SnAP reagents for the synthesis of piperazines and morpholines

Article abstract of DOI:10.1021/ol500210z

Substituted piperazines and morpholines are valuable structural motifs in biologically active compounds, but are not easily prepared by contemporary cross-coupling approaches. In this report, we introduce SnAP reagents for the transformation of aldehydes into N-unprotected piperazines and morpholines. This approach offers simple, mild conditions compatible with aromatic, heteroaromatic, aliphatic, and glyoxylic aldehydes and provides mono- and disubstituted N-heterocycles in a single step.

Full text of DOI:10.1021/ol500210z

Letter
pubs.acs.org/OrgLett
SnAP Reagents for the Synthesis of Piperazines and Morpholines
Michael U. Luescher, Cam-Van T. Vo, and Jeffrey W. Bode*
Laboratorium fur Organische Chemie, ETH Zurich, CH-8093 Zurich, Switzerland
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̈
̈
S
* Supporting Information
ABSTRACT: Substituted piperazines and morpholines are
valuable structural motifs in biologically active compounds, but
are not easily prepared by contemporary cross-coupling
approaches. In this report, we introduce SnAP reagents for
the transformation of aldehydes into N-unprotected piper-
azines and morpholines. This approach offers simple, mild
conditions compatible with aromatic, heteroaromatic, aliphatic,
and glyoxylic aldehydes and provides mono- and disubstituted
N-heterocycles in a single step.
e have recently introduced SnAP1 reagents for the
Wsimple synthesis of saturated N-heterocycles including
thiomorpholines2 and medium-sized rings.3 This process allows
widely available aliphatic, aromatic, and heteroaromatic
aldehydes to be converted to various N-heterocycles by a
simple, general reaction protocol. It affords directly N-
unprotected products, has an outstanding substrate scope and
functional group tolerance, and offers an easily recognized
retrosynthetic disconnection. Mechanistically, we currently
favor a CuII-promoted generation of a stabilized radical that
undergoes endo cyclization with the intermediate imine. We
envision that readily prepared SnAP reagents and their
equivalents will become commercially available building blocks
for direct incorporation of saturated N-heterocycles via
aldehyde synthetic handles (Figure 1).
In this report, we document SnAP reagents 1−6 for the
synthesis of substituted, N-unprotected piperazines and
morpholines (Figure 2). We also introduce Me-substituted
SnAP reagents for the diastereoselective synthesis of disub-
stituted morpholines and piperazines.
SnAP reagents 1−6 were prepared on a multigram scale by
straightforward and efficient routes (see Supporting Informa-
tion for full synthetic details). The SnAP reagents are easily
handled, air- and moisture-stable liquids that can be stored for
several weeks without decomposition.4 For the purposes of
evaluation, a single reaction protocol was used in all of the
cyclization reactions.
Piperazines prepared with SnAP Pip 1 were obtained in good
yield using electron-poor and electron-rich aromatic, hetero-
aromatic, and aliphatic aldehydes (Scheme 1). Sterically
demanding 2-chloro-4-fluorobenzaldehyde (7b) and pivalde-
hyde (7f) afforded the 6-endo products in good yield.
Products containing groups suitable for further elaboration,
including esters, organohalides, and a variety of heterocycles,
were easily prepared. Additionally, we were pleased to discover
that unprotected indole (7j) was incorporated in good yield.
Piperazines from unbranched aliphatic aldehydes were observed
in lower yields, presumably due to the facile enamine
Figure 1. SnAP reagents for the synthesis of N-heterocycles from
aldehydes.
formation. The major side products observed in the cyclization
reactions were the protodestannylated imines.
The synthesis of morpholines using SnAP M 4 showed again
a broad substrate scope and functional group tolerance and
afforded the desired N-unprotected heterocycles in good to
excellent yields from electron-poor and electron-rich aromatic,
heteroaromatic, and glyoxylic aldehydes (Scheme 2). Branched
aliphatic aldehydes (8g−8h) also afforded the desired product
in moderate to good yield. The reaction with bulky 2,4,6-
mesitylaldehyde (8d) was slow, promoting the formation of a
destannylated side product. Elevated temperature did not
improve the overall yield; only traces of the desired product
Received: January 21, 2014
© XXXX American Chemical Society
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a
Scheme 2. Morpholine Synthesis with SnAP M 4
Figure 2. SnAP reagents. Overall yields are from commercially
available starting materials.
a
Scheme 1. Piperazine Synthesis with SnAP Pip 1
a
Conditions: SnAP M 4 (1.0 equiv, 0.5 mmol), aldehyde (1.0 equiv,
0.5 mmol), MS 4A, CH2Cl2 (0.2 M), 2 h, rt; Cu(OTf)2 (1.0 equiv, 0.5
mmol), 2,6-lutidine (1.0 equiv, 0.5 mmol), 4:1 CH2Cl2/HFIP (0.05
b
M), 12 h, rt; isolated yield. 4:1 DCE/HFIP, 12 h, 60 °C; yield
1
determined by H NMR with 1,3,5-trimethoxybenzene as an internal
c
standard. As a mixture of diastereomers.
line synthesis as a drying agent, can be left out without
deterioration of product formation. We anticipated that
substrate specific optimization will be possible if higher yields
or faster reaction times are necessary.5 An advantage of this
protocol for the preparation of diverse N-heterocycles is the
simple reaction setup: the SnAP reagent is combined with the
aldehyde in the presence of molecular sieves to afford the
corresponding imine, which is cyclized with stoichiometric
Cu(OTf)2 and 2,6-lutidine in 4:1 CH2Cl2/HFIP at rt for 12 h.
