A facile synthesis of stable β-amino-N-/O-hemiacetals through a catalyst-free three-component Mannich-type reaction

Article abstract of DOI:10.1016/j.tetlet.2017.02.084

A practical, straightforward and one-step procedure for the synthesis of novel and stable β-amino-N-/O-hemiacetals (i.e. γ-aminoalcohols) is provided. The title compounds were obtained in good to excellent yields through an uncatalyzed three-component reaction by treatment of secondary amines with polyformaldehyde and electron-rich alkenes in acetonitrile as solvent at ambient temperature. The reactions proceeded with the formation of iminium ions, through a Mannich-type reaction, as the key intermediates for the generation of the target products. Single crystal X-ray analysis of derivative 4l confirmed unequivocally the structure and stability of the obtained compounds.

Full text of DOI:10.1016/j.tetlet.2017.02.084

Accepted Manuscript
A facile synthesis of stable β-amino-N-/O-hemiacetals through a catalyst-free
three-component Mannich-type reaction
Rodrigo Abonia, Juan C. Castillo, Alexander Garay, Braulio Insuasty, Jairo
Quiroga, Manuel Nogueras, Justo Cobo, Richard D'Vries
PII:
S0040-4039(17)30272-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.084
TETL 48695
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 February 2017
21 February 2017
27 February 2017
Please cite this article as: Abonia, R., Castillo, J.C., Garay, A., Insuasty, B., Quiroga, J., Nogueras, M., Cobo, J.,
D'Vries, R., A facile synthesis of stable β-amino-N-/O-hemiacetals through a catalyst-free three-component
Mannich-type reaction, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.084
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Tetrahedron Letters
journal homepage: www.els evier.com
A facile synthesis of stable β-amino-N-/O-hemiacetals through a catalyst-free three-
component Mannich-type reaction
Rodrigo Aboniaa, ∗, Juan C. Castilloa,b, Alexander Garaya, Braulio Insuastya, Jairo Quirogaa, Manuel
Noguerasc, Justo Coboc and Richard D´Vriesd,e
a Research Group of Heterocyclic Compounds, Department of Chemistry, Universidad del Valle, A. A. 25360, Cali, Colombia
b Bioorganic Compounds Research Group, Department of Chemistry, Universidad de los Andes, Carrera 1 No. 18A-10, Bogotá, 111711, Colombia
c Department of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spain
d Instituto de Fisica de São Carlos, Universidade de São Paulo, CP 369, 13560-970 - São Carlos, SP, Brazil
e Universidad Santiago de Cali, Calle 5 # 62-00, Cali, Colombia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A practical, straightforward and one-step procedure for the synthesis of novel and stable β-
amino-N-/O-hemiacetals (i.e γ-aminoalcohols) is provided. The title compounds were obtained
in good to excellent yields through an uncatalyzed three-component reaction by treatment of
secondary amines with polyformaldehyde and electron-rich alkenes in acetonitrile as solvent at
ambient temperature. The reactions proceeded with the formation of iminium ions, through a
Mannich-type reaction, as the key intermediates for the generation of the target products. Single
crystal X-ray analysis of derivative 4l confirmed unequivocally the structure and stability of the
obtained compounds.
Available online
Keywords:
Multicomponent reactions
Aminoalcohols
Hemiacetals
2009 Elsevier Ltd. All rights reserved.
Green chemistry
Mannich-type reaction
Introduction
considerable attention has been focused on the opiate-
agonists Tramadol and analogues.4d (Figure 1).
Contemporary research in organic synthesis focuses on
atom economy.1 Indeed, the efficiency of a synthetic
sequence is dependent upon the average molecular
complexity produced per operation, which depends in turn
on the number of chemical bonds being created. Therefore,
devising reactions that achieve multi-bond formation in one
operation is becoming one of the major challenges in
searching for step-economic synthesis. Multicomponent
reactions (MCR´s) are processes in which three or more
reactants are combined in a single chemical step to afford
products that incorporate substantial fragments of all the
components.2a-e Indeed, many important reactions such as
Strecker (1850),2f Hantzsch (1882),2g Biginelli (1891),2h
Mannich (1912),2i Passerini (1921),2j Ugi (1959),2k among
others, are all multicomponent.
