Reductive Fragmentation of Tetrazoles: Mechanistic Insights and Applications toward the Stereocontrolled Synthesis of 2,6-Polysubstituted Morpholines

Article abstract of DOI:10.1021/acs.orglett.9b01842

A new methodology to synthesize 2,6-di-, and 2,2′,6-trisubstituted morpholines via the reduction of oxabicyclic tetrazoles under mild conditions is described. The reaction proved successful for a wide range of tetrazoles, including sterically encumbered ones harboring gem-substituents on tertiary carbon centers. The mechanism for the decades-old reduction of tetrazoles to secondary amines is elucidated.

Full text of DOI:10.1021/acs.orglett.9b01842

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Reductive Fragmentation of Tetrazoles: Mechanistic Insights and
Applications toward the Stereocontrolled Synthesis of 2,6-
Polysubstituted Morpholines
̂
Edouard Duchamp, Benoit Deschenes Simard, and Stephen Hanessian*
́
́
́
́
Department of Chemistry, Universite de Montreal, P.O. Box 6128, Succ., Centre-ville, Montreal, Quebec, Canada H3C 3J7
S
* Supporting Information
ABSTRACT: A new methodology to synthesize 2,6-di-, and
2,2′,6-trisubstituted morpholines via the reduction of
oxabicyclic tetrazoles under mild conditions is described.
The reaction proved successful for a wide range of tetrazoles,
including sterically encumbered ones harboring gem-substitu-
ents on tertiary carbon centers. The mechanism for the decades-old reduction of tetrazoles to secondary amines is elucidated.
Scheme 1. First Report of the Reduction of Tetrazoles to
Amines by Laforge and Co-workers
n spite of its availability for many decades, it is only recently
that the incorporation of a tetrazole core unit in drug
I
substances has gained enormous popularity with a number of
FDA-approved entities for a variety of medical uses.1 Its
electronic structure, stability under a variety of chemical and
physiological conditions, and physical properties appear to
confer highly beneficial, pharmacological properties to the
parent molecules, resulting in enhanced biological activities
across a wide spectrum of biomedical applications.2 Con-
sequently, there has been a sustained interest in the synthesis
of tetrazoles in general.3 The first synthesis of the tetrazole
nucleus was reported by Bladin in 1885 and involved the
thermal cyclization of an organic nitrile with sodium azide.4
The first intermolecular cycloaddition reaction between an
organic azide and a nitrile is credited to Hantzch and Vagt in
1901.5 Over the next century and a half, and following a
German patent by von Kereszty and Wolf,6 the synthesis of
1,5-disubstituted tetrazoles by inter- and intramolecular
cycloaddition reactions has been extensively investigated.7
We recently showed that proximity effects in such intra-
molecular cycloaddition reactions in the presence of BF3·OEt2
were highly favorable to give bicyclic and polycyclic tetrazoles
under remarkably mild conditions at room temperature or
below. Extension to acetals and TMSCN led to oxabicyclic
tetrazoles.8 By and large, tetrazoles have been used as whole
entities rather than to exploit their synthetic potential in other
contexts. For example, N-substituted tetrazoles are considered
as “neutral” heterocycles that are inert to reductants.3c,9
However, over six decades ago, LaForge, Cosgrove, and
D’Adamo reported the reductive transformation of 1-phenyl-5-
methyltetrazole to N-ethylaniline in the presence of lithium
aluminum hydride in refluxing ether10 (Scheme 1).
esters and ketones, which were transformed to the correspond-
ing secondary amines. They studied the stoichiometry of the
reaction showing that at least 0.75 equiv of the hydride reagent
was required to complete the reaction. Since the resulting
secondary amine products could also be accessed by alternative
and more conventional synthetic methods (albeit in lower
yields in some cases), they made the following statement:
“While this reaction has no general preparative value, it may be a
very useful tool in special cases.” Surprisingly, since the
publication of the original paper in 1956, we are aware of
only four examples of such reductions.11 Furthermore, no
mechanistic rationales have been proposed for this intriguing
extrusion of three nitrogen atoms from the tetrazole nucleus
under hydride reductive conditions.
Herein, we report our studies toward a proposed mechanism
of this decades-old reaction, and we show applications toward
the synthesis of stereochemically defined 2,6-di- and 2,2′,6-
trisubstituted morpholines. Suspecting that the mechanism
might involve a fragmentation with the release of azide ion, we
conducted a time course study of the reduction of 1-phenyl-5-
methyltetrazole (1) with lithium aluminum hydride by IR and
indeed confirmed our postulate.12 The characteristic peak for
azide ion at 2100 cm−1 steadily increased in intensity as the
reaction progressed, reaching a maximum after 4−6 h. The
white precipitate formed in the reaction mixture and presumed
to be LiN3 (possibly as an Al(OH)3 complex) was isolated
after removal of the organic material by washing with ether.
