Direct Synthesis of Hemiaminal Ethers via a Three-Component Reaction of Aldehydes, Amines and Alcohols

Article abstract of DOI:10.1002/adsc.201500588

The reaction of aldehydes, amines and alcohols usually leads to a series of equilibria from which isolation of one product is difficult to achieve. We have found that this three-component reaction can be controlled and directed in an exclusive manner toward the formation of the hemiaminal ether. A series of 33 hemiaminal ethers has been obtained in high yields, from different aldehydes, amines and alcohols, under very mild conditions just with molecular sieves as promoter.

Full text of DOI:10.1002/adsc.201500588

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DOI: 10.1002/adsc.201500588
Direct Synthesis of Hemiaminal Ethers via a Three-Component
Reaction of Aldehydes, Amines and Alcohols
a
b
a,

lvaro Beltrµn, Eleuterio lvarez, M. Mar Díaz-Requejo, *
a,
and Pedro J. PØrez *
Laboratorio de Catµlisis HomogØnea, Unidad Asociada al CSIC, CIQSO-Centro de Investigación en Química Sostenible,
a
Departamento de Química, Campus de El Carmen s/n, Universidad de Huelva, 21007 Huelva, Spain
Fax: (+34)-959-219942; phone: (+34)-959-219956; e-mail: mmdiaz@dqcm.uhu.es or perez@dqcm.uhu.es
Instituto de Investigaciones Químicas Isla de la Cartuja, CSIC-Universidad de Sevilla, Avenida de AmØrico Vespucio 49,
b
41092 Sevilla, Spain
Received: June 17, 2015; Published online: September 11, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500588.
Abstract: The reaction of aldehydes, amines and al-
cohols usually leads to a series of equilibria from
which isolation of one product is difficult to ach-
ieve. We have found that this three-component re-
action can be controlled and directed in an exclu-
sive manner toward the formation of the hemiami-
nal ether. A series of 33 hemiaminal ethers has
been obtained in high yields, from different alde-
hydes, amines and alcohols, under very mild condi-
tions just with molecular sieves as promoter.
products derived from different interactions and equi-
libria between the species formed in solution. This is
a consequence of the thermodynamic control of the
[3]
different steps that are quasi-barrierless. Scheme 1
shows a general view with all possible compounds
that can be formed in the presence of a Brønsted
acid. The interaction of the aldehyde with the alcohol
or the amine affords the hemiacetal and the hemami-
nal, respectively. A second incorporation of alcohol to
the hemiacetal provides the acetal. In the case of the
hemiaminal, with the aid of a Brønsted acid, an elec-
trophilic iminium ion is formed that can further react
with amine or alcohol yielding the aminal or hemia-
minal ether correspondingly. The isolation of the
latter from this strategy in an exclusive manner seems
elusive due to the overall equilibria. Recently, an ele-
Keywords: alcohol, amine and aldehyde three-com-
ponent reaction; hemiaminal ethers; molecular
sieve
[4]
gant work by Anslyn and co-workers based on the
use of zinc(II) ions as the template has allowed the in
Nearly a century ago, McLeod and Robinson report- situ formation of hemiaminals including those of the
ed the reaction of formaldehyde with an amine (ali- less reactive secondary alcohols. However, such hemi-
phatic and secondary) and an alcohol, yielding an aminal, even when bonded to the zinc centre, is in
[
1]
hemiaminal ether [Eq. (1)]. Thirty years after that equilibrium with the dissociated forms and the metal
discovery, Stewart and Hauser expanded that reaction precursor (Scheme 2), precluding the isolation of the
to aromatic aldehydes, again with secondary aliphatic tetradentate ligand in a free form. The use of secon-
[
2]
amines, and 1-butanol [Eq. (2)]. However, in a gen- dary alcohols was also described, in spite of the lower
eral manner the direct reaction of aldehydes, amines nucleophilicity of such substrates that could be acti-
and alcohols usually leads to a complex mixture of vated on the basis of the electrophilicity of the imini-
um ion.
