Proline-catalyzed facile access to Mannich adducts using unsubstituted azoles

Article abstract of DOI:10.1016/j.tetlet.2008.09.155

A novel and facile method for the direct construction of C-C-N bond with unsubstituted azoles under Mannich conditions is developed for the first time. The reaction is catalyzed efficiently by l-proline to give the Mannich adducts 1a-10b in DMSO, whereas in water, insertion of two successive bonds, C-C-N and C-C-O occurred to give compounds 11a-20b. The latter are deformylated readily into the desired products 1a-10b under basic conditions. Mechanistic aspects for the formation of these products are discussed.

Full text of DOI:10.1016/j.tetlet.2008.09.155

Tetrahedron Letters 49 (2008) 7070–7073
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Proline-catalyzed facile access to Mannich adducts using unsubstituted azoles q
*
Nagarapu Srinivas, Kalpana Bhandari
Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and facile method for the direct construction of C–C–N bond with unsubstituted azoles under
Received 20 August 2008
Revised 24 September 2008
Accepted 26 September 2008
Available online 1 October 2008
Mannich conditions is developed for the first time. The reaction is catalyzed efficiently by L-proline to
give the Mannich adducts 1a–10b in DMSO, whereas in water, insertion of two successive bonds, C–C–
N and C–C–O occurred to give compounds 11a–20b. The latter are deformylated readily into the desired
products 1a–10b under basic conditions. Mechanistic aspects for the formation of these products are
discussed.
Keywords:
Azoles
Ó 2008 Elsevier Ltd. All rights reserved.
Mannich adduct
Mannich-aldol
L-Proline
Aza-Michael addition
Deformylation
The Mannich reaction is extremely useful for the construction of
nitrogenous molecules.1 In this transformation, three components,
a ketone, an aldehyde, and an amine react to form a b-amino-
ketone. A large number of methods with different amines are
reported in the literature which involve conjugate addition of an
enol to a preformed iminium ion.2 To date no direct Mannich
adduct from unsubstituted azoles (C–C–N bond) has been reported,
as these are unreactive under normal Mannich conditions3 and are
not able to form iminium ions with aldehyde. Andreani et al.4 have
prepared Mannich adducts of imidazoles indirectly by amine
exchange reactions, with Mannich salts (Scheme 1). The same
method has been followed for synthesis of related compounds
for various applications.5
N
X
R
N
X
N
HN
n
n
NH R'
H
Amine exchange
with azole
O R, R'=alkyl
O
Mannich adduct
Mannich salt
Scheme 1. Mannich adducts of azoles via amine exchange.
we hypothesized that, generation of an
a,b-unsaturated carbonyl
intermediate in situ, formation of the Mannich adduct (C–C–N
bond) would be possible by reaction with unsubstituted azoles
(by aza-Michael addition).10 For this, we chose cheap and readily
As is widely known, azoles are potential targets for drug discov-
ery,6 because of their diverse biological properties such as antipar-
asitic, antibacterial, antiviral, antiepileptic, anti-allergic, and
others.7 More recently, we have demonstrated the high antileish-
manial activity of novel benzocycloalkyl azoles, which makes these
compounds promising targets for the development of effective
therapeutic agents. We have synthesized N-substituted azoles8
by the reported amine exchange method. Attempts have been
made to introduce such bonds directly, and in this Letter we report
the details of our investigations and proposed mechanisms
involved in the formation of these products.
available
the reaction of a ketone (1.0 equiv), imidazole (1.0 equiv), parafor-
maldehyde (1.0 equiv), and -proline (0.3 equiv) in DMSO at 60 °C.
L-proline as the organo catalyst. We initially investigated
L
As expected, the Mannich adduct 1a was obtained in 96% yield Ta-
ble 1. Subsequently, we found that on increasing the quantity of
paraformaldehyde, product 1a condensed with excess formalde-
hyde and afforded the Mannich-aldol-type product 11a (Table 2).
In order to show the generality and scope of this transformation,
different ketones were used. As shown in Table 1, a wide range
of ketones were suitable. Five- to seven- membered cyclic ketones
participated efficiently in the process to furnish products 1a–7b in
high yields. Acyclic ketones were also good substrates affording
8a–10b with moderate yields. The substituents on the phenyl ring
did not have any significant effect on the reaction (Table 1, 3a–5a
and 9a–10b). Further, imidazole was found to be more reactive
than triazole which can be attributed to its higher pKa value
(14.5) in aqueous media compared to triazole (9.4).11
Recent literature reports show the success of organo catalysts in
the formation of a
,b-unsaturated ketones.9 Based on this precedent
q
CDRI communication No. 7527.