Adding benzyl bromide to the solid and heating in a 1:1
In this remarkable reductive ring-cleavage reaction, the
authors noted that the formation of the amine product also
resulted in the loss of three nitrogen atoms without specifying
the nature of the extruded nitrogenous product. The reaction
was extended to pentamethylene tetrazole and other
carbobicyclic tetrazoles containing reducible groups such as
Received: May 27, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01842
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
mixture of acetonitrile and water gave benzyl azide (Scheme
2).
the cis-tetrazole was being converted into the trans-tetrazole 3a
as the reaction was progressing. Suspecting that the hydride
was acting as a base and as a nucleophile, we performed the
reduction of 3a containing a deuterium atom at the benzylic
position with LiEt3BH, only to recover the deuterated trans-
morpholine 4a-d1 without loss of deuterium. Reduction of 3a
with deuterated Super-Hydride or LiAlD4 led to the 3,3′-
dideuterio morpholine 4a-d2. Moreover, reduction of 3a with
LiEt3BH or LiAlH4 followed by addition of D2O or MeOD
revealed no incorporation of deuterium in the resulting trans-
morpholine. Quenching the reaction mixture with benzyl
bromide gave the trans-N-benzylmorpholine derivative of 4a in
70% yield.
In the light of these results, it was clear that the reductive
fragmentation reaction of the oxabicyclic tetrazole 3a was
under kinetic control favoring the trans-isomer and leading to
the trans-morpholine 4a. An X-ray crystal structure of the N-
tosyl amide derivative confirmed the stereochemistry.12 The
conservation of the benzylic hydrogen atom during the
reductive fragmentation of the oxabicyclic cis-tetrazole 3a
while undergoing an inversion of configuration as evidenced in
the product trans-morpholine 4a suggests that a direct attack of
hydride on the tetrazole as may have been the case in the
LaForge substrate is not likely (Scheme 3). An alternative
mechanism, which is consistent with the observed results, is
proposed and illustrated in Scheme 5.
Scheme 2. Extrusion of Azide Anion over the Course of the
Reductive Cleavage of Tetrazoles
To the best of our knowledge, this represents the first
example of azide ion extrusion from a tetrazole and attests to
the astute observation made by LaForge and co-workers.10
A
plausible mechanism involving hydride attack at C5 followed
by concomitant or stepwise release of azide ion is shown in
Scheme 3. Consistent with this proposal, reduction of 1-
phenyl-5-methyltetrazole 1 with LiAlD4 afforded the dideu-
terated N-ethylaniline 2.
Scheme 3. Proposed Mechanism for the Reductive Cleavage
Scheme 5. Proposed Mechanism of the Reduction of
Disubstituted Oxabicyclic Tetrazoles
In an effort to extend the reaction to a more complex
substrate, we used a model oxabicyclic cis-tetrazole 3a, which
in the event of a successful extrusion of azide anion would lead
to the corresponding 2,6-disubstituted cis-morpholine (Scheme
4). Indeed, treatment with LiAlH4, or more conveniently
Super-Hydride (LiEt3BH), in ether at room temperature led to
4a as the major isomer in excellent yield. Curiously, the
product was the trans-morpholine. The same results were
observed with the m-methoxy (4b) and naphthyl (4c)
analogues. When the course of the reaction was monitored
by 1H NMR with increasing ratios of LiEt3BH, we realized that
Thus, attack of the first hydride leads to a charged tetrazole
anion which undergoes β-elimination to the benzylic carbanion
in an SNAr fashion. This transient species cyclizes back from
the face opposite to the bulky TBDPS ether group, affording
the now epimerized oxabicyclic trans-tetrazoline, which
undergoes fragmentation to the corresponding trans-morpho-
line with loss of azide. Alternative mechanisms to describe this
dynamic process may also involve imidoyl azide intermediates.
Capitalizing on these successful reductive fragmentations as
a means to access trans-2,6-disubstituted morpholines, we
directed our efforts toward the reduction of oxabicyclic
tetrazoles containing geminal 2,2′-substituents, which would
lead to the corresponding arduously accessible 2,2′,6-branched
morpholines as racemates or in enantiomerically enriched
forms.
Scheme 4. Reductive Cleavage of Oxabicyclic Tetrazoles to
2,6-Disubstituted Morpholines
Thus, treatment of oxabicyclic tetrazoles 5a−e derived from
symmetrical ketones8a with Super-Hydride led to the
corresponding novel 2,2′-spirocyclic morpholines 6a−e in
good to excellent yields (Scheme 6).