Figure 1. Some representative examples of biologically active γ-
aminoalcohols.
Hemiacetals are commonly formed when an equivalent
of alcohol adds to the carbonyl carbon of an aldehyde.5
Reaction proceeds in an equilibrium and contrary to the
The γ-aminoalcohols are valuable building blocks in
organic synthesis,3a,b in particular, because they are
important precursors in the preparation of a variety of
natural occurring products and compounds of biological
interest.3c-i Thus, Venlafaxine is an antidepressant of the
serotonin-norepinephrine reuptake inhibitor (SNRI) class,4a
Haloperidol is a potent dopamine antagonist,4b,c while
stability displayed by their five-
/
six-membered
intramolecular cyclic analogues (called lactols),5a,b in the
most cases, the open chain hemiacetals are intrinsically
unstable and the equilibrium tend to favor the parents
aldehyde and alcohol.5c,d There are just few examples of
stable and isolable open chain hemiacetals, especially from
———
∗ Corresponding author. Tel.: +57-2-339-3248; fax: +57-2-339-3248; e-mail: rodrigo.abonia@correounivalle.edu.co

2
aldehydes
bearing
electron-withdrawing
groups,6
component
Mannich-type
reaction/intramolecular
particularly, several of them derived from chloral.6e-h
electrophilic aromatic substitution sequence would be
possible to obtain the desired product 5 by stirring at room
temperature a mixture of benzylmethylamine 1a (1 equiv),
polyformaldehyde 2 (1.2 equiv) and N-vinyl-2-pyrrolidone
3a (1 equiv) in methanol (MeOH) as protic solvent. After
analysis by spectroscopic techniques, we noticed that the
formation of the desired product 5 did not occur and instead
the unexpected γ-aminoether 7 was obtained as unique
product (Scheme 1, route 1). This finding indicated that
MeOH acted not only as the solvent but also as the
nucleophile, trapping the carbocationic species 6 before the
expected intramolecular cyclization process could occur.11c
According to this result, we decided to repeat the same
experiment but using an aprotic an non nucleophilic solvent
(i.e. dry acetonitrile, ACN) instead of methanol in order to
avoid the competition by the cation 6 and address the
reaction toward the desired product 5. After 72 h of stirring
(TLC control), a dense oily material was obtained and
purified by column chromatography on silica gel using a
mixture CHCl3:MeOH (15:1) as eluent. After analysis by
spectroscopic techniques, we confirmed that the formation
of the expected product 5 did not occur again, and instead
Attempts have been made in the past to improve
methodologies based on direct or indirect Mannich-type
reactions involving nucleophiles such as enolates, enol
ethers, and enamines.7 These processes were found to be
extremely substrate- and conditions-dependent, long
reactions time and often required the use of an appropriate
catalyst such as organocatalysts,8 transition metal-based
Lewis acids,9 and Brønsted acid/bases.10 Therefore, the
development of new versions of the Mannich-type reaction
working under mild conditions have been declared a subject
of great importance.
In connection with our current program on the synthetic
utilization of benzylamine derivatives for multiple bond-
forming reactions,11 herein, we wish to report our results on
the unplanned, catalyst-free and highly efficient synthesis of
novel
and
stable
β-amino-N-/O-hemiacetals
(γ-
aminoalcohols), through a three-component Mannich-type
approach.
Results and discussion
the
unexpected
β-amino-N-hemiacetal
(also
γ-
In an attempt to obtain the novel 2-benzazepine
derivative 5 (Scheme 1), a scaffold of high synthetic and
biological interest,12 we considered that through a three-
aminoalcohol) 4a was obtained as the sole product in 71%
isolated yield, (Scheme 1, route 2).
Scheme 1. Synthesis of the novel β-amino-N-hemiacetal 4a.
