Silicon Amine Reagents for the Photocatalytic Synthesis of Piperazines from Aldehydes and Ketones

Article abstract of DOI:10.1021/acs.orglett.6b00722

Silicon amine protocol (SLAP) reagents for photocatalytic cross-coupling with aldehydes and ketones to form N-unprotected piperazines have been developed. This blue light promoted process tolerates a wide range of heteroaromatic, aromatic, and aliphatic aldehydes and structurally and stereochemically complex SLAP reagents. It provides a tin-free alternative to SnAP (tin amine protocol) reagents for the synthesis of substituted piperazines.

Full text of DOI:10.1021/acs.orglett.6b00722

Letter
pubs.acs.org/OrgLett
Silicon Amine Reagents for the Photocatalytic Synthesis of
Piperazines from Aldehydes and Ketones
Sheng-Ying Hsieh and Jeffrey W. Bode*
Laboratorium fur Organische Chemie, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
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̈
̈
S
* Supporting Information
ABSTRACT: Silicon amine protocol (SLAP) reagents for
photocatalytic cross-coupling with aldehydes and ketones to
form N-unprotected piperazines have been developed. This
blue light promoted process tolerates a wide range of
heteroaromatic, aromatic, and aliphatic aldehydes and
structurally and stereochemically complex SLAP reagents. It
provides a tin-free alternative to SnAP (tin amine protocol) reagents for the synthesis of substituted piperazines.
ubstituted saturated N-heterocycles are among the most
valuable scaffolds for the development of new pharmaceut-
Scheme 1. Comparison of SnAP and SLAP Chemistry for the
Piperazine Synthesis
S
icals,1 and a great deal of contemporary synthetic methodology
is currently devoted to improved methods for their
construction.2 Progress in lithiation chemistry,3 C−H functio-
nalization,3b,c intramolecular hydroamination,4 and photo-
catalytic cross-coupling5 offer promising new entries, but
these methods are often limited in substrate scope or require
difficult-to-remove groups on the nitrogen atom. As a powerful
alternative, we have recently developed SnAP (stannyl amine
protocol) reagents that cross-couple with aldehydes and
ketones to provide one-step access to a wide variety of
saturated N-heterocycles,6 including thiomorpholines,6a mor-
pholines,6b piperazines,6b and diazepanes,6c as well as more
elaborate bicyclic and spirocyclic compounds (Scheme 1).6d,e
The SnAP chemistry is characterized by a broad substrate scope
and versatility under a standard set of reaction conditions,
making it ideally suited for the preparation of libraries of
saturated N-heterocycles. Its main drawback is a reliance on
potentially toxic tin reagents,7 currently being phased out of
pharmaceutical research and production. To address this issue,
we now report SiLicon Amine Protocol (SLAP) reagents that
provide access to piperazines from aromatic, heteroaromatic,
and aliphatic aldehydes and ketones using an iridium
photoredox catalyst without additional reagents or the
generation of toxic byproducts.
Silicon moieties are known surrogates for tin in many radical-
based processes.8 Although Kagoshima reported an example of
Cu-promoted additions of α-trimethylsilyl alcohols to imines,9
we were unable to translate this finding to our own work.
Inspired by the pioneering studies of the Yoon and Mariano
groups10 and the Pandey group11 on the photochemical
generation of α-amino radicals via desilylation, as well as
recent photocatalytic variants reported by Nishibayashi12 and
Yoon,13 we considered the application of photochemistry to
piperazine formation. We therefore selected the inexpensive
and easily prepared trimethylsilyl (TMS) reagents 1−3 for
more detailed studies, including screening of conditions for
cyclization.
The TMS reagent 1 readily condensed with para-
fluorobenzaldehyde to give a corresponding imine 4, but this
did not react under the standard conditions used for cyclization
of the tin reagents (Table 1, entry 1). Nishibayahi’s conditions
for the photocatalytic addition of α-silyl-N-Ph amines to enones
utilized Ir[(ppy)2dtbbpy]PF6 and blue light irradiation. We
applied these conditions to the cyclization of 4 (entry 2).
