Capture of benzotriazole-based Mannich electrophiles by CH-acidic compounds

Article abstract of DOI:10.1039/c3ra22826f

The Mannich-type capture reaction of aminoalkylbenzotriazoles by CH acidic compounds is documented. The pK_a of the benzotriazole counteranion is key to the success of such reactions, whereas the global electrophilicity of the reactive iminium m

Full text of DOI:10.1039/c3ra22826f

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Capture of benzotriazole-based Mannich electrophiles
by CH-acidic compounds3
Cite this: RSC Advances, 2013, 3, 4152
Jean-Christophe M. Monbaliu,ab Lucas K. Beagle,a Finn K. Hansen,ac Christian
V. Stevens,b Ciaran McArdled and Alan R. Katritzky*ae
Received 8th November 2012,
Accepted 14th January 2013
DOI: 10.1039/c3ra22826f
www.rsc.org/advances
The Mannich-type capture reaction of aminoalkylbenzotriazoles
by CH acidic compounds is documented. The pKa of the
benzotriazole counteranion is key to the success of such reactions,
whereas the global electrophilicity of the reactive iminium moiety
is secondary.
Mannich bases, have found numerous applications as building
blocks. Classically, the reaction requires harsh and prolonged
conditions thus restricting its scope. A significant diversification is
exemplified by the development of mild benzotriazole-mediated
aminoalkylations and related reactions.12–15 Benzotriazole-based
aminoalkylating reagents have been readily utilized with various
nucleophiles, including: enolates,16 imidazolidine derivatives,17
isonitriles,18 enol ethers,19–22 enamines,20,22,23 and enamides.22,23
Many active pharmaceutical ingredients (APIs) are obtained
through a key Mannich step or display the typical core of a
Mannich base.24,25 The most famous include tropanone and
derivatives,26 rifamycin,27 tramadol,28–30 procyclidine,31–33 fali-
cain,34 fluoxetine,35,36 rolitetracycline37,38 and tolmetin.39–41
In this communication, we now report the reaction of various
aminoalkylbenzotriazoles with a small library of C–H acidic
compounds. The reactivity of aminoalkylbenzotriazoles (1) is
rationalized by means of computational chemistry (global electro-
nic properties and thermodynamic considerations).
Developing facile methods for carbon–carbon bond formation
continues to be a synthetic challenge, especially in the context of
continuously expanding molecular diversity. Aminoalkylations are
powerful synthetic tools since they combine the creation of a new
carbon–carbon bond with an increase in molecular diversity and
functionality by the introduction of an amino moiety. For instance,
Patterson et al. recently reported an aminoalkylation reaction as a
key step in the synthesis of 1-(1-(benzo[b]thiophen-2-yl)cyclohex-
yl)piperidine analogs as inhibitors of trypanothione reductase.1
Over many decades, the Mannich reaction has been considered as
the most important methodology for the aminoalkylation of C–H
acidic compounds.
In the Mannich reaction, a C–H group is a-aminomethylated by
an iminium compound, generally formed in situ.2 Overall the
acidic H of the C–H group is converted to CR1R2–NR3R4.
Originally, R1 and R2 were both H, but the versatility of the
reaction was broadened by the development of variants using
preformed aldimines, iminium salts, aminals or hemiaminals as
Mannich electrophiles. Recent developments in the field have
renewed interest in the Mannich reaction, including intramole-
cular, organocatalytic,3–6 catalytic7 and stereoselective variants,8–10
often supported by new technological breakthroughs.11
Furthermore, the products of such reactions, the so-called
We selected a small library of representative compounds 1a–i
(Fig. 1) from the range of aminoalkylbenzotriazoles reported in the
literature.12,42–44 The behavior of compounds 1a–i has been
studied in the past by spectroscopic and semi-empirical methods,
in solution and in the solid state.45–47 They have been shown to act
as milder sources of electrophilic iminium cations 3a–e than the
corresponding Eschenmoser’s salts 2a,b.16,48 It is well-known that
aminoalkylbenzotriazoles equilibrate in solution to mixtures of N1
and N2 isomers, the reactivity of which towards nucleophilic
displacement is similar,45–47 in agreement with our computations.