The reaction of amines and aldehydes toward
[5]
imines, on one side, and of imines and alcohols into
[6]
hemiaminals, on the other, are well-known processes
in organic chemistry, that usually require the use of
acid catalysis. We have focused on the development
of synthetic strategies toward hemiaminal ethers that
escape from the drawbacks of multiple equilibria as
well as of reduced scope. We have found that the use
of molecular sieves in the dual role of acid and dehy-
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lvaro Beltrµn et al.
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Scheme 1. Interaction of aldehydes, amines and alcohols in the so-called reversible covalent chemistry.
Scheme 2. Reversible zinc-mediated three-component reaction toward hemiaminal formation.
drating agent has provided the isolation as the main Table 1. Screening of promoters for the reaction of tosyla-
[
a]
product of a series of more than thirty hemiaminal mine, ethanal and ethanol yielding 1.
ethers in a simple procedure.
[
b]
Entry
Additives
Conversion
Our first approach consisted of the screening of
Lewis acids, the first choice being the copper complex
Br3
[c]
1
2
3
4
5
6
7
8
9
Tp Cu(NCMe)
20%
60%
38%
50%
57%
>99%
18%
53%
67%
95%
Br3
Br3
Tp Cu(NCMe) [Tp =hydrotris(3,4,5-tribromo)pyr-
CuI
AlCl3
azolylborate], that has previously been proven to
show such an acidic feature. In order to shift the
equilibrium toward the iminium side (see Scheme 1)
[
7]
FeCl2
CuI/MgSO4
[
d]
CuI/molecular sieves
we have chosen TsNH as the amine, where the elec-
2
[d]
MgSO4
ZSM-5
tron-withdrawing Ts group (Ts=p-toluenesulfonyl)
could help toward that end. The probe reaction was
completed with ethanol and ethanal as the model al-
cohol and aldehyde, with a six-fold excess of each rel-
ative to amine [Eq. (3)]. The reaction was carried out 12
at room temperature for 12 h using dichloromethane
[d]
[d]
Al O acid
2
3
[d]
1
1
0
1
molecular sieves
molecular sieves
no additives
[
e]
>99% (98%)
<1%
[
a]
Reaction conditions: 0.05 mmol of metal source,
.25 mmol of TsNH , 1.5 mmol ethanol, 1.5 mmol etha-
(
DCM) as solvent. Under these conditions and upon
0
2
nal, 5 mL of CH Cl as solvent, room temperature, reac-
2
2
tion time 12 h.
Yields were determined by H NMR spectroscopy and
[
b]
1
are based on initial amine. Isolated yield in brackets.
[
[
[
c]
d]
e]
Br3
0
1
1
.025 mmol of Tp Cu.
g.
.5 g.
completion the reaction time, N-(1-ethoxyethyl)-4-
methylbenzenesulfonamide 1 was obtained in 20%
yield (Table 1, entry 1), the hemiaminal ether formed
from the three component amine–aldehyde–alcohol cedented, we have confirmed its structure by means
reaction. This compound has been previously report- of an X-ray study, which is shown in Figure 1 (see
[
8]
ed, using a completely different methodology: the also the Supporting Information). After the modest
Br3
metal-catalyzed nitrene insertion into the CÀH bond results obtained with Tp Cu(NCMe), we evaluated
vicinal to an O-ether atom. Since its formation by the other Lewis acids for this reaction. As shown in
three component reaction shown in [Eq. (3)] is unpre- Table 1, entries 2–4, CuI, AlCl and FeCl improved
3
2
2
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Direct Synthesis of Hemiaminal Ethers
characterized (see the Supporting Information). The
reaction is selective towards the formation of the
hemiaminal ether, with yields being within the range
8
0–98% with the sole exception of 23. It is worth
mentioning that for the sake of comparison, all reac-
tions were carried out under the same reaction condi-
tions to test the effect of different substituents on this
chemical transformation, therefore some yields have
yet margin to be optimized. The results shown in
Figure 1. ORTEP of compound 1. 50% thermal ellipsoids
are shown. Most hydrogen atoms have been omitted for Table 2 allow the proposal of this methodology as
clarity.