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Scheme 6. Reduction of Trisubstituted Oxabicyclic
Tetrazoles Derived from Ketones to Spirocyclic
Morpholines
Scheme 7. Reductive Cleavage of Trisubstituted Oxabicyclic
Tetrazoles
A crystal structure of the 4-methylcyclohexyl HCl salt 6e
showed the equatorial disposition of the CH2OTBDPS group.
The scope of the reductive cleavage reaction toward 2,2′-
geminally disubstituted morpholines with different groups
could be widened by alkylation of 3a with suitable electrophiles
in the presence of LiHMDS at −78 °C.
It is of interest that alkylation of the generated carbanion
took place to give the corresponding trans-tetrazole as the
major product depending on the bulkiness of the electrophile
(Scheme 7).12 Reduction in the presence of Super-Hydride in
Et2O in a pressure vial at 55 °C afforded the trans-2,2′,6-
trisubstituted morpholines 8a−j. The stereochemistry was
assigned by NMR and NOE experiments. We suggest that in
these cases hydride attack occurs with concomitant expulsion
of azide ion as shown in Scheme 3, rather than generating the
corresponding benzylic disubstituted carbanion, which would
have led to partial epimerization upon ring closure.13
Scheme 8. Stereoselective Additions of Oxabicyclic
Tetrazole 3a to Benzylic Aldehydes
The acidity of the benzylic hydrogen in 3a8b allows facile
reactions via the corresponding lithium anion with aldehydes.
Thus, treatment of 3a with p-anisaldehyde in the presence of
LiHMDS in THF at −78 °C afforded the syn-trans product 9
in crystalline form (Scheme 8). Reaction with benzaldehyde
led to a mixture of diastereoisomeric alcohols 10 in a ratio of
1/3 in favor of the syn-trans product in 92% yield. In view of
the ability of the σ lone pairs of the tetrazole moiety to engage
in H-bonding with biological receptors,2a−c,14 there is an
opportunity to generate a diverse set of functionalized
oxabicyclic tetrazoles (formally viewed as fused triazinomor-
pholines) with stereochemically defined tertiary centers from a
variety of aldehydes for biological screening. Indeed, the crystal
structure of adduct 11 revealed two H-bonded molecules of
ethanol attached to N4 of the tetrazole unit.
In conclusion, we have elucidated the mechanism of the
original LaForge reductive fragmentation of 1,5-disubstituted
tetrazoles after 60 years since it was first reported. The
extrusion of an intact azide moiety as the Li salt is
unprecedented and lends itself to further computational
studies in simple and more complex systems. We have
extended the reductive fragmentation to oxabicyclic tetrazoles
affording hitherto diastereomerically enriched 2,6-disubsti-
tuted15 and 2,2′,6-trisubstituted morpholines.16 In view of
the importance of morpholines in medicinal chemistry1,2,17 and
their natural occurrence as alkaloid metabolites,18 we hope that
the three-step synthesis of such 2,6- and 2,2′,6-substituted
morpholines starting from commercially available enantioen-
riched 3-chloro- and 3-azidopropane-1,2-diols via readily
accessible oxabicyclic precursors8 will expand their scope of
applications toward medicinally relevant compounds.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01842.
■
S
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Experimental procedures, compound characterizations,
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Accession Codes
CCDC 1917618−1917622 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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(12) See the Supporting Information.
(13) We thank one of the reviewers who brought this to our
attention.
AUTHOR INFORMATION
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Corresponding Author
*E-mail: stephen.hanessian@umontreal.ca
ORCID
(14) (a) Nichols, D. A.; Jaishankar, P.; Larson, W.; Smith, E.; Liu,
G.; Beyrouthy, R.; Bonnet, R.; Renslo, A. R.; Chen, Y. J. Med. Chem.
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(b) Gharpure, S. J.; Anuradha, D.; Jonnalagadda, V. K. P.; Srinivasa
Rao, P. Eur. J. Org. Chem. 2015, 86−90.
Stephen Hanessian: 0000-0003-3582-6972
Notes
The authors declare no competing financial interest.
́
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ACKNOWLEDGMENTS
We acknowledge financial support from NSERC IRC 513339-
17 and NSERC discovery grant RGPIN/04726-2015. We also
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́
́
thank the Universite de Montreal - Departement de Chimie
staff: Dr. Michel Simard, Dr. Thierry Maris, and Dr. Daniel
Chartrand for X-ray structures, Dr. Pedro Aguiar for NMR
́
́
discussions, and the Centre regional de spectrometrie de masse
for HRMS analyses.
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DOI: 10.1021/acs.orglett.9b01842
Org. Lett. XXXX, XXX, XXX−XXX