* Corresponding author. Tel.: +91 522 2612411 18; fax: +91 522 2623405.
E-mail address: bhandarikalpana@rediffmail.com (K. Bhandari).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.155

N. Srinivas, K. Bhandari / Tetrahedron Letters 49 (2008) 7070–7073
7071
In view of the interest in reactions in aqueous medium,12 the
reaction was run in water instead of DMSO. The reaction occurred
very cleanly to afford the corresponding 2-hydroxymethyl-2-azol-
1-ylmethyl derivatives 11a–20b, instead of the expected Mannich
Table 2
Insertion of two consecutive (C–N, C–O) bonds on reaction with an unsubstituted
azole, paraformaldehyde, and a ketone in water catalyzed by L-proline
R
R
1) (HCHO)n (2 equiv)
3) L-proline (0.3 equiv)
N
X
N
n
N
n
+
X
Table 1
N
H2O / 100 ºC
n= 0-2
Ketone
H
L-Proline-catalyzed direct Mannich adducts prepared from an unsubstituted azole,
paraformaldehyde, and a ketone in DMSO
O
11a-20b
O
X= CH; Imidazole
X= N; 1,2,3-triazole
OH
1
R
1) (HCHO)n (1 equiv)
3) L-proline (0.3 equiv)
R
Comp. no.
X
Producta,b,d
Time (h)
Yieldc
N
n
n
+
N
X
N
X
º
N
N
DMSO / 60 - 80
C
X
N
n= 0-2
Ketone
H
O
O 1a- 10b
11a
11b
CH
N
4.5
7
95
82
X= CH; Imidazole
X= N; 1,2,3-triazole
1
OH
O
O
Comp.
no
X
Ketone 1
Producta,d
Time Yieldb,c
(h)
N
X
N
12a
12b
CH
N
6
8.5
92
79
N
X
OH
O
N
1a
CH
N
1.5
2
96
81
1bc
O
O
H3CO
Cl
N
X
13a
14a
CH
CH
4
4
90
92
N
N
X
N
2a
CH
N
2
2.5
93
76
OH
N
2bc
O
O
X
N
H3CO
H3CO
N
X
N
OH
O
3a
4a
CH
CH
2
3
91
93
F
O
O
N
N
X
15a
CH
3.5
88
Cl
Cl
N
N
N
X
N
OH
O
O
X
N
O
O
16a
16b
CH
N
2.5
6
92
82
F
F
OH
O
X
N
5a
CH
3
89
O
O
O
O
O
OH
17a
17b
CH
N
5
9
92
61
X
N
N
H3C
N
O
X
N
6a
6b
CH
N
2
4
96
72
N
X
N
O
O
18a
19a
CH
CH
12
36
39
O
OH
O
O
7a
CH
N
3
4.5
94
69
X
N
N
N
H3CO
Cl
H3C
H3C
7bc
X
O
N
O
11.5
OH
N
O
N
X
N
8a
9a
CH
CH
5.5
51
50
X
N
20a
20b
CH
N
13
24
33
12
O
O
OH
O
H3CO
H3CO
N
X
N
a
Unless specified, a mixture of ketone 1 (100 mg, 1 equiv), imidazole (46 mg,
-proline (0.3 equiv) in water
6
1 equiv), paraformaldehyde (132 mg, 2 equiv), and
L
(0.5–1.5 mL) (for detailed procedure see Supplementary data) were stirred at 100 °C
(at 60 °C the product conversion was very slow).
O
O
Cl
b
Cl
The same ketones as in Table. 1 were used.
Isolated yields.
c
N
X
N
10a
CH
N
5.5
8
55
26
d
No enantio selectivity was observed.
10bc
O
O
a
Reactions of triazoles in DMSO were carried at 80 °C.
Isolated yields.
Less than 0.3 equiv of catalyst gave low yields, loading above 0.3 equiv gave the
adducts 1a–10b. However, the reaction did not reach completion
(starting materials remained). Therefore, the reaction was per-
formed with 2 equiv of paraformaldehyde and proceeded to
completion to afford the Mannich-aldol-type products 11a–20b
b
c
same yields.
d
Reactions were not enantio selective.

7072
N. Srinivas, K. Bhandari / Tetrahedron Letters 49 (2008) 7070–7073
anhy. K2CO3
/
L-proline /
under heating
paraformaldehyde
abs. ethanol, 90 ºC
N
N
n
N
X
N
n
X
N
or
n
n
n
OH
usual aldol
anhy. K2CO3
CH3CN, 80 ºC
/
H2O
O
N
b
X
O
a
O
OH
11a-20b
1a-10b
O
O
O
ketone
N
X
N
HN
n
N
L-proline
paraformaldehyde
X
N
n
retro-aldol
HCHO
X
OH
n
n
d
O
N
OH
X
N
c
O
N
Mannich-adduct
OH
Scheme 3.