The main spectroscopic features of the structure of
compound 4a correspond to the presence of O-H, C=O and
C-O absorption bands at 3411, 1682 and 1107 cm-1,
respectively, in the IR spectrum. A NCH3 signal at 2.22
ppm, six methylenic signals between 1.57-3.64 ppm and a
doublet of doublets integrating for 1H at 5.62 ppm (dd, J =
9.0, 3.4 Hz) assigned to the new aza-hemiacetal proton
(NCH-OH), along with five (but not four if product 5 had
been obtained) aromatic protons are the most relevant
Although, the aza-hemiacetal 4a in principle, was not our
expected product, owing to the practical usefulness of its
structural parents γ-aminoalcohols,3,4 we decided to explore
in more detail this process. Then, in order to determine the
reproducibility of this experiment, a chemset of diversely
substituted secondary amines 1a-q was evaluated, Table 1.
Particularly, the commercially unavailable amines 1d-n
were synthesized from a one-pot reductive amination of
primary benzylamines with arenealdehydes, involving the
pre-formation of their respective imines followed by
reduction with NaBH4 in methanol at room temperature (see
Supplementary data).11a
1
signals in the H NMR spectrum. The signal corresponding
to the hydroxyl proton (O-H) is not observed due to a rapid
chemical proton exchange. The presence of six methylene
carbon atoms at 18.1, 29.5, 31.8, 41.8, 54.6 and 62.5 ppm,
the NCH3 signal at 41.6 ppm, the signal of the aza-
hemiacetal carbon atom (NCH-OH) at 76.5 ppm, three
aromatic CH signals at 127.4, 128.4, 129.1 ppm and two
quaternary carbon atoms at 137.5 and 175.0 (C=O) ppm in
the 13C NMR spectrum, are in agreement with the proposed
structure for compound 4a. A molecular ion peak with m/z
262, also confirmed its structure.
Thus, applying this multicomponent methodology to the
further amines 1b-q with N-vinyl-2-pyrrolidone 3a under
the established conditions (i.e. (CH2O)n, ACN, room
temperature and stirring for 72 h), to our satisfaction, the
corresponding β-amino-N-hemiacetals 4b-q were obtained
as shown in Table 1. In all cases reactions proceeded with
the same behavior and yields in the range of 51-93%, except
for compound 4q (see Table 1 foot note).

Table 1. Three-component synthesis of novel and stable β-amino-N-hemiacetals 4a-q
[a]These compounds were obtained as mixtures (95:5) and (17:83) ratios, respectively, along with their cyclization side-products (i.e.
tetrahydroquinolines). Reported yields are after isolation from column chromatography.
Additionally, to increase the scope of this protocol,
heterocyclic amines 1r,s and the cyclic vinyl ethers 3b,c,
(Figure 2), were assayed under the established reaction
conditions.
Figure 2. Additional amines 1r,s and cyclic vinyl ethers 3b,c
employed as reagents for the synthesis of a further family of β-amino-
N-/O-hemiacetals 4.
Satisfactorily, all reactions afforded the desired products
4r-w in good yields (Table 2). In general, all products 4
were obtained as colorless or pale yellow oily materials
except for compounds 4c and 4l which were obtained as
white solids.
Table 2. Additional examples of β-amino-N-/O-hemiacetals 4 obtained from the chemset of amines 1r,s and cyclic ethers
3b,c
Most compounds 4 were obtained as air and light stable
oily materials (only 4c and 4l were solids). Particularly, 4a-
s were isolated as racemic mixtures due to the chirality of
the carbon atom of their aza-hemiacetal functionalities
(NCH-OH) formed. While, compounds 4t-w (bearing two
chiral carbon atoms), were obtained as mixtures of their
corresponding cis and trans diastereomers, being the trans
isomer the main component for 4t (i.e. d.r = 48:52 cis:trans)
and 4u (i.e. d.r = 33:67 cis:trans). In contrast, the cis isomer
was the main component for 4v (i.e. d.r = 71:29 cis:trans)
and 4w (i.e. d.r = 79:21 cis:trans). The diastereomeric ratios
(d.r) were calculated from the 1H NMR spectra of their
crudes. Although the signal corresponding to the hydroxyl
proton in the 1H NMR spectra should be an important
structural feature, only compounds 4b, 4j, 4k, 4p, 4q and 4s
showed a broad singlet in the range of (4.97-6.12 ppm) for
this functionality. A rapid chemical proton exchange should
explain this outcome.