aCenter for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, FL 32611-7200, USA. E-mail: katritzky@chem.ufl.edu
bDepartment of Sustainable Organic Chemistry and Technology, Faculty of Bioscience
Engineering, Ghent University, B-9000 Ghent, Belgium
c
¨
¨
Institut fur Pharmazeutische and Medizinische Chemie, Heinrich Heine Universitat
¨
¨
¨
Dusseldorf, Universitatsstr. 1, 40225 Dusseldorf, Germany
dHenkel Ireland Ltd., Tallaght Business Park, Whitestown Industrial Estate, Tallaght,
Dublin 24, Ireland
eChemistry Department, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
Fig. 1 Selection of Mannich electrophiles (see Tables 1 and 2 for Gibbs free energies
Electronic supplementary information (ESI) available: Detailed computational
3
and enthalpies of reaction).
procedures and thermochemical data. See DOI: 10.1039/c3ra22826f
4152 | RSC Adv., 2013, 3, 4152–4155
This journal is ß The Royal Society of Chemistry 2013

View Article Online
RSC Advances
Communication
Table 1 Chemical potential (m), global hardness (g) and global electrophilicity
(v) for iminium species 3a–e
Table 3 Reaction parameters for the formation of iminium species 3b from 1f–i.
Reaction parameters are given in kcal mol21. No significant differences in
activity were computed between the 5- and the 6-substituted benzotriazoles
(see ESI)
Iminium
m (u.a.)
g (u.a.)
v (eV)
3a
3b
3c
3d
3e
20.4108
20.3862
20.3733
20.3996
20.4303
0.2776
0.2470
0.1276
0.1353
0.1629
8.3
8.2
14.9
16.1
15.5
Gas phase rt
THF rt
THF reflux
Compound EDG/EWG DGu
DHu
DGu DHu DGu
DHu
1f
Me
OMe
Cl
108.8
108.3
101.9
102.2
120.9
121.3
114.1
113.3
21.1 33.3 19.4
21.3 34.5 19.5
17.3 29.7 15.6
20.6 31.9 10.2
33.3
34.5
29.6
24.1
1g
1h
1i
NO2
The values reported in Table 1 refer to the N1 isomers. Data for the
N2 isomer can be found in the ESI.
3
At first, we looked at global electrophilicity (v) of the iminium
Ethyl cyanopropanoate 4a is commercially available and was
species 3a–e (see Table 1 and ESI for detailed procedure), as we
3
selected as a model CH-acidic compound for a preliminary
investigation. N-Aminoalkylbenzotriazoles 1a–i and the related
chloro-compounds 2a,b were screened for Mannich-type capture
suspected that global electronic properties would be responsible
for reactivity towards nucleophiles.49–57 Results from Table 1 show
that the iminium species 3a–e are strong electrophiles on the
electrophilicity scale57 and this electrophilicity is enhanced in the
aromatic pyrrolyl 3c, imidazoyl 3d and triazoyl 3e iminium species.
The position of the equilibrium linking precursors 1a–e, 2a,b
and the corresponding iminium species 3a–e was computed at the
B3LYP/6-31+G** level of theory in the gas phase at room
temperature and in THF at room temperature and reflux (see
reactions (see Scheme 1 and experimental details in the ESI ).
3
The best results were obtained for compound 1b, with 61%
conversion after 18 h under reflux in THF (Table 4). A lower
conversion was observed for the reaction with 1a. For the
heteroaromatic series, 20% conversion was obtained for 1c while
reactions with 1d,e failed. This trend in capture activity for
compounds 1a–e follows the variation in DGu disclosed in Table 2.
Surprisingly, the capture reaction with the classical Mannich
electrophiles 2a,b failed, although the computed DGu indicated a
favorable shift of the equilibrium towards the iminium species
3a,b. Furthermore, modification of the benzotriazole moiety either
computational details in ESI ). In total agreement with experi-
3
mental observations, the equilibrium is predicted to be more
towards the formation of the iminium species 3a,b in the case of
the Eschenmoser’s salts than for their benzotriazole surrogates.
The latter are thus latent sources of iminium cations. Table 2
indicates that, despite the very high electrophilicity of the
corresponding iminium cations, the pyrrolyl (1c), imidazoyl (1d)
and triazoyl (1e) compounds are significantly less prone to release
their iminium counterpart than the dimethyl (1a) or pyrrolidine
(1b) analogs.
