Heterogeneous borrowing hydrogen reactions with Pd/C and ZnO: Diol scope

Article abstract of DOI:10.1016/j.tetlet.2017.11.039

A borrowing hydrogen reaction with different diols was employed for the preparation of complex beta- gamma- or epsilon-amino alcohols from p-toluidine and tetrahydroquinoline with the aim of better understanding the applicability of the Pd/C ZnO heterogeneous catalyst.

Full text of DOI:10.1016/j.tetlet.2017.11.039

Accepted Manuscript
Heterogeneous Borrowing Hydrogen Reactions with Pd/C and ZnO: Diol Scope
Pedro J. Llabres-Campaner, Patricia Woodbridge-Ortega, Rafael Ballesteros-
Garrido, Rafael Ballesteros, Belén Abarca
PII:
S0040-4039(17)31453-3
https://doi.org/10.1016/j.tetlet.2017.11.039
TETL 49482
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 October 2017
13 November 2017
17 November 2017
Please cite this article as: Llabres-Campaner, P.J., Woodbridge-Ortega, P., Ballesteros-Garrido, R., Ballesteros, R.,
Abarca, B., Heterogeneous Borrowing Hydrogen Reactions with Pd/C and ZnO: Diol Scope, Tetrahedron Letters
(2017), doi: https://doi.org/10.1016/j.tetlet.2017.11.039
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Heterogeneous Borrowing Hydrogen Reactions with Pd/C and ZnO: Diol Scope
Pedro J. Llabres-Campaner, Patricia Woodbridge-Ortega, Rafael Ballesteros-Garrido*, Rafael
Ballesteros and Belén Abarca
Departament de Química Orgànica, Universitat de València, Av. Vicent Andrés Estellés s/n, 46100
Burjassot, Valencia, Spain. Phone: 0034963543054. e-mail rafael.ballesteros-garrido@uv.es
Abstract
A borrowing hydrogen reaction with different diols was employed for the preparation of complex
beta- gamma- or epsilon- amino alcohols from p-toluidine and tetrahydroquinoline with the aim of
better understanding the applicability of the Pd/C ZnO heterogeneous catalyst.
1

Introduction
Borrowing hydrogen (BH) reactions,1 also known as hydrogen auto-transfer (HA) reactions,2
between amines and alcohols represent a unique opportunity to create molecular complexity from
readily accessible reagents while being in coherence with green chemistry principals.3 Among the
different methodologies proposed, Pd, Ru, Mn, Ir and Co complexes have shown significant
relevance under homogeneous conditions.1b,4,5 Additionally, heterogeneous catalysts have been
developed for this purpose.6 Diols represent challenging compounds in BH reactions, ethylene glycol
for example has recently been employed, however, double reactions are common.4,7 In the course of
our studies we have reported a catalyst combination (Pd/C 7 mol%, ZnO 3 equiv.)8a which is able to
mono activate ethylene glycol to create -amino alcohols. Herein, we report an extension of this
methodology to more complex alcohols in order to understand the limitations of this system (Scheme
1).
Scheme 1: BH/HA reactions with different diols
Results and Discussion
p-Toluidine 1a and tetrahydroquinoline 1b were selected as reagents using the same
conditions that were employed for ethylene glycol 2.8a Indeed, in our previous studies these
2

compounds behaved differently under identical conditions; p-toluidine 1a gave amino alcohol
3a in excellent yields, and tetrahydroquinoline 1b afforded a mixture of amino alcohol 3b and
indole
4 -amino alcohols are BH/HA
(Scheme 2).8 At this point, is important to note that
products, however, indoles do not require the final hydrogenation steep. This is known as an
acceptor-less dehydrogenate condensation (ADC)9 pathway which has been proposed as a
powerful strategy for the preparation of heterocycles, and has been exclusively observed with
1b under our conditions, but not with 1a
.
Scheme 2: Chemical behavior of p-toluidine 1a and tetrahydroquinoline 1b with ethylene glycol. NMR yields;
isolated yields are given in parenthesis.
Propane 1,2-diol
5 was first selected due to its unsymmetrical structure (Scheme 3). When
this diol was submitted to the reaction with p-toluidine 1a, amino alcohol 6a was formed in
95% yield (NMR); however, isolation from the remaining diol was difficult and resulted in
only a 45% isolated yield. When tetrahydroquinoline 1b was submitted to these conditions the
corresponding amino alcohol 6b was obtained in 30% yield (NMR), in the presence of a
mixture of indoles
7
(85:15) which were obtained via an ADC process as previously reported.
3