4
Tetrahedron
According to the results, it may be suggested that the
synthesis of the hemiacetals 4 commenced with the
formation of a hemiaminal 8 from the reaction of the
secondary amine 1 and formaldehyde 2, which should be
simultaneously in equilibrium with the aminal 9 and the
iminium ion 10 (its counter ion Y = OH- if comes from 8 or
(R1CH2)R2N- if comes from 9), as shown in Scheme 2. In all
cases during the course of the reactions, we detected by
TLC the partial transformation of the secondary amines 1
into aminals type 9 although they were completely re-
consumed during the reaction. Particularly, the aminal 9a
(R1 = Ph, R2 = CH3) was isolated and thoroughly
characterized (see Supplementary data). Moreover,
treatment of aminal 9a (1 equiv) with polyformaldehyde 2
(0.7 equiv) and alkene 3a (2 equiv) under the established
reaction conditions also afforded the expected product 4a;
so confirming its presence as an intermediate in this three-
component reaction. Subsequently, the iminium ion 10
should be trapped by the alkene 3 via a Mannich-type
reaction leading to the carbocationic species type 6
(stabilized by a resonant effect with the free electronic pair
of the X-substituent), through an irreversible process
affording the new C-C bond. Formation of the proposed
hydroxyl species 10 (a tightly ionic pair) from 8 and 9,
should be the key intermediate and source of the OH- ions
for the synthesis of the isolated hemiacetals 4. The
intermolecular attack of the hydroxyl counter ion or a water
molecule over the species 6 should led the isolated β-amino-
N-/O-hemiacetals 4.
Scheme 2. Proposed mechanistic sequence for the
formation of the β-amino-N-/O-hemiacetals 4 via the
iminium ion 10.
Albeit, all compounds 4 showed in their IR spectra broad
bands in the range of (3325-3517 cm-1) associated with the
O-H stretching vibration of the hydroxyl functionality,
1
some of them were not observed in their H NMR spectra.
For
a further confirmation of the presence of this
functionality, we performed a couple of derivatization
reactions involving such functional group. Thus, the
oxidation of 4c with o-iodoxybenzoic acid (IBX) afforded
the corresponding solid amide 11c isolated in moderate
46% yield as shown in Scheme 3. The following experiment
consisted in the conversion of the N-hemiacetal 4c into the
alkene 12c in 48% yield, via a dehydration process by
treatment with triphenylphosphine and iodine.13 In
consequence, the chemical transformation of 4c into both
oxidation and dehydration products 11c and 12c,
respectively, confirmed the presence of the hydroxyl
functionality in structures 4.
Scheme 3. Oxidation and dehydration reactions over the N-hemiacetal 4c.
In addition to the above experiments and in order to confirm
unequivocally the presence of this functionality and the stability
of these compounds, after several attempts, we finally could
grow single crystals suitable for X-ray diffraction of compound
4l in ethyl ether at room temperature. As shown in Figure 3 (and
Supplementary data), there is no doubt that the obtained
compounds 4 effectively corresponds to the hemiacetal structures
proposed in Scheme 1 and Tables 1, 2.
Figure 3. ORTEP drawing of the asymmetric unit for the N-hemiacetal 4l;
ellipsoids are displayed at the 50% probability level.

Chem. Soc. 1953, 75, 4458–4461; (f) Risi, C.; Fanton, G.; Pollini,
G. P.; Trapella, C.; Valente, F.; Zanirato, V. Tetrahedron: Asymm.
2008, 19, 131–155; (g) Robertson, D. W.; Krushinski, J. H.;
Fuller, R. W.; Leander, J. D. J. Med. Chem. 1988, 31, 1412–1417;
(h) Liu, D.; Gao, W.; Wang, C.; Zhang, X. Angew. Chem. Int. Ed.
2005, 44, 1687–1689; (i) Afarinkia, K.; Bahar, A. Tetrahedron:
Asymm. 2005, 16, 1239–1287.