To extend the scope of this preliminary study, we also
considered the effect that various EWG (electron-withdrawing)
and EDG (electron-donating) groups would have on the benzo-
triazole moiety modulating the reactivity of the corresponding
aminoalkylbenzotriazoles 1f–i, using 1-((pyrrolidin-1-yl)methyl)-
1H-benzo[d][1,2,3]triazole 1b for comparison (Table 3).
Thermochemical computations revealed that strong electron
withdrawing groups such as NO2 allowed for similar DGu values
as the chloro-analogs 2a,b (see compound 1i in Table 3).
Scheme 1 Mannich type capture of CH-acidic compounds 4a–d with
N-aminoalkylbenzotriazoles 1a–i and related chloro-compounds 2a,b.
Table 4 Yield of the Mannich type capture of ethyl cyanopropanoate 4a with
N-aminoalkylbenzotriazoles 1a–i and related chloro-compounds 2a,b
Table 2 Reaction parameters for the formation of iminium species 3a–e from
1a–e and 2a,b. Reaction parameters are given in kcal mol21
Mannich electrophile
Yield (%)
1a
1b
1c
1d
1e
1f
1g
1h
1i
44
61
20
0
Gas phase rt
THF rt
THF reflux
Compound
DGu
DHu
DGu
DHu
DGu
DHu
1a
1b
1c
1d
1e
2a
2b
112.3
107.6
139.6
152.8
162.9
110.9
106.3
124.9
119.8
151.1
164.3
174.9
119.1
114.1
22.0
19.9
51.1
61.8
70.7
9.2
34.6
32.3
63.0
74.1
82.6
16.0
15.2
20.4
18.3
49.5
60.2
69.1
8.3
34.5
32.2
62.9
74.1
82.5
15.9
15.2
0
39
49
54
51
0
2a
2b
8.4
7.4
0
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 4152–4155 | 4153

View Article Online
Communication
RSC Advances
5 J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M. Quaedflieg and
F. P. J. T. Rutjes, Chem. Soc. Rev., 2008, 37, 29.
6 W. Notz, F. Tanaka, S. I. Watanabe, N. S. Chowdari, J.
M. Turner, R. Thayumanavan and C. F. J. Barbas, J. Org.
Chem., 2003, 68, 9624.
7 U. Kazmaier, Angew. Chem., Int. Ed., 2009, 48, 5790.
8 M. Hatano and K. Ishihara, Synthesis, 2010, 22, 3785.
9 C. Mukhopadhyay, A. Datta and R. J. Butcher, Tetrahedron Lett.,
2009, 50, 4246.
10 S. Kobayashi and R. Matsubara, Chem.–Eur. J., 2009, 15, 10694.
11 A. Cukalovic, J.-C. M. R. Monbaliu and C. V. Stevens, Top.
Heterocycl. Chem., 2010, 23, 161.
12 A. R. Katritzky, M. S. Kim and K. Widyan, ARKIVOC, 2008, iii,
91.
13 A. R. Katritzky, H. Yang and S. K. Singh, J. Org. Chem., 2005, 70,
286.
14 A. R. Katritzky, K. Manju, S. K. Singh and N. K. Meher,
Tetrahedron, 2005, 61, 2555.
15 A. R. Katritzky and P. A. Harris, Tetrahedron, 1990, 46, 987.
16 P. C. B. Page, S. M. Allin, E. W. Collington and R. A. E. Carr, J.
Org. Chem., 1993, 58, 6902.
17 J. S˛aczewski and M. Gdaniec, Tetrahedron Lett., 2007, 48, 7624.
18 A. R. Katritzky, P. P. Mohapatra, S. K. Singh, N. Clemens and K.
J. Kirichenko, J. Serb. Chem. Soc., 2005, 70, 319.
19 B. Merla and N. Risch, J. Prakt. Chem., 1999, 341, 472.
20 A. R. Katritzky, C. N. Fali and D. C. Oniciu, Tetrahedron, 1995,
51, 1069.
by including EDG or EWG substituents (compounds 1f–1i)
lowered the yield in comparison to the original compound 1b.