a general and efficient method for the selective gener-
ation and isolation of hemiaminal ethers.
the yields, the simple copper iodide leading to the for-
Hemiaminals are molecules of high relevance due
mation of 1 in 60% yield, based on the initial amine. to their intermediacy in synthetic protocols involving
[
10]
[11]
Since the formation of the hemiaminal involves the coupling
and cyclization
reactions or enzymatic
[12]
loss of a molecule of H O, we decided to add dehy- processes, for instance. Their preparation has been
2
drating agents as additives to the best metal-based described by a-CH amidation reactions of ethers via
[
8]
catalyst, CuI. The addition of 1 g of MgSO did not insertion with metal-based
or metal-free proto-
4
[13]
provide a detectable change in yield (Table 1, cols, involving hypervalent iodine oxidants or addi-
entry 5). Experiments in the absence of the copper tives, and affording undesired by-products. At var-
salt were run with MgSO , zeolite ZSM-5, acid alumi- iance with that, the simple method described herein
4
na and molecular sieves, the latter providing an im- provides an excellent atomic economy, given that only
pressive 95% yield (Table 1, entry 10), that converted a molecule of H O is eliminated from the reactants.
2
into quantitative upon increasing the amount of such
As mentioned above, the reaction between TsNH2,
an additive (Table 1, entry 11). Finally, no reaction ethanal and tert-butyl alcohol led to the formation of
progress was observed in the absence of any additive the product 23 with a yield significantly lower than
(
Table 1, entry 12). To the best of our knowledge, the for the other examples (Table 2, entry 22). Isopropyl
formation and isolation of a hemiaminal ether from alcohol and 2-methylpropanol (Table 2, entries 19 and
amine, aldehyde and alcohol in the presence of mo- 20) gave 86%, whereas for linear alcohols yields
lecular sieves as the sole promoter was previously un- >90% were observed, assessing a certain steric effect
described. In contrast, the use of such material for the in this transformation. In these cases, the imine inter-
generation of imines from the condensation reaction mediate formed from aldehyde and amine was ob-
[
3,9]
between an amine and an aldehyde is known.
served at the end of the reaction time (12 h in all
Having identified the most promising reaction con- cases). Such an intermediate could also be detected at
ditions, we studied the scope of this transformation. lower yield with the long chain linear aldehydes such
The general reaction, shown in [Eq. (4)], has been ap- as pentanal (Table 2, entry 4). In this case, a final mix-
ture of 5:TsNH :imine in a 80:13:7 ratio (see the Sup-
2
porting Information) ratio was obtained. Longer reac-
tion times in these cases led to very high yields in the
targeted hemiaminal ethers.
When formaldehyde was used as substrate (Table 2,
plied to a series of 23 combinations, the reaction out- entries 16–18), the corresponding hemiaminal ethers
comes being shown in Table 2. The corresponding dif- 17a–19a were obtained albeit in a lower yield. This is
ferent hemiaminal ethers from this three-component due to the formation of a minor by-product derived
reaction of TsNH , aldehyde and alcohol, with linear from the reaction of two molecules of formaldehyde
2
or branched alkyl substituents have been isolated and
characterized on the basis of their spectroscopic and
analytical data. The products 2–23 shown in Table 2
were not previously described in the literature. There-
fore, their characterization has been accomplished by
1
13
1
multinuclear H and C{ H} NMR as well as high res-
1
olution mass spectrometry. A characteristic H NMR
resonance in the range from 4.50 to 4.79 ppm is
common to all compounds 2–23, being assigned to the
OÀCHÀNH proton. The corresponding carbon OÀ
CHÀNH resonates within the range 79–86 ppm. In ad-
dition, compounds 2 and 6 have been structurally
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lvaro Beltrµn et al.