At this stage, remarkable features of our methodology are the
facts that it does not involve the use of any catalyst, three new
bonds are formed in sequence during the process and the reaction
proceeds smoothly at room temperature. Moreover, the OH
source for the last step of the process depicted in Scheme 2
corresponded to the H2O (OH-) released from the formation of 9
or 10, respectively. In consequence, the starting compounds 1, 2
and 3 are consumed stoichiometrically in the formation of
products 4 without releasing by-products. These findings are in
agreement with the atomic economy concept providing also an
environmentally friendly character to this three-component
procedure.
4. (a) Yardley, J. P.; Husbands, G. E. M.; Stack, G.; Butch, J.;
Bicksler, J.; Moyer, J. A.; Muth, E. A.; Andree, T.; Fletcher, H.;
James, M. N. G.; Sielecki, A. R. J. Med. Chem. 1990, 33, 2899–
2905; (b) Atlas, D.; Friedman, Z.; Litvin, Y.; Steer, M. L. Br. J.
Pharmac. 1982, 75, 213–217; (c) Scherz, M. W.; Fialeix, M.;
Fischer, J. B.; Reddy, N. L.; Server, A. C.; Sonders, M. S.; Tester,
B. C.; Weber, E.; Wong, S. T.; Keana, J. F. W. J. Med. Chem.
1990, 33, 2421–2429; (d) Gais, H. J.; Greibel, C.; Buschmann, H.
Tetrahedron: Asymm. 2000, 11, 917–928.
In summary, we have implemented an efficient and
straightforward approach for the synthesis of novel and stable β-
amino-N-/O-hemiacetals (γ-aminoalcohols) 4 in good to excellent
yields from an uncatalyzed three-component Mannich-type
reaction at ambient temperature. The fact that all three precursors
(i.e. amine, formaldehyde and alkene), were stoichiometrically
consumed in the course of the reactions and three new bonds (i.e.
C-O, C-N and C-C) were formed in only one-step without
producing by-products, provide an outstanding bond-forming
efficiency and environmentally friendly quality to this approach.
Further studies oriented to increase of the scope of this
methodology (i.e. try with primary amines, superior aldehydes
instead of CH2O and other activated alkenes), as well as, the
variation of the reaction conditions attempting to force the
reaction toward the cyclized benzazepinic systems 5, are
currently in progress.
5. (a) Moss, G. P.; Smith, P. A. S.; Tavernier, D. Pure Appl. Chem.
1995, 67, 1307–1375; (b) Liu, J.; Wong, C-H. Angew. Chem. Int.
Ed.
2002,
41,
1404–1407;
(c)
See:
www.chtf.stuba.sk/~szolcsanyi/education/files/Chemia%20heteroc
yklickych%20zlucenin/Prednaska%206/Odporucane%20studijne
%20materialy/Acetaly.pdf; (d) Chiang, Y.; Kresge, J. J. Org.
Chem. 1985, 50, 5038–5040.
6. (a) Meester, W. J. N.; van Maarseveen, J. H.; Schoemaker, H. E.;
Hiemstra, H.; Rutjes, F. P. J. T. Eur. J. Org. Chem. 2003, 2519–
2529; (b) Miller, J. F.; Spaltenstein, A. Tetrahedron Lett. 1996,
37, 2521–2524; (c) Gunaratne, H. Q. N.; Nockemann, P.; Seddon,
K. R. Chem. Commun. 2015, 51, 4455–4457; (d) Vinogradov, V.
M.; Starosotnikov, A. M.; Shevelev, S. A. Mendeleev Commun.
2002, 12, 198–200; (e) See: Cloxotestosterone at:
www.chemicalbook.com/ProductChemicalPropertiesCB61178371
_EN.htm; (f) Ram, R. N.; Meher, N. K. Tetrahedron, 2002, 58,
2997–3001; (g) Hashimoto, M.; Isono, T.; Mano, K. Ber.
Bunsenges. Phys. Chem. 1994, 98, 793–803; (h) Jensen, R. B.;
Munksgaard, E. C. Acta Chem. Scand. 1964, 18, 1896–1904.