Scheme 3: Chemical behavior of 1a and 1b with propane 1,2-diol 4. Isolated yields are given in parenthesis.
Although these results clearly reveal the selectivity of the process to afford
amino alcohols such as compounds 6a and 6b, it is important to note that the oxidation of
asymmetrical diol has been proposed to be affordable in both primary and secondary
-substituted--
5
alcohols (Fig. 1; top).10 Oxidation on the primary alcohol affords aldehyde 8a while oxidation
of the secondary alcohol affords ketone 8b. In addition a tautomeric equilibrium is present in
this system through compound 8c 11
However, the more stable iminium intermediate (less
.
steric hindrance) may be associated with the aldehyde alcohol 8a. The lower yield for
tetrahydroquinoline 1b may also be related to steric hindrance. Being a cyclic amine 1b, the
iminium intermediate (Fig. 1, center) may possess steric hindrance due to the absence of free
rotation. Both BH products (6a and 6b) clearly indicate that the reaction of aldehyde 8a is
preferred. The corresponding ADC products
7 observed with tetrahydroquinoline 1b also
indicate this feature although a minimal 15% of the other isomer was present; this adds
evidence for an equilibrium process.
4

Figure 1: Imine equilibrium during the formation of alcohol 5a
.
When symmetrical propane diol
products was also obtained (Scheme 4). For compound 1a, 90% conversion was observed,
however the corresponding BH product -amino acid 10a was only obtained in 10% isolated
yield. A major component of this reaction was the corresponding propyl amine 11a
9 was submitted to the reaction conditions a mixture of

.
Dehydroxylation of these compounds is rare,12 however Bruneau and co-workers previously
observed this feature under homogeneous BH conditions, presumably involving elimination
and hydrogenation reactions.13 Additionally, quinoline 12 was isolated in 15% yield,
presumably via a Skraup-like mechanism.14
Scheme 4: Chemical behavior of p-toluidine and tetrahydroquinoline with propane 1,3-diol. Isolated yields are
given in parenthesis.
5

Comparing these results with tetrahydroquinoline 1b, similar behavior was observed,
however the conversion was decreased. Compounds 10b and 11b were obtained in poor
yields. Under these conditions quinolines were not observed since secondary amines such as
tetrahydroquinoline cannot afford these kinds of products.
Finally, diol 13 was employed with the aim of exploring more complex systems. Diol 13
contains a central ether that in principle should avoid any tautomeric pathways, thus, only -
amino alcohols should be expected. Indeed p-toluidine 1a afforded compound 14a in good
yield (Scheme 5), however isolation from the remaining diols proved difficult (38% isolated
yield). Nevertheless, this methodology did not require desymmetrization of diol 13. Similar
results were obtained with 1b, albeit in lower yield; in this case no side-products were
observed.
Scheme 5: Chemical behavior of p-toluidine 1a and tetrahydroquinoline 1b with diethylene glycol 12. Isolated
yields are given in parenthesis.
Conclusion
The combination of Pd/C and ZnO has been proven to be an adequate heterogeneous catalyst
for the single-alcohol activation of different diols, with particularly interesting results
6

obtained using propane-1,2-diol
5 and diethylene glycol 13. In all cases the corresponding
amino alcohols could be obtained, thus this methodology represents a different approach for
the preparation of these compounds. No derivatization of the diols was required and all
reactions were performed in water:diol mixtures. The use of 1,3-propanodiol
9 afforded
dehydroxylated compounds 11a and 11b and quinoline 12 via a Skraup-like mechanism.
Associated Content
Supporting Information.
1
Experimental procedure, compound characterization and H- and 13C-NMR spectra of new
compounds (PDF).
Author Information
Corresponding Author:
*E-mail: rafael.ballesteros-garrido@uv.es
Notes
The authors declare no competing financial interest.
Acknowledgements
R. B-G is much indebted to the Postdoctoral fellow 2013 of the “Ministerio de Economía y
Competitividad” (Spain, FPDI-2013-17464). This work was financially supported by the “Ministerio
de Ciencia e Innovación” (Spain) (Project CONSOLIDER-INGENIO SUPRAMED CSD 2010-
00065 and from University of Valencia (Spain) (UV-INV-AE 15-332846)). Acknowledgments to the
“Central Services for Experimental Research” (SCSIE) of University of Valencia and NANBIOSIS
platform. We gratefully acknowledge the suggestions and advice from the referee and the editor in
order to improve the quality of this contribution.
7

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9

Mono functionalization of diols is achieved with heterogeneous borrowing hydrogen catalyst.
Evidences of tautomeric equilibrium are found.
Diethylene glycol can be used to prepare epsilon amino alcohols with central ether.
Pd/C, ZnO Combination can be applied to other diols different from ethylene glycol.
10