L-Proline-catalyzed aldol/aza-Michael addition pathway.
Scheme 2. Conversion of Mannich-aldol-type products into Mannich adducts.
anilide V and
L-proline-chloro anilides VII were found to be ineffec-
(Table 2) in good to excellent yields typically. Moreover, the
reaction in water comprised a highly efficient one-pot insertion
of two successive bonds, that is, C–C–N and C–C–O. Further, we
were excited to find that the Mannich-aldol-type products
11a–20b were converted smoothly to the corresponding Mannich
adducts 1a–10b with anhydrous K2CO3 in absolute ethanol. On
replacing ethanol with acetonitrile, the rate of transformation in
the case of acyclic compounds was better than with the corres-
ponding cyclic compounds. We propose a retro-aldol deformyla-
tion13 mechanism for this transformation Scheme 2.
tive catalysts for the process (entries 12 and 15) and furnished 1a
and 11a in almost equal ratios. Satisfactory yields with
nitro anilide VI (entries 13 and 14) were observed.
L-proline-
In order to determine whether the carboxylic function was
essential, we carried out the same reaction with secondary amines,
namely, pyrrolidine III and morpholine IV. The reaction conversion
was high, but instead of the expected Mannich adducts, normal
Mannich bases of the corresponding amines were furnished in
major amounts along with product 11a (entries 8–11).
II was comparable to -proline (entries 5–7). The best results were
obtained with -proline. In water, Mannich-aldol-type product 11a
L-Alanine
L
To demonstrate the feasibility of the proposed organo catalytic
Mannich reaction, we carried out a model reaction of a-tetralone 1
L
was observed exclusively, irrespective of the catalyst used (entries
7, 9, 11, and 14). In isopropanol, ethanol, and t-butanol, low yields
of Mannich adducts 1a were observed (entries 2–4). However, in
solvents other than water and alcohols, both products 11a and
1a were obtained in varying ratios. The results of this study
prompted us to select DMSO to prepare Mannich adducts and
water for Mannich-aldol-type products as the reaction media and
(1 equiv) with imidazole (1 equiv) and paraformaldehyde (1 equiv)
in the presence of different catalysts (0.3–0.5 equiv) and solvents
(Table 3). Examination of the results of the catalyst screening
revealed that the catalyst activities varied significantly. L-Proline-
Table 3
Solvent and catalyst optimizationa
L
-proline as the catalyst.
To propose a possible mechanism for this process, the reaction
N
N
1) (HCHO)n (1 equiv)
2) cat (0.3 equiv)
was carried out under controlled conditions. On carefully monitor-
ing the course of the reaction of the ketone, paraformaldehyde,
imidazole, and 0.3 equiv of L-proline in DMSO, we were able to iso-
OH
K2CO3 / Abs.ethanol
90 º
N
11a
1a
O
+
solvent,60-100 º
C
N
H
C
N
O
late a b hydroxy ketone a (aldol product) from the reaction mixture
along with the Mannich product c (Scheme 3). As expected, on
further reaction, the b hydroxy ketone a disappeared completely,
and c was isolated as the only product.
1
2
N
O
O
O
R
O
COOH
N
H3C
OH
N
N
H
H
On the basis of the above observations and literature reports,14
it can be postulated that the reaction involves the formation of an
aldol product a which undergoes dehydration and generates
N
NH2
L-Alanine
II
N
H
H
H
L-proline
Pyrrolidine
(V) R=H, (VI) R=NO2
(VII) R=Cl
Morpholine
I
III
IV
in situ, an
a,b-unsaturated carbonyl intermediate b. This reacts
Entry
Solvent
Catalyst
Time
(h)
Temp.
(°C)
Yieldb (%)
Ratio of
11a/1ac
readily with an azole (via aza-Michael addition) to give the Man-
nich adduct c. In the presence of excess formaldehyde, an enamine
forms with the catalyst and reacts via aldol condensation to afford
the 2-hydroxymethyl-2-azol-1-ylmethyl (Mannich-aldol-type)
product d.