7. (a) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338–
339; (b) Matsunaga, S.; Kumagai, N.; Harada, S.; Shibasaki, M. J.
Am. Chem. Soc. 2003, 125, 4712–4713; (c) Juhl, K.; Gathergood,
N.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2995–2997;
(d) List, B. J. Am. Chem. Soc. 2000, 122, 9336–9337; (e) List, B.;
Pajarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002,
124, 827–833.
Acknowledgments
Authors thank COLCIENCIAS, Universidad del Valle-Project
No CI-7812, the Spanish “Consejería de Innovación, Ciencia y
Empresa, Junta de Andalucía” the “Centro de Instrumentación
Científico-Técnico de la Universidad de Jaén” and AUIP for
financial support. R.D. acknowledges to CAPES/PNPD
scholarship from Brazilian Ministry of Education (MEC).
8. (a) Chandler, C.; Galzerano, P.; Michrowska, A.; List, B. Angew.
Chem., Int. Ed. 2009, 48, 1978–1980; (b) Dubs, C.; Hamashima,
Y.; Sasamoto, N.; Seidel, T. M.; Suzuki, S.; Hashizume, D.;
Sodeoka, M. J. Org. Chem. 2008, 73, 5859–5871.
9.
(a) Yang, Y. Y.; Shou, W. G.; Wang, Y. G. Tetrahedron 2006,
62, 10079–10086; (b) Shou, W. G.; Yang, Y. Y.; Wang, Y. G.
Tetrahedron Lett. 2006, 47, 1845–1847; (c) Azizi, N.; Torkiyan,
L.; Saidi, M. R. Org. Lett. 2006, 8, 2079–2082.
References and notes
1. For step economy: (a) Wender, P. A.; Verma, V. A.; Paxton, T. J.;
Pillow, T. H. Acc. Chem. Res. 2008, 41, 40–49. For atom
economy: (b) Trost, B. M. Acc. Chem. Res. 2002, 35, 695–705.
For redox economy: (c) Burns, N. Z.; Baran, P. S.; Hoffmann, R.
W. Angew. Chem. Int. Ed. 2009, 48 (16), 2854–2867.
10. Yamashita, Y.; Suzuki, H.; Kobayashi, S. Org. Biomol. Chem.
2012, 10, 5750–5752; (b) Wu, H.; Chen, X. M.; Wan, Y.; Ye, L.;
Xin, H. Q.; Xu, H. H.; Yue, C. H.; Pang, L. L.; Ma, R.; Shi, D. Q.
Tetrahedron Lett. 2009, 50, 1062–1065; (c) Akiyama, T.; Takaya,
J.; Kagoshima, H. Tetrahedron Lett. 2001, 42, 4025–4028.
11. (a) Abonia, R.; Castillo, J.; Insuasty, B.; Quiroga, J.; Nogueras,
M.; Cobo, J. Eur. J. Org. Chem. 2010, 6454–6463; (b) Castillo, J.;
Abonia, R.; Cobo, J.; Glidewell, C. Acta Cryst. 2009, C65, o303–
o310; (c) Abonia, R.; Castillo, J.; Insuasty, B.; Quiroga, J.;
Nogueras, M.; Cobo, J. ACS Comb. Sci. 2013, 15, 2–9.
12. (a) Buolamwini, J. Curr. Pharm. Des. 2000, 6, 379–392; (b)
Luckhurst, C. A.; Ratcliffe, M.; Stein, L.; Furber, M.; Botterell, S.;
Laughton, D.; Tomlinson, W.; Weaver, R.; Chohan, K.; Walding,
A. Bioorg. Med. Chem. Lett. 2011, 21, 531–536; (c) Grunewald,
G. L.; Dahanukar, V. H.; Criscione, K. R. Bioorg. Med. Chem.
Lett. 2001, 9, 1957–1965; (d) Basolo, L.; Beccalli, E. M.; Borsini,
E.; Broggini, G.; Pellegrino, S. Tetrahedron 2008, 64, 8182–8187;
(e) Grunewald, G. L.; Caldwell, T. M.; Dahanukar, V. H.; Jalluri,
R. K.; Criscione, K. R. Bioorg. Med. Chem. Lett. 1999, 9, 481–
486.