The latter results clearly indicate the impact of the pKa of the
counteranion generated (X) on the capture reaction: in the cases of
2a,b, the counteranions generated are weak bases, unable to
deprotonate 4a, despite a favourable equilibrium towards 3a. For
compounds 1h,i, the introduction of an EWG on the benzotriazole
lowers DGu but also impacts on the pKa of the corresponding
benzotriazolate (pKa = 8.56, 7.62 and 6.31 for X = H, Cl and NO2,
respectively).58 The introduction of an EDG (compounds 1f,g)
slightly increases the pKa of the corresponding benzotriazolate but
also impacts on DGu, becoming less favorable for the iminium
species 3b. According to these results, 1b was selected for further
testing.
To obtain further evidence for the pKa-sensitivity of the
Mannich-type capture step, other commercially available CH
acidic compounds were considered for reaction with 1b including
ethyl 2-methyl-3-oxobutanoate 4b (pKa = 12.3),59 methyl malonitrile
4c (pKa = 12.4),60 diethyl 2-methylmalonate 4d (pKa = 17)58 and
ethyl cyanopropanoate 4a (pKa = 9).59 The following yields were
obtained: 61, 29, 27 and 4% for the capture of 1b by 4a–d,
respectively, showing clearly a linear correlation between the pKa
of the CH acidic compound and the yield of the reaction with 1b.
Conclusions
21 A. R. Katritzky, S. Rachwal, B. Rachwal and P. J. Steel, J. Org.
Chem., 1992, 57, 4932.
22 A. R. Katritzky, S. Rachwal and B. Rachwal, J. Org. Chem., 1993,
58, 812.
23 A. R. Katritzky, S. Rachwal and B. Rachwal, J. Org. Chem., 1994,
59, 5206.
24 M. P. Dewick, Medicinal Natural Products: A Biosynthetic
Approach, John Wiley & Sons Ltd, 2002, 2nd edn.
25 R. S. Vardanyan and V. J. Hruby, Synthesis of Essential Drugs,
Elsevier, 2001.
This preliminary work documents the reactivity of aminoalk-
ylbenzotriazoles as Mannich electrophiles. In their reaction with
CH acidic compounds, several factors have been identified: (i) the
reaction heat for the formation of the iminium cation, (ii) the pKa
of the counteranion X, and (iii) the pKa of the CH acidic partner.
The pKa of both X and the CH acidic compound appears to be
crucial, whereas global electrophilicity of the corresponding
iminium cation seems to be secondary. These observations are
consistent with thermodynamic control of the reaction.
26 A. J. Humphrey and D. O’Hagan, Nat. Prod. Rep., 2001, 18, 494.
27 N. Maggi, A. Vigevani and R. Pallanza, Experientia, 1968, 24,
209.
Acknowledgements
28 A. C. Nikolopoulos and H. C. Schickaneder, Eur. Pat.
0996613B1, 2002.
29 Z. Itov and H. Meckler, Org. Process Res. Dev., 2000, 4, 291.
30 P. Blaney, R. Grigg, Z. Rankovic and M. Thoroughgood,
Tetrahedron Lett., 2000, 41, 6639.
31 J. W. Olney, U.S. Pat. 5037848, 1989.
32 E. Jassmann and H. Pfanz, Ger. Pat. 1084734, 1960.
33 W. Adamson, U.S. Pat. 2891890, 1959.
This work was supported by the Research Foundation-Flanders
(FWO-Vlaanderen; fellowship to JCMM). JCMM acknowledges
the ICT Department of Ghent University for access to HPC
facilities. The authors acknowledge the Kenan Foundation
(University of Florida), the King Abdulaziz University (Saudi
Arabia) and Henkel Ireland Ltd. for financial support and
permission to publish. Dr N. Lefevre is acknowledged for
stimulating discussions.
34 G. R. Brown, A. M. Bamford, J. Bowyer, D. S. James, N. Rankine,
E. Tang, V. Torr and E. J. Culbert, Bioorg. Med. Chem. Lett., 2000,
10, 575.
Notes and references
35 B. Ahmed-Omer and A. J. Sanderson, Org. Biomol. Chem., 2011,
9, 3854.
1 S. Patterson, D. C. Jones, E. J. Shanks, J. A. Frearson, I.
H. Gilbert, P. G. Wyatt and A. H. Fairlamb, ChemMedChem,
2009, 4, 1341.
2 M. Arend, B. Westermann and N. Risch, Angew. Chem., Int. Ed.,
1998, 37, 1044.