In summary, we have developed an efficient method for the di-
rect construction of Mannich adducts with unreactive imidazoles
and triazoles using the readily available and inexpensive catalyst,
1
2d
3d
4d
5
DMF
EtOH
IPA
t-Butanol
DMSO
DMF
H2O
DMSO
H2O
DMSO
H2O
DMSO
DMSO
H2O
I
I
I
I
II
II
II
III
III
IV
IV
V
VI
VI
VII
None
5
12
24
24
5
60
90
90
90
60
83
27
24
18
89
81
86
16
18
13
12
39
56
67
22
0
6:94
0:100
0:100
0:100
12:88
21:79
100:0
100:0
100:0
100:0
100:0
40:60
53:47
100:0
45:55
—
6
6
6
60
70
7d
8e
18
18
24
24
48
18
24
48
48
100
100
100
100
60
60
70
60
60
9e
L-proline. We have also reported a method for insertion of two con-
10e
11e
12
13
14d
15
16
secutive functional arms, that is, C–C–N and C–C–O at the -posi-
a
tion of a keto group. This reaction is applicable to a wide range of
ketones, affording good to excellent yields of products. We are cur-
rently utilizing this method for the synthesis of bioactive mole-
cules bearing azolylmethyl and hydroxymethyl moieties and
related compounds.15
DMSO
DMSO
a
A mixture of
a-tetralone 1 (100.0 mg, 1 equiv), Imidazole (46.0 mg, 1 equiv),
paraformaldehyde (66.0 mg, 1 equiv), and catalyst (0.3 equiv) in a specified solvent
Acknowledgments
(0.5–1.5 mL) was stirred at 60–100 °C.
b
Total isolated yield of 1a and 11a.
Ratio with respect to isolated yield.
Reaction was not complete (starting materials remained).
Reaction run using 0.5 equiv of catalyst.
The authors are grateful to SAIF for analytical data and to A. K.
Srivastava for technical assistance. N.S.V. is thankful to the UGC,
New Delhi, India, for financial support.
c
d
e

N. Srinivas, K. Bhandari / Tetrahedron Letters 49 (2008) 7070–7073
7073
Braemer, A. C.; Hitt, S.; Jones, R. E.; Matthews, T. R. J. Med. Chem. 1978, 21, 840–
843; (d) Sato, M.; Arimoto, M.; Ueno, K.; Kojima, H.; Yamasaki, T.; Sakurai, T.;
Kasahara, A. J. Med. Chem. 1978, 21, 1116–1120.
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data and NMR spectra) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.09.155.
7. (a) Lingi, A.; Alfonso, M.; Pierluigi, R.; Afro, G.; Enzo, Z.; Nicola, D. T.; Walter, M.
J. Med. Chem. 1969, 12, 122–126; (b) Brik, F.; Godefrot; Reatge, J. J. Med. Chem.
1972, 15, 336–337; (c) Verma, M.; Chaturvedi, A. K.; Chaudary, A.; Parmar, S. S.
J. Pharm. Sci. 1974, 463, 1740–1744.
8. (a) Bhandari, K.; Srinivas, N.; Shiva Keshava, G. B.; Shukla, P. K. Eur. J. Med.
Chem., in press; (b) Bhandari, K.; Srinivas, N.; Nishi; Palne, S.; Gupta, S. Ind. Pat.
22NF/2008, 7.3.2008.
References and notes
9. (a) Wang, W.; Mei, Y.; Li, H.; Wang, J. Org. Lett. 2005, 7, 601–604; (b) Sato, K.;
Kuriyama, M.; Shimazawa, R.; Morimoto, T.; Kakiuchi, K.; Shirai, R. Tetrahedron
Lett. 2008, 49, 2402–2406; (c) Erkkila, A.; Pihko, P. M. J. Org. Chem. 2006, 71,
2538–2541. For a review, see: (d) Heathcock, C. H. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.; Springer: Berlin, 1991;
Vol. 2, p 133; (e) Mogilaiah, K.; Reddy, N. V. Synth. Commun. 2003, 33, 73–76;
(h) Husson, J.; Migianu, E.; Beley, M.; Kirsch, G. Synthesis 2004, 267–271.
10. (a) Horvath, A. Tetrahedron Lett. 1996, 37, 4423–4426; (b) Barra, D. E.; Guerra,
J.; Hornillos, V.; Merino, S.; Tejeda, J. Tetrahedron Lett. 2004, 45, 6937; (c)
Moran, J.; Dornan, P.; Beauchemin, M. A. Org. Lett. 2007, 9, 3893–3896.
11. Catalan, J.; Menendez, M.; Elguero, J. Bull. Soc. Chim. Fran. 1985, 30–33.
12. (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic and
Professional: London, 1998; (b) Li, C. J. Chem. Rev. 1993, 93, 2023.
13. (a) Nagata, H.; Miyazawa, N.; Ogasawara, K. Org. Lett. 2001, 3, 1737–1740; (b)
Peng, L.; Ma, M.; Zhang, X.; Zhang, S.; Wang, J. Tetrahedron Lett. 2006, 47, 8175–
8178.