2. (a) Dömling, A. in Multicomponent reactions (Eds.: J. Zhu, H.
Bienaymé), Wiley-VCH, Weinheim, 2005, pp. 76–80; (b)
Coquerel, Y.; Boddaert, T.; Presset, M.; Mailhol, D.; Rodriguez, J.
in Ideas in chemistry and molecular sciences: Advances in
synthetic chemistry (Ed.: B. Pignataro), Wiley-VCH, Weinheim,
2010, pp. 187–202; (c) Tietze, L. F.; Brasche, G.; Gericke, K. M.
(Eds.) in Domino reactions in organic synthesis, Wiley-VCH,
Weinheim, 2006, pp. 542–565; (d) Dömling, A. Chem. Rev. 2006,
106, 17–89; (e) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G.
Angew. Chem. Int. Ed. 2006, 45, 7134–7186; (f) Jarusiewicz, J.;
Choe, Y.; Yoo, K. S.; Park, C. P.; Jung, K. W. J. Org. Chem.
2009, 74, 2873–2876; (g) Kumar, A.; Maurya, R. A. Synlett. 2008,
883–885; (h) Ryabukhin, S. V.; Plaskon, A. S.; Ostapchuk, E. N.;
Volochnyuk, D. M.; Tolmachev, A. A. Synthesis 2007, 417–427;
(i) Cordoba, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F.
J. Am. Chem. Soc. 2002, 124, 1866–1867; (j) Andrade, C. K. Z.;
Takada, S. C. S.; Suarez, P. A. Z.; Alves, M. B. Synlett 2006,
1539–1541; (k) Akritopoulou-Zanze, I.; Gracias, V.; Djuric, S. W.
Tetrahedron Lett. 2004, 45, 8439–8441.
13. Alvarez-Manzaneda, E. J.; Chahboun, R.; Alvarez-Manzaneda, R.;
Cabrera-Torres, E.; Haidour, A.; Ramos, J. Tetrahedron Lett.
2004, 45, 4453–4455.
3. (a) Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. Rev. 2007, 107,
767–796; (b) Szakonyi, Z.; Gonda, T.; Ötvös, S. B.; Fülöp, F.
Tetrahedron: Asymm. 2014, 25, 1138–1145; (c) Kotland, A.;
Accadbled, F.; Robeyns, K.; Behr, J. B. J. Org. Chem. 2011, 76,
4094–4098; (d) Calvet, G.; Blanchard, N.; Kouklovsky, C. Org.
Lett. 2007, 9, 1485–1488; (e) Pohland, A.; Sullivan, H. R. J. Am.
Supplementary Material
Supplementary data related to this article can be found at
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6
Tetrahedron
Graphical Abstract
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A facile synthesis of stable β-amino-N-/O-hemiacetals through a
catalyst-free three-component Mannich-type reaction
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Rodrigo Abonia,a,* Juan C. Castillo,a,b Alexander Garay,a Braulio Insuasty,a Jairo Quiroga,a Manuel Nogueras,c Justo Coboc and
Richard D´Vriesd,e
aDepartment of Chemistry, Universidad del Valle, A. A. 25360, Cali, Colombia.
bBioorganic Compounds Research Group, Department of Chemistry, Universidad de los Andes, Carrera 1 No. 18A-10, Bogotá,
111711, Colombia.
cDepartment of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spain.
dInstituto de Fisica de São Carlos, Universidade de São Paulo, CP 369, 13560-970 - São Carlos, SP, Brazil.
e Universidad Santiago de Cali, Calle 5 # 62-00, Cali, Colombia.

A catalyst-free three-component Mannich-type
reaction is proposed
Novel and stable β-amino-N-/O-hemiacetals were
obtained from this strategy
Reactions proceeded with the formation of iminium
ions as the key intermediates
Single crystal X-ray analysis confirmed the
structure and stability of the obtained compounds