Angewandte
Chemie
DOI: 10.1002/anie.200903922
Hydroamination
Synthesis of Pyridines and Pyrazines Using an Intramolecular
Hydroamination-Based Reaction Sequence**
Toni Rizk, Eric J.-F. Bilodeau, and Andrꢀ M. Beauchemin*
The prevalence and diversity of aromatic nitrogen hetero-
cycles found in natural products and used in medicinal
chemistry continues to fuel the development of new methods
and strategies for their syntheses.[1] Recently, advances in
hydroamination of substrates such as 1. Whereas several
nitrogen-containing precursors could provide the required
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oxidation state adjustment (e.g., N OH, N SO2Ar, N NR2),
oxime precursors were selected since the only by-product of
the reaction would be H2O. Therefore, initial efforts focused
on the transformation of precursor 1a into 2-picoline (2a),
and selected optimization data is shown in Table 1.
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amination chemistry (e.g., C H insertions, metal-catalyzed
annulations, Buchwald–Hartwig cross-couplings, oxidative
aminations, hydroaminations) have enabled routes to diverse
aromatic ring systems and offer excellent potential for broad
applicability in heterocycle synthesis. Specifically, several
hydroamination routes to access unsaturated nitrogen func-
tional groups are emerging.[2] The hydroamination of alkynes
using amines (and equivalents thereof) affords enamines or
imines reliably, and alkene “hydroiminiumation” reactivity of
imines recently reported by Bertrand et al.[3] are representa-
tive examples. However, hydroamination routes to aromatic
nitrogen heterocycles are rare and have so far been mostly
limited to five-membered ring systems.[4] Analogously, metal-
catalyzed alkyne annulations have been thoroughly studied,[5]
such as indole formation from o-alkynylanilines or isoquino-
line formation from o-alkynylbenzaldimines,[6] but reports of
such cyclizations to form pyridines or pyrazines are rare.[7]
Herein we report a simple acid-catalyzed hydroamination/
isomerization/aromatization sequence leading to pyridines
and pyrazines from simple acyclic alkynyl oxime (LG = OH)
precursors [Eq. (1)].
Table 1: Formation of 2-picoline from oxime precursor 1a.[a]
Entry
Acid (equiv)
T [8C]
Yield of 2 [%][c]
1
none
180
120
120
120
120
160
160
160
160
15 (3)
0
35
37
45
80
12
80
99
2[b]
3[b]
4
CH3CO2H (1 equiv)
CF3CO2H (1 equiv)
CCl3CO2H (5 equiv)
CF3CO2H (5 equiv)
CF3CO2H (5 equiv)
TsOH (1.25 equiv)
TsOH (0.1 equiv)
TsOH (0.02 equiv)
5[b]
6
7
8
9
[a] Reaction conditions: in iPrOH (0.1m), 5 h, in a Biotage Initiator EXP
US microwave reactor (MW; 0–400 W). [b] EtOH used as solvent.
[c] Determined by NMR analysis. Ts=4-toluenesulfonyl.
As a continuation of our efforts on Cope-type hydro-
amination reactivity of hydroxylamines,[8,9] and drawing
inspiration from the work of Grigg et al. on intramolecular
aza-protio transfer (hydroamination) reactivity of oximes
with p bonds,[10] thermolysis of 1a was attempted (Table 1,
entry 1) and resulted in the formation of a modest yield of 2-
picoline N-oxide (3). A variety of approaches were surveyed
and control experiments revealed that a stoichiometric
amount of TFA (CF3CO2H) resulted in the formation of 2a
in modest yield (Table 1, entry 3). Optimization of the
reaction conditions using TFA showed that the reaction is
more efficient with excess acid (Table 1, entry 5) or at higher
temperatures (Table 1, entry 6), which suggests reversible
protonation of the oxime precursor and rate-limiting cycliza-
tion. In stark contrast, the reaction with TsOH was almost
inhibited in the presence of excess acid (Table 1, entry 7),
suggesting irreversible protonation of the oxime by TsOH.
However, the sequence could be catalyzed efficiently using
2 mol% TsOH at 1608C (Table 1, entry 9). Given that the
product 2a inherently buffers the acidity of the medium, these
results illustrate that the nature of the counteranion is crucial
for this reactivity.[11]
Combining the necessary requirement of using more-
oxidized precursors to access aromatic six-membered nitro-
gen heterocycles, and the prior work showing that intermedi-
ates such as I aromatize readily to form pyridine rings,[1] we
sought to form pyridines and pyrazines by intramolecular
[*] T. Rizk, E. J.-F. Bilodeau, Prof. Dr. A. M. Beauchemin
Centre for Catalysis Research and Innovation
Department of Chemistry, University of Ottawa
10 Marie-Curie, Ottawa, ON K1N 6N5 (Canada)
Fax: (+1)613-562-5170
E-mail: andre.beauchemin@uottawa.ca
[**] We thank the University of Ottawa (start-up), CFI, MRI (Ontario),
and NSERC for support of this work. Prof. Derrick L. J. Clive is
thanked for an insightful discussion.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2009, 48, 8325 –8327
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8325