Received: March 12, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00722
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Letter
Table 1. Screening of Imines and Optimization of
Cyclization
Scheme 2. Substrate Scope via Basic SLAP Reagent 3
a
a
See the Supporting Information for the conditions of imine/ketimine
b
formation. The reaction was carried out in MeCN/MeOH (9:1,
0.05 M).
piperazine products 9b−9i were obtained in good yields within
3 h (Scheme 2). A salient feature of SnAP chemistry is its
remarkably high tolerance for unprotected functional groups.
Any alternative must match the substrate scope of the SnAP
chemistry, particularly with regard to compatibility with basic
aromatic N-heterocycles. The piperazine forming SLAP
reagents fulfill these criteria; heteroaromatic substrates pose
no difficulty and gave excellent conversion. Aliphatic aldehydes
also gave the desired products, albeit with somewhat reduced
yields. In preliminary experiments, the combination of ketones
with SLAP reagents provided access to spirocyclic piperazines.
The high chemical stability of the TMS group allows the
construction of bespoke SLAP reagents by assembly of various
commercially available trimethylsilylmethylene building blocks
(Scheme 3A). This enables the preparation of SLAP reagents
10−15 by amidation/reduction, epoxide opening, or amine
alkylation. All of these reagents proved to be suitable partners
in the photocatalytic piperazine formation, regardless of the
sterics or stereochemistry of the SLAP reagents. In all cases, the
piperazine products were formed with excellent diastereose-
lectivity, in favor of the more thermodynamically stable isomers
(Scheme 3B).
a
b
All reactions were conducted at room temperature. Imine formation
was performed with p-fluorobenzaldehyde and MS 4A in MeCN.
c
d
Isolated yield under 0.5 mmol scale. Calculated yield from 1H NMR
measurement of unpurified reaction mixture under 0.1 mmol scale
with 1,3,5-trimethoxybenzene as an additional internal standard.
e
f
Along with unidentified products in small amounts. The unidentified
products were desilylated. BL = blue light; DCE = 1,2-dichloroethane;
dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine; HFIP = 1,1,1,3,3,3-hexa-
fluoro-2-propanol; Pg = protecting group; ppy = 2-phenylpyridine;
TFE = 2,2,2-trifluoroethanol.
The postulated mechanism features the generation of an
aminoalkyl radical via oxidation by the photoexcited
Although no product was observed with the imine formed from
the N-Boc reagent, full conversion of the N-Ph imine 5 was
observed within a few hours (entry 3). These conditions were
fortunately also applicable to the more synthetically attractive
N-Bn piperazine reagent 3 (entry 4).14 Further optimization of
the reaction conditions (entries 5−7) and control reactions
(entries 8 and 9) to establish the necessity of both the blue light
and the iridium photocatalyst lead to the optimized conditions.
In general, MeCN was the optimal solvent, but slightly better
results were obtained with alcohols as cosolvents (10% v/v).
