and the catalyst 8 is
regenerated which takes part in the cycle of reaction again. The
presence of water probably accelerates the reaction by helping in
hydrolysis and regeneration of the catalyst. The proposed reaction
mechanism is depicted in Scheme 3.
selective on the direction of attack on the
a-position of the car-
bonyl group giving two products 6 and 7, respectively. Subse-
quently, we observed two different diastereomers of
7 as
indicated from the 1H NMR spectra. However compound 5 was
found to be much less reactive than cyclohexanone and required
40 mol % of catalyst for completion. The anti-form was the major
product in these reactions.
In order to observe the chemoselectivity of cyclohexanone to-
wards the in situ-formed aldimines with the present protocol, an-
other set of reactions were accomplished as shown in Scheme 2.
The results highlight the fact that there is no aldol type of reaction
between aldehyde and cyclohexanone moiety. The chemoselectiv-
NH
O
2
CHO
Br
O
HN
Adenine/H2O2
+
+
rt
Br
O
CHO
Adenine/H2O2
rt
No reaction
+
Br
Scheme 2. Chemoselectivity of the present protocol.
R2
N
R1
11
H
N
N
R1CHO
R2NH2
N
N
N
N
N
N
H
N
H
N
R2
9
N
R1
O
10
H
N
N
N
N
H
N
12
R2
HN
R1
H
N
N
N
N
hydrolysis
N
N
N
N
N
R1
O
NH2
H
13
8
R2
N
H
14
Scheme 3. Probable reaction mechanism towards the synthesis of Mannich products.

2388
P. Goswami, B. Das / Tetrahedron Letters 50 (2009) 2384–2388
8. For review of asymmetric Mannich reactions see Verkade, J. M. M.; van Hemert,
In conclusion, we have reported an environmentally green and
L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc. Rev. 2008, 37, 29.
9. (a) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338; (b) Matsunaga, S.;
Kumagai, N.; Harada, S.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 4712; (c) Juhl,
K.; Gathergood, N.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2995; (d)
List, B. J. Am. Chem. Soc. 2000, 122, 9336; (e) List, B.; Pojarliev, P.; Biller, W. T.;
Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827; (f) Cordova, A.; Notz, W.; Zhong,
G.; Betancort, J. M.; Barbas, C. F., III J. Am. Chem. Soc. 2002, 124, 1842; (g)
Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem. Soc. 2002, 124, 5640; (h)
Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.; Shoji, M.; Sakai, M. Angew.
Chem., Int. Ed. 2003, 42, 3677; (i) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 12964.
10. (a) Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N. J. Am. Chem. Soc. 2003, 125,
11208; (b) Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.; Shoji, M.; Sakai,
K. Angew. Chem., Int. Ed. 2003, 42, 3677; (c) Hayashi, Y.; Urushima, T.; Shoji, M.;
Uchimaru, T.; Shiina, I. Adv. Synth. Catal. 2005, 347, 1595; (d) Hayashi, Y.;
Urushima, T.; Shin, M.; Shoji, M. Tetrahedron 2005, 61, 11393; (e) Hayashi, Y.;
Urushima, T.; Tsuboi, W.; Shoji, M. Nat. Protocols 2007, 2, 113.
11. For direct enantioselective Mannich reactions, see: (a) Trost, B. M.;
Jaratjaroonphong, J.; Reutrakul, V. J. Am. Chem. Soc. 2006, 128, 2778; (b)
Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048; (c) Shibasaki, M.;
Matsunaga, S. J. Organomet. Chem. 2006, 691, 2089; (d) Cordova, A. Acc. Chem.
Res. 2004, 37, 102.
12. (a) Cordova, A.; Barbas, C. F., III Tetrahedron Lett. 2003, 44, 1923; (b) Notz, W.;
Tanaka, F.; Watanabe, S.; Chawdari, N. S.; Turner, J. M.; Thayumanavan, R.;
Barbas, C. F., III J. Org. Chem. 2003, 68, 9624; (c) Azizi, N.; Torkiyan, L.; Saidi, M.
