The reductive cleavage of picolinic amides

Article abstract of DOI:10.1016/j.tetlet.2016.05.068

Treatment of picolinic amides with excess zinc in aqueous hydrochloric acid at room temperature affords the corresponding amines in good to excellent yields. The mild reaction conditions exhibit useful functional group tolerance and facilitate the application of the picolinic amide moiety as a protecting group which can be easily introduced and selectively removed.

Full text of DOI:10.1016/j.tetlet.2016.05.068

Accepted Manuscript
The Reductive Cleavage Of Picolinic Amides
Daniel H. O’ Donovan, Claudia De Fusco, David R. Spring
PII:
S0040-4039(16)30601-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.068
TETL 47687
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 April 2016
13 May 2016
18 May 2016
Please cite this article as: O’ Donovan, D.H., De Fusco, C., Spring, D.R., The Reductive Cleavage Of Picolinic
Amides, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.05.068
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The Reductive Cleavage Of Picolinic Amides
Daniel H. O’ Donovan,*a Claudia De Fusco,b David R. Springb
(a) AstraZeneca, The Darwin Building, Milton Road, Cambridge, UK (b) Department of
Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK.
Abstract
Treatment of picolinic amides with excess zinc in aqueous hydrochloric acid at room
temperature affords the corresponding amines in good to excellent yields. The mild reactions
conditions exhibit useful functional group tolerance and facilitate the application of the
picolinic amide moiety as a protecting group which can be easily introduced and selectively
removed.
Introduction
The picolinic amide group has been used as a ligand,1 as a protecting group,2 and more
recently as a directing group for transition-metal catalysed CH activation reactions.3
However, few general methods for the mild and selective conversion of picolinic amides to
the corresponding amines have been reported. The most widely used procedures employ
strongly hydrolytic or nucleophilic conditions at elevated temperatures,4 leading to poor
functional group tolerance and limiting the utility of these methods in the context of complex
molecule synthesis, where selectivity is desirable. Another reported cleavage reaction
suggests the use of Cu (II) salts to promote the cleavage of picolinic amides,2b however in our
hands we found the reported conditions to afford little or no reactivity for a variety of
substrates.
We therefore sought to develop a simple, high-yielding procedure to convert picolinic amides
to the corresponding amines under mild reaction conditions. We were inspired by an earlier
study in which Barrière and co-workers reported the reductive cleavage of the 3-hydroxy-
picolinamide group within the polyamide antibiotic pristinamycin.5 However, in spite of
detailed mechanistic investigations by the same authors,6 there have been no further reports
* Corresponding author. Tel: +44 (0) 1 582 837837. Email: daniel.odonovan@astrazeneca.com.

on the reductive cleavage of picolinic amides exhibiting high chemical yields and broad
functional group tolerance.
Results and Discussion
Our studies began with the preparation of a collection of diverse picolinic amides. The
conversion of amines to the corresponding picolinic amides is trivial; many methods have
been reported, including amide coupling procedures such as DCC or EDCI coupling,7 mixed
anhydride methods8 and Schotten-Baumann methods.9 In order to expedite our studies, we
chose the HATU amide coupling procedure10 to afford a series of picolinic amides in good to
excellent yields. Treatment of these amides with excess zinc dust in aqueous HCl (1.5 M) at
room temperature led to regeneration of the parent amines in good to excellent yield for most
substrates (Table 1).
Table 1. Protection and deprotection of amines as picolinic amides.
Step 1
% Isolated Yield
Step 2
% Yield by Internal
Standarda (Isolated Yield)
Entry
Substrate
1
85
79 (65)b
2
3
98
94
94 (91)
99 (96)
4
92
69 (60)

5
6
82
99
99 (95)
67 (57)c
7
8
9
96
86
75
63 (59)
31 (30)c
20 (not isolated)
1
b
aDetermined by H NMR using (MeO)3Ph as Internal Standard. No evidence of the debrominated
1
c
product was observed by H NMR analysis of the crude reaction mixture. Solvent changed to 1:1
THF/H2O, reaction time 1.5 h.
The reaction tolerates a broad range of functional groups including aryl halides (entry 1),
ethers (entry 2), alcohols (entry 4) and nitrogenous heterocycles (entries 5 and 6). As
evidenced by entry 6, even acid sensitive substrates such as methyl esters can be successfully
converted to the parent amine with careful control of the reaction time. Notably, entries 6 and
8 also necessitated the addition of tetrahydrofuran as a co-solvent as the parent amides were
insoluble in water alone; this demonstrates that even substrates with poor aqueous solubility
can be used in this reaction.
Entry 8 resulted in a complex mixture from which the desired product was isolated in just
30% yield. It is likely that facile reduction of the aromatic ketone moiety competes with the
desired reaction; this suggests that the Zn/HCl cleavage procedure is poorly compatible with

other readily-reduced functional groups. In the case of entry 9, the poor yield for selective
cleavage in the presence of the lactam functionality is consistent with the earlier report on the
polyamide pristinamycin5 in which the authors also observed a complex mixture of products;
this suggests that these conditions have limited compatibility with compounds containing
other sensitive amide functional groups.
The reaction mechanism is likely to proceed via a sequence of protonation/reduction steps as
outlined in Scheme 1; the proposed mechanism is supported by earlier work by Fleury and
co-workers.6 Protonation of the pyridine nitrogen facilitates zinc reduction within the
aromatic ring 1 followed by protonation of the resulting anion 2. A further
protonation/reduction sequence leads to hemiaminal 4 which dissociates under acidic
conditions to afford the product amine 6 and pyridine-2-carboxaldehyde 5, which is further
reduced under the reaction conditions to pyridin-2-ylmethanol 7.11
Scheme 1. Proposed mechanism for the Zn/HCl reductive cleavage of picolinic amides.

In summary, we have demonstrated a facile procedure for the Zn/HCl promoted cleavage of
picolinic amides. The mild conditions and broad functional group tolerance suggest that this
reaction should be useful in complex molecule synthesis and related synthetic applications.
Acknowledgements
The authors thank Prof. Dr. Nuno Maulide (University of Vienna, Austria) for his kind
support of this research and insightful discussions. We acknowledge the Max-Planck-Institut
für Kohlenforschung (Mülheim, Germany) where preliminary studies were carried out. The
authors also acknowledge the support of the AstraZeneca oncology iMED in Cambridge
(UK), the University of Cambridge Department of Chemistry and the Herchel Smith Fund for
providing a postdoctoral research fellowship to Dr. Claudia De Fusco.
References
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11 1H NMR spectra of the crude reaction mixtures showed no evidence for the presence of pyridine-2-
carboxaldehyde, however pyridin-2-ylmethanol was often observed. This byproduct was readily removed by
chromatography.

Graphical Abstract (for review)

Highlights



A simple procedure for the conversion of picolinic amides to the parent amines using zinc in
aqueous hydrochloric acid is described
The reaction exhibits generally good yields, mild conditions and broad substrate tolerance,
including acid sensitive functional groups
The limitations of the method and a mechanistic hypothesis are also discussed