Condensation of 3 with a variety of aromatic and aliphatic
aldehydes occurred smoothly, and the additional N-Bn
*IrIII[(ppy)2dtbbpy]PF6 (represented as Ir(III)* in Figure
1).8c,12 This excited Ir(III)* species (E1/2
*
= +0.66 V vs
III/II
SCE in MeCN)15 effects single electron oxidation of the
tertiary amine of 22 (Ep = +0.65 V vs SCE for 1-
((trimethylsilyl)methyl)piperidine)16 to generate the nitrogen
stabilized carbon-centered radical 23 via desilylation and
generates the Ir(II) species. Although the reduction of cyclized
red
N-centered radical 24 (E1/2
= −1.70 V vs SCE for
dialkylaminyl radicals)17 by the Ir(II) species (E1/2
=
III/II
−1.51 V vs SCE)15 seems to be unfavorable, the substituents
(R1 and R2) may stabilize the N-centered radical, allowing it to
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a
Scheme 3. (a) Custom SLAP Reagents 10−15 and the TMS Building Blocks (Shown in Blue) Used in Their Synthesis; (b)
a b c
, ,
Representative Piperazine Products Formed by Photocatalytic Coupling of SLAP Reagents with Aldehydes or Ketones
a
b
Yields are of isolated, analytically pure products. SLAP reagents 10 and 14 and piperazines 16 and 20 are enantiopure forms. See Scheme 2 for
c
1
photocatalytic cyclization conditions. The diastereomeric ratios were determined by H NMR measurement of unpurified reaction mixtures. The
relative configurations were analyzed by 2D NOESY spectra. See the Supporting Information for details.
IrIII[(ppy)2dtbbpy]PF6 catalyst allows this sequence of single
electron oxidation and reduction with low catalyst loadings and
without forming toxic byproducts. This highlights the impact of
photocatalytic methods for improving both the scope and
sustainability of organic reactions, such as our SnAP chemistry.
At present, the silicon-based reagents are limited to the
formation of piperazines; the corresponding reagents for
morpholines, diazepanes, and thiomorpholines did not give
acceptable yields of the desired products under these
conditions. We attribute this to the lower oxidation potential
of α-TMS substituted amines than that of corresponding
sulfides and ethers.10a,19 We anticipate that the continued
development of more active photoredox catalysts or other
strategies to lower the oxidation potential of the SLAP reagents
will address this limitation in the near future.
Figure 1. Postulated mechanism for photocatalytic piperizine
formation. Ir(III) = IrIII[(ppy)2dtbbpy]PF6.
In summary, we have applied the principles of photoredox
catalysis to the development of silicon-based SLAP reagents for
the one-step conversion of aldehydes and ketones into
substituted piperazines. This chemistry is distinguished by the
mild and attractive reaction conditions, high tolerance of
unprotected functional groups and steric hindrance, direct
formation of N-unprotected products, and ready availability of
customized SLAP reagents. Although it is not yet applicable to
the extremely broad range of saturated N-heterocycles suitable
for tin-based SnAP chemistry, it provides an attractive
alternative to piperazine synthesis and a basis for extending
be reduced to give, after protonation by TFE, the piperazine
product and the starting Ir(III) catalyst. It is worth noting that
other photoredox catalysts, such as RuI(bpy)3+ (E1/2II/I = −1.33
V vs SCE),18 were probably not able to reduce N-centered
II/I
radical 24, despite having sufficient oxidizing ability (E1/2
*
=
18
2+
+0.77 V vs SCE for *RuII(bpy)3
)
to perform the
desilylation13 (Table 1, entry 11). It is remarkable that the
combination of SLAP reagents and the unique nature of the
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00722.
́
(7) Le Grognec, E.; Chretien, J.-M.; Zammattio, F.; Quintard, J.-P.
Experimental procedures and characterization data
(PDF)
Crystallographic data for 18c (CIF)
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AUTHOR INFORMATION
Corresponding Author
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*E-mail: bode@org.chem.ethz.ch.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the European Research Council
(ERC Starting Grant No. 306793 − CASAA). We appreciate
the construction of blue light reactors by Mr. Benedikt Wanner
(ETH Zurich). We thank Drs. Cam-Van Vo and Tuo Jiang
̈
(ETH Zurich) for preliminary experiments. We are grateful to
̈
the Laboratorium fur Organische Chemie at ETH Zurich on
̈
̈
NMR service for NOSEY measurement, to Mr. Oswald Greter
and Mr. Louis Bertschi (ETH Zurich) for MS analysis service,
̈
and to Dr. Nils Trapp for the acquisition of X-ray structure
(ETH Zurich).
̈
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