R. Org. Lett. 2006, 8, 2079; (d) Shimizu, S.; Shimada, N.; Sasaki, Y. Green Chem.
2006, 8, 608.
benign protocol for the synthesis of diastereoselective Mannich
products using adenine as the aminocatalyst. The lack of column
chromatography for majority of the compounds partially over-
comes the major problem of epimerisation of the Mannich prod-
ucts,15 faced during their purification through column
chromatography. Additionally, the non-requirement of work-up
procedure with organic solvents provides a greener edge to our
protocol. In a nutshell, our modus operandi should find a signifi-
cant place in the sphere of green synthetic organic chemistry.
Acknowledgements
The work was carried out with the financial Grant No. SR/FTP/
CS-15/2007 of DST, New Delhi, India. The authors are grateful to
the Director, IIT Guwahati for providing general facilities for this
work. The reviewers are duly acknowledged for their valuable
suggestions.
References and notes
13. Experimental procedure: To a mixture of aldehyde (1 mmol), cyclohexanone
(1 mmol) and amine (1 mmol) in ethanol–water 4:1 was added catalyst (20–
1. (a) List, B. Chem. Commun. 2006, 819; (b) Melchiorre, P.; Marigo, M.; Carlone, A.;
Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138.
40 mol %) followed by 40
lL of 30% H2O2. The reaction mixture was allowed to
2. Hupe, D. J.. In New Comprehensive Biochemistry; Page, M. I., Ed.; Elsevier:
Amsterdam, 1984; Vol. 6, pp 271–301.
stir at room temperature until the completion of the reaction as indicated by
thin layer chromatography (TLC). On completion, the reaction mixture was
poured in water upon which the product precipitates out. The product was
separated out by filtration and washed with water. The crude product was
recrystallised from chloroform and directly analysed for certain compounds
without further purification. Some compounds required purification by column
chromatography (hexane–ethyl acetate 9:1) and were later analysed.
3. (a) Pizzarello, S.; Weber, A. L. Science 2004, 303, 1151; (b) Tanaka, F.;
Thayumanavan, R.; Mase, N.; Barbas, C. F., III Tetrahedron Lett. 2004, 45, 325;
(c) Cordova, A.; Ibrahem, I.; Casas, J.; Sunden, H.; Engqvist, M.; Reyes, E. Chem.
Eur. J. 2005, 11, 4772; (d) Amedjkouh, M. Tetrahedron: Asymmetry 2005, 16,
1411; (e) Cordova, A.; Zou, W.; Ibrahem, I.; Reyes, E.; Engqvist, M.; Liao, W.-W.
Chem. Commun. 2005, 3586; (f) Zou, W.; Ibrahem, I.; Dziedzic, P.; Sunden, H.;
Cordova, A. Chem. Commun. 2005, 4946; (g) Ibrahem, I.; Zou, W.; Engqvist, M.;
Xu, Y.; Cordova, A. Chem. Eur. J. 2005, 11, 7024; (h) Bassan, A.; Zou, W.; Reyes,
E.; Himo, F.; Cordova, A. Angew. Chem., Int. Ed. 2005, 44, 7028; (i) Xu, Y.;
Cordova, A. Chem. Commun. 2006, 460; (j) Xu, Y.; Zou, W.; Sunden, H.; Ibrahem,
I.; Cordova, A. Adv. Synth. Catal. 2006, 348, 418.
4. (a) Witkop, B. J. Am. Chem. Soc. 1956, 78, 2873; (b) Pfau, M.; RibiKre, C. J. Chem.
Soc. D 1970, 66; (c) Clark, R. A.; Parker, D. C. J. Am. Chem. Soc. 1971, 93, 7257; (d)
De Jeso, B.; Pommier, J.-C. J. Chem. Soc., Chem. Commun. 1977, 565; (e) Boyd, D.
