Iridium-catalyzed Synthesis of Saturated N-Heterocycles from Aldehydes and SnAP Reagents with Continuous Flow Photochemistry

Article abstract of DOI:10.1021/acs.orglett.8b00611

Commercially available tin amine protocol (SnAP) reagents provide a simple approach to the synthesis of a wide variety of saturated N-heterocycles from aldehydes. In this report, we disclose that the copper(II) promoter and hexafluoroisopropanol can be replaced by photocatalytic conditions using Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ in CH₃CN. Continuous flow photochemical conditions provide a clean, scalable approach to valuable products including morpholines, piperazines, thiomorpholines, diazepanes, and oxazepanes from aldehyde starting materials.

Full text of DOI:10.1021/acs.orglett.8b00611

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iridium-catalyzed Synthesis of Saturated N‑Heterocycles from
Aldehydes and SnAP Reagents with Continuous Flow
Photochemistry
Chalupat Jindakun, Sheng-Ying Hsieh, and Jeffrey W. Bode*
Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
̈
̈
S
* Supporting Information
ABSTRACT: Commercially available tin amine protocol (SnAP) reagents provide a simple approach to the synthesis of a wide
variety of saturated N-heterocycles from aldehydes. In this report, we disclose that the copper(II) promoter and
hexafluoroisopropanol can be replaced by photocatalytic conditions using Ir[dF(CF3)ppy]2(dtbbpy)PF6 in CH3CN. Continuous
flow photochemical conditions provide a clean, scalable approach to valuable products including morpholines, piperazines,
thiomorpholines, diazepanes, and oxazepanes from aldehyde starting materials.
Scheme 1. Synthesis of Saturated N-Heterocycles with SnAP
and SLAP Reagents
in amine protocol (SnAP) reagents are widely used,
commercially available starting materials for the one-step
T
conversion of aldehydes to saturated N-heterocycles such as
morpholines, piperazines, thiomorpholines, oxazepanes, diaze-
panes, substituted pyrrolidines, and piperidines (Scheme 1a).1
The SnAP chemistry is distinguished by exceptionally broad
substrate scope that tolerates aromatic heterocycles as well as
unprotected functional groups including anilines, phenols, esters,
nitriles, and halides under simple, consistent reaction conditions.
These features make SnAP chemistry well suited to the
preparation of small amounts of N-unprotected saturated N-
heterocycles from readily available precursors.
The limitations of SnAP chemistry, particularly on larger scale,
include the use of tin reagents,2 the requirement for halogenated
solvents,3 and sometimes complicated aqueous workups to
remove copper salts. To address these concerns, we have
introduced the corresponding silicon (SLAP) reagents, which
afford similar products under photocatalytic conditions (Scheme
1b).4 While effective, most of the SLAP reagents require the
addition of superstoichiometric amounts of Lewis acid additives
and are therefore not compatible with all substrate combinations,
particularly N-Boc protected amines.4b,c The SnAP reagents are
also currently more readily available and provide access to many
more types of saturated N-heterocycles.5
In this report, we document continuous flow, photocatalytic
conditions6 for the formation of saturated N-heterocycles from
aldehydes and commercially available SnAP reagents (Scheme
1c). Although tin reagents are still employed, this approach offers
the replacement of stoichiometric copper with catalytic amounts
of an iridium photocatalyst, the use of CH3CN/TFE rather than
CH2Cl2/HFIP as the reaction solvent, and simplified workup.
Received: February 20, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00611
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The reactions can be easily scaled up using a simple flow reactor
without variation of the reaction conditions.
Table 1. Optimization of Reaction Conditions for
Photocatalytic SnAP Reactions
The shift from a stoichiometric, copper-mediated process to a
catalytic, photoredox variant8−10 began with the recognition that
theSnAPchemistryproceedsbyaseriesofsingleelectrontransfer
stepsinitiatedbycopper(II)andmostlylikelyinvolvesfreeradical
intermediates (Figure 1).11 We sought to mimic this sequence of
events with a suitable photoredox catalyst.
Figure 1. Proposed catalytic cycle for copper-promoted SnAP reactions7
and the photoredox alternative. This catalytic cycle features a single