¨
36 P. J. Kairisalo, A. H. Jarvinen and P. J. Hukka, U.S. Pat. 5166437,
1992.
37 M. Nelson, W. Hillen and R. A. Greenwald, Tetracyclines in
¨
Biology, Chemistry and Medicine, Birkhauser Verlag, Switzerland,
3 Y. Zhao, Y. Pan, S.-B. D. Sim and C.-H. Tan, Org. Biomol. Chem.,
2012, 10, 479.
2001.
38 M. Johansen and H. Bundgaard, Arch. Pharm. Chem., Sci. Ed.,
1981, 9, 40.
4 J. W. Yang, C. Chandler, M. Stadler, D. Kampen and B. List,
Nature, 2008, 452, 453.
4154 | RSC Adv., 2013, 3, 4152–4155
This journal is ß The Royal Society of Chemistry 2013

View Article Online
RSC Advances
Communication
39 L. A. Reddy, S. Chakraborty, R. Swapna, D. Bhalerao, G.
C. Malakondaiah, M. Ravikumar, A. Kumar, G. S. Reddy,
J. Naram, N. Dwivedi, A. Roy, V. Himabindu, B. Babu,
A. Bhattacharya and R. Bandichhor, Org. Process Res. Dev.,
2010, 14, 362.
40 F. Corelli, A. Garofalo, S. Massa, R. Silvestri and P. Prosiniand
M. Artico, J. Heterocycl. Chem., 1990, 27, 1489.
41 J. R. Carson, D. N. McKinstry and S. Wong, J. Med. Chem., 1971,
14, 646.
42 A. R. Katritzky, M. Qi, D. Feng and D. A. Nichols, J. Org. Chem.,
1997, 62, 4121.
43 A. R. Katritzky, N. Shobana and P. A. Harris, Tetrahedron Lett.,
1990, 31, 3999.
44 A. R. Katritzky, M. Drewniak-Deyrup, X. Lan and F. Brunner, J.
Heterocycl. Chem., 1989, 26, 829.
45 A. R. Katritzky and K. Yannakopoulou, J. Org. Chem., 1990, 55,
5683.
46 A. R. Katritzky, K. Yannakopoulou, W. Kuzmierkiewicz, J.
M. Aurrecoechea, G. J. Palenik, A. E. Koziol and M. Szczesniak,
J. Chem. Soc., Perkin Trans. 1, 1987, 2673.
47 J. R. L. Smith and J. S. Sadd, J. Chem. Soc., Perkin Trans. 1, 1975,
1181.
48 E. F. Kleinman, Comprehensive Organic Synthesis, ed. B. M.
Trost, I. Fleming and C. H. Heathcock, Pergamon, Oxford,
1991, vol. 2, p. 893.
´
49 L. R. Domingo and P. Perez, Org. Biomol. Chem., 2011, 9, 7168.
´
50 L. R. Domingo and J. A. Saez, Org. Biomol. Chem., 2009, 7, 3576.
´
51 L. R. Domingo, E. Chamorro and P. Perez, J. Org. Chem., 2008,
73, 4615.
´
´
52 L. R. Domingo, J. A. Saez and P. Perez, Chem. Phys. Lett., 2007,
438, 341.
´
53 M. J. Aurell, L. R. Domingo, P. Perez and R. Contreras,
Tetrahedron, 2004, 60, 11503.
´
54 P. Perez, L. R. Domingo, M. J. Aurell and R. Contreras,
Tetrahedron, 2003, 59, 3117.
´
55 L. R. Domingo, P. Perez and R. Contreras, J. Org. Chem., 2003,
68, 6060.
´
56 L. R. Domingo, M. J. Aurell, P. Perez and R. Contreras,
Tetrahedron, 2002, 58, 4417.
´
57 R. G. Parr, L. von Szentpaly and S. Liu, J. Am. Chem. Soc., 1999,
121, 1922.
58 R. Wasik, M. Łebska, K. Felczak, J. Poznanski and D. Shugar, J.
Phys. Chem. B, 2010, 114, 10601.
´
59 N. Vicart, J. Gore and B. Cazes, Tetrahedron, 1998, 54, 11063.
60 R. Vianello and Z. B. Maksic, Eur. J. Org. Chem., 2004, 5003.
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 4152–4155 | 4155