R.; Jennings, W. B.; Waring, L. C. J. Org. Chem. 1986, 51, 992; (f) Capon, B.; Wu,
Z.-P. J. Org. Chem. 1990, 55, 2317.
5. (a) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069; (b) Denmark, S. E.;
Nicaise, O. J.-C. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Ed.;
Springer: Berlin, 1999; p 923; (c) Arend, M.; Westermann, B.; Risch, N. Angew.
Chem., Int. Ed. 1998, 37, 1044; (d)Enantioselective Synthesis of R-Amino Acids;
Juaristi, E., Ed.; VCH: Weinheim, Germany, 1997; (e) Kleinman, E. F.. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford,
1991; Vol. 2, p 893. Chapter 2.3; (f) Marques, M. M. B. Angew. Chem., Int. Ed.
2006, 45, 348.
Compound 4a: Dirty white solid; 1H NMR (400 MHz, CDCl3,
A (syn)/B
(anti)) = 17/83): d 1.51–1.66 (m, 4H), 1.68–1.73 (m, 1H), 1.81–1.91 (m, 1H),
2.01–2.04 (m, 1H), 2.29–2.43 (m, 1H), 2.72–2.79 (m, 1H), 4.61 (d, 0.83H,
J = 6.8 Hz for B), 4.79 (d, 0.17H, J = 4.0 Hz for A), 6.52 (t, 2H, J = 8.4 Hz), 6.60–
6.64 (m, 1H), 7.03–7.08 (m, 2H), 7.19 (t, 2H, J = 7.6), 7.27–7.31 (m, 2H), 7.35 (t,
2H, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3, A/B = 17/83): d for A 25.09, 27.29,
28.90, 42.67, 56.89, 57.45, 114.34, 117.82, 127.29, 127.45, 128.79, 129.36,
142.24, 147.53, 212.47; for B 23.89, 28.19, 31.56, 42.03, 57.75, 58.19, 113.88,
117.76, 127.55, 127.79, 128.75, 129.35, 142.00, 147.53, 213.26. Anal. Calcd for
C19H21NO: C, 81.68; H, 7.58; N, 5.01. Found: C, 81.51; H, 7.61, N, 5.21.
Compound 4b: 1H NMR (400 MHz, CDCl3, A (syn)/B (anti)) = 71/29): d 1.65–1.69
(m, 4H), 1.84–1.93 (m, 1H), 1.98–2.23 (m, 1H), 2.28–2.35 (m, 1H), 2.38–2.42
(m, 1H), 2.63–2.77 (m, 1H), 4.53 (d, 0.29H, J = 6.8 Hz for B), 4.72 (d, 0.71H,
J = 4.4 Hz for A), 6.39 (t, 2H, J = 5.6 Hz), 7.11 (d, 1H, J = 8.0 Hz), 7.12 (d, 1H,
J = 8.0 Hz), 7.19 (t, 1H, J = 6.0 Hz), 7.27–7.32 (m, 4H); 13C NMR (100 MHz,
CDCl3, A/B = 71/29) for A: d 23.95, 28.06, 31.65, 42.07, 57.45, 58.29, 109.25,
115.39, 127.32, 127.57, 128.59, 131.81, 141.07, 146.45, 211.42; for B 24.94,
27.03, 28.61, 42.48, 56.49, 58.31, 109.45, 115.80, 127.45, 128.59, 131.81,
141.31, 146.65, 212.87. Anal. Calcd for C19H20BrNO: C, 63.70; H, 5.63; N, 3.91.
Found: C, 63.89; H, 5.75, N, 3.83.
6. (a) Muller, R.; Goesmann, H.; Waldmann, H. Angew. Chem., Int. Ed. 1999, 38,
184; (b) Bohme, H.; Haake, M. In Advances in Organic Chemistry; Taylor, E. C.,
Ed.; John Wiley and Sons: New York, 1976; p 107.
14. Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 6366.
15. Notz, W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004, 37, 580.
7. Holy, N.; Fowler, R.; Burnett, E.; Lorenz, R. Tetrahedron 1979, 35, 613.