Angewandte
Chemie
DOI: 10.1002/anie.201208544
Cross-Coupling
Mild and Rapid Pd-Catalyzed Cross-Coupling with Hydrazine in
Continuous Flow: Application to the Synthesis of Functionalized
Heterocycles**
Andrew DeAngelis, Dong-Hui Wang, and Stephen L. Buchwald*
Functionalized arylhydrazines are of widespread importance
as intermediates in the syntheses of nitrogen-containing
heterocycles.[1] In this regard, indoles,[1,2] arylpyrazoles/pyr-
azolones,[1,3] and aryltriazoles,[1,4] among others,[1] can be
efficiently generated from arylhydrazines. These heterocyclic
motifs are prevalent structural elements in numerous com-
pounds of significant biological/medicinal value.[5] Among
current strategies to generate arylhydrazines, nucleophilic
aromatic substitution to an aryl halide (ArX)[6] or diazotiza-
tion of an aniline followed by reduction of the diazonium
salt[7] have long been preparative methods of choice [Eq. (1)].
However, the former method typically requires an arene
activated by electron-withdrawing groups, while the diazoti-
zation/reduction sequence is redox-exhaustive and involves
the generation of unstable diazonium intermediates.
cant safety issues exist with the use of hydrazine in the
presence of transition metals, particularly with heating; many
metal–hydrazine complexes are known to be powerful
explosives.[12] We have recently demonstrated the feasibility
[13]
À
of C N cross-coupling reactions in continuous flow, and
this strategy represents an attractive solution to minimizing
the hazards associated with hydrazine/transition metal mix-
tures.[14,15] Described herein is a mild and potentially scalable
method for the direct cross-coupling of aryl chlorides with
hydrazine through the use of continuous flow technology
[Eq. (3)], and the application of this technology to the rapid
construction of a range of heterocyclic scaffolds.
Modern cross-coupling technology has provided chemists
with powerful tools to construct carbon–nitrogen bonds,[8] and
thus presents an alternative method of synthesizing aryl
hydrazines.[9] Accordingly, several such cross-coupling strat-
egies have been reported utilizing hydrazine equivalents[10]
such as benzophenone hydrazone [Eq. (2)].[10a–f] The only
We began our investigation by carrying out several small-
scale (ꢀ 0.20 mmol) batch experiments to identify suitable
reaction conditions; the cross-coupling reaction of 4-chloro-
toluene and a commercially available 1.0m solution of
hydrazine in THF (2.0 equiv) was selected for optimization
(Table 1). A screen of precatalysts[16] revealed tBuXPhos (L2)
and BrettPhos (L3) as efficient ligands in promoting the
desired monoarylation of hydrazine with 3 mol% catalyst
loading at 608C for 1 h. Under these conditions, 4-tolyl-
hydrazine 1 was formed in high yield with high selectivity over
diarylated products 2 and 3 (entries 2–4).[17,18] We subse-
quently found that the BrettPhos-based catalyst was
extremely active as it provided 1 in 84% yield with
1.2 equiv of hydrazine at room temperature in only 3 min,
albeit with slightly decreased selectivity over diarylation
(entry 6). Interestingly, the effect of the stoichiometry of
hydrazine on the selectivity over diarylation was not dramatic.
While a ratio of 96:2:2 of 1:2:3 was observed with 2.0 equiv of
hydrazine at room temperature (entry 10), good selectivity
(92:5:3) for arylation of the more nucleophilic hydrazine was
still achieved using only 1.2 equiv (entry 6). Further studies
were conducted using 1.6 equiv (entry 8), as slightly better
selectivity (95:2.5:2.5) was observed compared to using less
hydrazine (entries 6 and 7), while increasing the amount of
hydrazine provided no significant advantage (entries 9 and
10).
À
example of direct C N cross-coupling with hydrazine was
recently reported by Stradiotto et al.[11] While this method
represented a notable advance, the reactions were set up in
a nitrogen-filled glovebox and required relatively high
catalyst loading (3–10 mol% Pd). More importantly, signifi-
[*] Dr. A. DeAngelis, Dr. D.-H. Wang, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
[**] We acknowledge Novartis International AG for funding. The Bruker
NMR spectrometers used in this work were supported by grants
from the National Science Foundation (CHE-9808061 and DBI-
9729592) and the National Institutes of Health (1S10RR13886-01).
We thank Dr. Nathan T. Jui for helpful discussions and Dr. Christine
Nguyen for experimental assistance. MIT has patents on some of
the ligands and precatalysts used in this work as well as metal-
catalyzed cross-coupling reactions with hydrazine from which S.L.B.
receives royalty payments.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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