The imines were processed by filtration over a glass sintered
funnel and evaporated to ensure clean and full conversion
before subjection to the cyclization. Alternatively, the imine
formation can be diluted with additional CH2Cl2 and
transferred to the heterogeneous copper/ligand suspension by
a syringe equipped with an HPLC filter.
a
Conditions: SnAP Pip 1 (1.0 equiv, 0.5 mmol), aldehyde (1.0 equiv,
0.5 mmol), MS 4A, CH2Cl2 (0.2 M), 2 h, rt; Cu(OTf)2 (1.0 equiv, 0.5
mmol), 2,6-lutidine (1.0 equiv, 0.5 mmol), 4:1 CH2Cl2/HFIP (0.05
M), 12 h, rt; isolated yield.
The introduction of additional substituents into the targeted
piperazine or morpholine can dramatically complicate their
synthesis by traditional methods. To examine the feasibility of
our approach for the facile diastereoselective synthesis of
disubstituted morpholines and piperazines, we prepared methyl
substituted SnAP reagents 2−3 and 5−6 via short reaction
sequences as the additional methyl group displays a valuable
extension for medicinal chemistry.6 Cyclization under standard
conditions afforded the representative disubstituted N-
were observed. As reported for the synthesis of the thiomor-
pholines,2 2-pyridinylaldehyde (8k), which can chelate the CuII,
also showed poor reactivity and the starting material was
recovered.
In general, the formation of the piperazines and morpholines
proved more efficient for a broad range of aldehydes and
occurred in overall higher yields compared to the thiomorpho-
line2 synthesis. CaSO4, which we employed in the thiomorpho-
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Letter
unprotected saturated heterocycles in moderate to good yields
with the usual broad substrate scope (Scheme 3).
Scheme 3. Synthesis of Disubstituted Piperazines and
a c
−
Morpholines with SnAP Reagents
Figure 3. X-ray structure of ( )-11b and ( )-9b and stereochemical
assignment by NOESY spectroscopy.
of 12b was detected using enantiomerically pure SnAP 3Me-M
6,7 permitting fast access to enantiomerically pure building
blocks.8
Piperazines and morpholines are important elements in
natural products and small bioactive molecules.9 Despite the
importance of these building blocks, their applications in
medicinal chemistry are challenging due to poor commercial
availability and the often-laborious synthetic routes that rely on
ring closure10 or α-functionalization.11 Successful approaches
using vinyl sulfonium salts,12 vinyl selenones,13 epoxides,14
aziridines,15 or glyoxal derivatives16 require rather advanced
precursors, making the preparation of diverse substitution
patterns or heterocycle types laborious. These new SnAP
reagents should therefore fulfill a need for the rapid preparation
of morpholines and piperazines not currently met by existing
methods. We also anticipate that the reagent design and
reactions can easily be adapted to accommodate SnAP reagents
with additional substituents and functional groups.
In summary, we have developed new SnAP reagents for the
synthesis of mono- and disubstituted piperazines and morpho-
lines. The cyclization takes place under mild conditions at room
temperature and affords the N-unprotected, saturated N-
heterocycles in good to excellent yields. This methodology
accepts a wide range of electronically and sterically diverse
aromatic, heteroaromatic, glyoxylic, and aliphatic aldehydes
bearing a variety of functional groups including esters,
protected amines, organohalides, ethers, and various hetero-
cycles were tolerated.
a
Conditions: SnAP reagent 2−3, 5−6 (1.0 equiv, 0.5 mmol), aldehyde
(1.0 equiv, 0.5 mmol), MS 4A, CH2Cl2 (0.2 M), 2 h, rt; Cu(OTf)2
(1.0 equiv, 0.5 mmol), 2,6-lutidine (1.0 equiv, 0.5 mmol), 4:1 CH2Cl2/
b
HFIP (0.05 M), 12 h, rt; isolated yield. Diastereomeric ratio was
determined by 1H NMR spectroscopy of the unpurified reaction
c
mixtures. Relative stereochemistry was confirmed by X-ray analysis of
( )-9b and ( )-11b; others were assigned by analogy and NOESY
d
spectroscopy. Yield of major and minor diastereomers combined.
e
f
Yield of major diastereomer. Enantioenriched (S)-SnAP 3Me-M 6
(ee >98%) was used.
The diastereomeric ratio varied depending on the SnAP
reagents used. 3,5-Disubstituted piperazines (10a−c) and
morpholines (12a−b) bearing substituents in a 1,3-relationship
generally showed a high diastereomeric ratio toward the
thermodynamically favored isomer. SnAP 2Me-M 5 gave
predominantly trans-configured 3,6-disubstituted morpholines
(11a−b) (Figure 3a), and SnAP 2Me-Pip 2 afforded the 1,4-
diazacyclohexanes (9a−9c) as a mixture of separable
diastereomers, favoring the cis-isomers (Figure 3b). We
attribute the reduced diastereoselectivity with SnAP 2Me-Pip
2 to the presence of the N-tert-butoxycarbonyl (Boc) group
next to the methyl, which is forced into the axial position to
reduce steric interactions. No racemization during the synthesis
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterizations, spectral data for all
new compounds, and the data for single-crystal X-ray
diffraction of compounds ( )-9b and ( )-11b (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bode@org.chem.ethz.ch.
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Letter
(16) Berree
Lett. 2001, 42, 3591−3594.
́
, F.; Debache, A.; Marsac, Y.; Carboni, B. Tetrahedron
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by an ETH Research Grant (ETH-12
11-1) and the European Research Council (ERC Starting Grant
No. 306793 − CASAA). The authors acknowledge the LOC
Mass Spectrometry Service, the LOC NMR Service, and the
Small Molecule Crystallography Center of ETH Zurich for the
X-ray measurement.
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