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1
2
Table 2. Scope of the reaction of TsNH , aldehydes and alcohols with alkyl substituents in R and R . Experiments car-
2
ried out as in Table 1, entry 11. See the Supporting Information for details.
[
a]
A by-product in ca. 25% was obtained; see text and [Eq. (5)]. Isolated yields given in brackets.
and amine, and subsequent dehydration and conden- quence of the development of a stereocenter (see the
[
14]
sation reaction with the alcohol.
In this case the Supporting Information).
We wondered about the effect that a change in the
consumption of the limiting reagent TsNH was com-
2
plete, with a distribution of ca. 75% of the corre- amine would have in the reaction scope. Thus, we
sponding hemiaminal ethers 17a–19a and ca. 25% of tested six different amines with ethanal and ethanol
the by-products 17b–19b [Eq. (5)]. Substrates such as as reactants under the same reaction conditions. As
2-butanol or 3-heptanol (Table 2, entries 20 and 21) shown in Scheme 3, yields were very high in all cases.
led to the formation of diastereoisomers as the conse- In addition to tosylamine, the aryl-substituted deriva-
2
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Direct Synthesis of Hemiaminal Ethers
Scheme 4. Synthesis of hemiaminals with unsaturated alco-
hols. Experiments carried out as in Table 1, entry 11. See the
Supporting Information for details. Isolated yields in brack-
ets.
Scheme 3. Synthesis of hemiaminals from different amines.
Experiments carried out as in Table 1, entry 11. See the Sup-
porting Information for details. Isolated yields in brackets.
tives behaved similarly, no matter if electron-with-
drawing or electron-donating groups were incorporat-
ed. The use of pyridin-2-amine, 3-chloropyridin-2-
amine or pyridimidine was also successful.
Scheme 5. The dual role of molecular sieves as Lewis acid
(LA) and water sponge (WS) in the formation of hemiami-
As a final probe of the versatility of this chemical nal ethers.
system, we employed unsaturated alcohols bearing
olefinic, alkynyl or aryl substituents (Scheme 4). Grat-
ifyingly, yields in the 95–99% range were obtained imine would react with alcohol, again in a Lewis acid-
with allylic alcohol, but-3-en-1-ol, propargyl alcohol catalyzed step induced by the molecular sieve.
or benzylic alcohol. In the case of using (2E,4E)-
hexa-2,4-dien-1-ol as substrate the yield dropped to simple methodology in which molecular sieves pro-
0%, with 20% of the imine intermediate completing mote the three-component reaction of amine, alcohol
In conclusion, we have discovered a new and
8
the final reaction mixture. It is worth mentioning that and aldehyde yielding 33 hemiaminal ethers in very
the unsaturated CÀC bonds at the chain remained un- high yields. This highly selective metal-free and acid-
altered, providing a reaction site available for further free method operates at room temperature and allows
transformations.
the isolation of the products, formed in an irreversible
The role of molecular sieve as the sole promoter manner, most of them previously unknown in spite of
and thus responsible of this transformation is inferred the simplicity of their structures.
from a study in which variable amount of this materi-
al was employed with three probe reactions leading to
compounds 1, 15 and 26 (see the Supporting Informa-
Experimental Section
tion), with ca. 1.5–2 g being required to achieve yields
of 90% or higher. A dual role must be invoked to ex-
plain this transformation (Scheme 5). On the one
hand, the well-known Lewis acidity of this material
would induce the formation of a hemiaminal inter-
Typical Experimental Procedure
A flask containing a magnetic stirring bar was charged with
freshly activated molecular sieves 3Š (1.5 g) and anhydrous
mediate from which a molecule of water is extruded dichloromethane (5 mL) and then aldehyde (1.5 mmol),
and fixed into the sieve. From here, the resulting amine (0.25 mmol) and alcohol (1.5 mmol) were added. The
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lvaro Beltrµn et al.