14. (a) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573–575; (b) Nakadai, M.;
Saito, S.; Yamamoto, H. Tetrahedron 2002, 58, 8167; (c) Ishihara, K.; Kurihara,
H.; Yamamoto, H. Synlett 1997, 597; (d) Yanagisawa, A.; Goudu, R.; Arai, T. Org.
Lett. 2004, 6, 4281–4283; (e) Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett.
2003, 5, 2559–2561.
15. (a) Silvestri, R.; Artico, M.; Regina, G. L.; Pasquali, A. D.; Martino, G. D.; Auria, F.
D.; Nencioni, L.; Palamara, A. T. J. Med. Chem. 2004, 47, 3924–3926; (b)
Karakurta, A.; Dalkara, S.; Ozalp, M.; Ozbey, S.; Kendi, E.; Stables, J. P. Eur. J.
Med. Chem. 2001, 36, 421–433; (c) Emami, E.; Falahati, M.; Banifetemi, A.;
Amanlou, M.; Shafiee, A. Bioorg. Med. Chem. 2004, 12, 3971–3976; (d) Emami,
S.; Foroumadi, A.; Falahati, M.; Lotfali, E.; Rajabalian, S.; Ebrahimi, S. A.;
Farahyar, S.; Shafiee, A. Bioorg. Med. Chem. 2008, 16, 4509–4515.
1. Reviews: (a) Kleinnmann, E. F. In Comprehensive Organic Synthesis; Trost, B. M.,
Ed.; Springer: Berlin, 1991, Vol. 2, Chapter 4.1; (b) Arend, M.; Westermann, B.;
Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044; (c) Denmark, S. E.; Nicaise, O. J.
C. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer: Berlin, 1999; pp 923–961; (d) Kobayashi, S.; Ishitani, H.
Chem. Rev. 1999, 99, 1069–1094; (e) Dickens, P. J.; Ellames, G. J.; Hare, N. J.;
Lawson, K. R.; Mckay, W. R.; Metters, A. P.; Mayers, P. L.; Pope, M. S.; Upton, R.
M. J. Med. Chem. 1991, 34, 2356–2360; (f) Bhandari, K.; Srivastava, S.; Shanker,
G.; Nath, C. Bioorg. Med. Chem. 2005, 13, 1739–1747; (g) Bhandari, K.;
Srivastava, S.; Shanker, G.; Nath, C. Bioorg. Med. Chem. 2006, 14, 2535–2544.
2. (a) Cordova, A. Acc. Chem. Res. 2004, 37, 102–112; (b) Manabe, K.; Kobayashi, S.
Org. Lett. 1999, 1, 1965–1967; (c) Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.;
Barbas, C. F., III. Tetrahedron Lett. 2001, 42, 199–201; (d) Katritzky, A. R.;
Galuszka, B.; Rachwal, S.; Black, M. J. Heterocycl. Chem. 1994, 31, 917–924; (e)
Cordova, A.; Barbas, C. F., III. Tetrahedron Lett. 2003, 44, 1923–1926; (f) Cordova,
A., ; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 1749–7752; (g) Notz, W.;
Tanaka, F.; Wantanabe, S. I.; Chowdari, N. S.; Turner, J. M.; Thayumenavan, R.;
Barbas, C. F., III. J. Org. Chem. 2003, 68, 9624–9634; (h) Zhao, G. L.; Cordova, A.
Tetrahedron Lett. 2006, 47, 7417–7421; (i) Dziedzic, P.; Ibrahem, I.; Cordova, A.
Tetrahedron Lett. 2008, 49, 803–807.
3. Bachman, G. B.; Heisey, L. V. J. Am. Chem. Soc. 1946, 68, 2496–2499.
4. (a) Andreani, F.; Andrisano, R.; Della casa, C.; Tramontini, M. Tetrahedron Lett.
1968, 1059–1061; (b) Andreani, F.; Andrisano, R.; Della casa, C.; Tramontini, M.
J. Chem. Soc. (C) 1970, 1157–1164.
5. Roman, G.; Comanita, E.; Comanita, B. Tetrahedron 2002, 58, 1617–1622.
6. (a) Nezhad, A. K.; Rad, M. N. S.; Mohabatkar, H.; Asraria, Z.; Hemmateenejad, B.
Bioorg. Med. Chem. 2005, 13, 1931–1938; (b) Godefroi, E. F.; Heeres, J.; Custem,
J. V.; Janssen, P. A. J. Med. Chem. 1969, 12, 784–791; (c) Walker, K. A. M.;