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mixture was stirred for 12 h at room temperature. After fil-
tration, volatiles were removed under vacuum and the resi-
due was characterized without purification. Attempts at
product purification by column chromatography were unsuc-
[6] a) G. Li, F. R. Fronczek, J. C. Antilla, J. Am. Chem.
Soc. 2008, 130, 12216–12217; b) K. Haejin, Y. H. Rhee,
Synlett 2012, 20, 2875–2879.
[7] a) M. R. Fructos, E. lvarez, M. M. Díaz-Requejo, P. J.
PØrez, J. Am. Chem. Soc. 2010, 132, 4600–4607; b) L.
Maestre, M. R. Fructos, M. M. Díaz-Requejo, P. J.
PØrez, Organometallics 2012, 31, 7839–7843.
[8] D. P. Albone, S. Challenger, A. M. Derrick, S. M. Fill-
ery, J. L. Irwin, C. M. Parsons, H. Takada, P. C. Taylor,
D. J. Wilson, Org. Biomol. Chem. 2005, 3, 107–111.
[15]
cessful due to decomposition.
Spectroscopic data (including NMR spectra) of the prod-
ucts 1–33, as well as crystal structure data for 1, 2 and 6 are
provided in the Supporting Information.
[
9] F. A. Davis, Y. Zhang, Y. Andemichael, T. Fang, D. L.
Acknowledgements
Fanelli, H. Zhang, J. Org. Chem. 1999, 64, 1403–1406.
[
[
10] a) C. Gunanathan, Y. Ben-Davis, D. Milstein, Science
2007, 317, 790–792; b) L. U. Nordstrøm, H. Vogt, R.
Madsen, J. Am. Chem. Soc. 2008, 130, 17672–17673.
11] a) J. J. Fleming, M. D. McReynolds, J. Du Bois, J. Am.
Chem. Soc. 2007, 129, 9964–9975; b) S. K. Ghosh, C.
Ko, J. Liu, J. Wang, R. P. Hsung, Tetrahedron 2006, 62,
We thank MINECO (CTQ2014-52769-C3-1-R) and Junta de
Andalucía (P10-FQM-06292) for funding.
References
10485–10496; c) H. Kim, W. Lim, D. Im, D. Kim, Y. H.
[
[
[
[
[
1] C. M. McLeod, G. M. Robinson, J. Chem. Soc. 1921,
19, 1470–1476.
2] A. T. Stewart, C. R. Hauser, J. Am. Chem. Soc. 1955,
7, 1098–1103.
3] Y. Jin, C. Yu, R. J. Denman, W. Zhang, Chem. Soc.
Rev. 2013, 42, 6634–6654.
4] L. You, J. S. Berman, E. V. Anslyn, Nat. Chem. 2011, 3,
Rhee, Angew. Chem. 2012, 124, 12221–12224; Angew.
Chem. Int. Ed. 2012, 51, 12055–12058.
1
[12] a) L. Xu, S. Hua, S. Li, Chem. Commun. 2013, 49,
1542–1544; b) B.-K. Liu, Q. Wu, D.-S. Lv, X.-Z. Chen,
X.-F. Lin, J. Mol. Catal. B: Enzym. 2011, 73, 85–89.
[13] J. Campos, S. K. Goforth, R. H. Crabtree, T. B.
Gunnoe, RSC Adv. 2014, 4, 47951–47957.
[14] R. G. Kallen, W. P. Jencks, J. Biol. Chem. 1966, 241,
5864–5878.
ˇ
[15] O. S. Miljani c´ , Nat. Chem. 2011, 3, 909–910.
7
9
43–948.
5] K. Wang, Z. Xing, Y. Ma, Q. Wang, Catal. Lett. 2008,
23, 129–134.
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