electron transfer oxidation to generate the stabilized C-centered radical
and reduction of the N-centered radical to form the N-heterocycle
product upon protonation.
NMR
flow rate
conv
yield
a
a
entry
1
catalyst
solvent
(mL/min) (%)
(%)
b
1 mol % 1
4:1 CH3CN/
MeOH
batch
batch
batch
batch
100
47
14
51
0
b
b
b
b
2
3
4
2.5 mol % 2 4:1 CH3CN/
14
100
0
MeOH
Based on the estimated potentials for oxidation of the carbon−
tin bond12 and subsequent reduction of the N-centered radical,13
we evaluated and screened a number of potential photoredox
catalysts14−16 using imine Im-6a as the model substrate (Table 1,
entry 1−5). As predicted from the compatible redox potentials of
2CzIPN (entry 3), it served as a competent photoredox catalyst
for the reaction; however, it is nearly insoluble in CH3CN, and no
product was formed in DMF, rendering it unsuitable for flow
chemistry.15 We selected instead Ir[dF(CF3)ppy]2(dtbbpy)PF6
(1) as the catalyst for further optimization under continuous flow
conditions. A preliminary result showed up to 50% of cyclized
product6awasobtainedundercontinuousflowconditions(entry
6), comparable with yields obtained under batch conditions
(entry 1). The use of slightly increased amounts of the
photoredox catalyst (entry 7) or more acidic alcohols (e.g.,
TFE or HFIP, entry 8−9) as the cosolvent facilitated the reaction
and improved the yield. In the CH3CN/TFE solvent system, the
yield of the cyclized product was further increased by higher flow
rate (entry 8 vs 10), while there was no such improvement in
CH3CN/MeOH (entry 7 vs 11). Presumably, the acidic alcohol
enhanced the reactivity of the substrate, resulting in over-reaction
(e.g., oxidation of α-radical or decomposition of the N-
heterocycle product) when the reaction time was extended.
Fortheexplorationofthesubstratescope, weappliedCH3CN/
TFE as the solvent system at 0.05 mM concentration and a flow
rate of 0.20 or 0.25 mL/min (Table 1, entry 10), which gave a
residence time of 7−9 min in our reactor.17 Morpholines and
oxazepanes were prepared from aromatic aldehydes with SnAP
reagents under the standard conditions in moderate yields.
Importantly, N-Boc protected piperazines and diazepanes, which
cannot currently be prepared using SLAP chemistry, were also
formed in good yields under the same reaction conditions. This
condition is also applicable to the synthesis of thiomorpholines
5 mol % 3
5 mol % 3
4:1 CH3CN/
MeOH
c
15:4:1 CH3CN/
MeOH/DMF
5
6
5 mol % 4
1 mol % 1
9:1 toluene/HFIP
batch
0.13
0
0
4:1 CH3CN/
MeOH
72
50
7
2.5 mol % 1 4:1 CH3CN/
0.13
82
69
MeOH
8
2.5 mol % 1 4:1 CH3CN/TFE
2.5 mol % 1 4:1 CH3CN/HFIP
2.5 mol % 1 1:1 CH3CN/TFE
0.13
0.13
0.25
0.25
92
91
93
89
58
55
65
58
9
10
11
2.5 mol % 1 1:1 CH3CN/
MeOH
a
1
Conversion (conv) and yield were measured from H NMR using
1,3,5-trimethoxybenzene as an internal standard. The reaction was
performed in a glass vial under exposure to blue light (see Supporting
Information). Used as a 1.0 M solution in DMF. TFE = 2,2,2-
b
c
trifluoroethanol. HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol.
with no need for additives or changes to the reaction conditions,
making this protocol more general and appealing than the Cu-
based catalytic condition7 or the SLAP chemistry.4
In the case of substrates such as 5f, which contained an easily
oxidizable thiophene, or highly hindered aldehydes (7i or 8e), the
flow rates were reduced to 0.15 mL/min for higher yields
(Scheme 2). For certain highly hydrophobic imines, a mixture of
1:1 CH2Cl2/TFE was employed instead of CH3CN.
In general, the yields of the N-heterocycle products from this
flow protocol are slightly lower than those from the copper
promoted SnAP chemistry. However, the iridium-catalyzed
photoredox conditions offer certain advantages including the
ability to employ 2-pyridyl aldehydes and related substrates
without the need for additional ligands7 and better results with
B
DOI: 10.1021/acs.orglett.8b00611
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Scheme 2. Substrate Scope of N-Heterocycles from Aldehydes and SnAP Reagents under Continuous Flow Conditions
a
b
c
Flow rate = 0.15 mL/min. Diastereomeric ratio (d.r.) was determined from 1H NMR spectroscopy of the unpurified reaction mixture. CH2Cl2/
d
TFE (1:1) was used as the solvent. Diastereomeric ratio was not determined. Isolated yields were determined on 0.50 mmol reaction scale. MS =
molecular sieves.
more sterically demanding aldehydes. The replacement of
stoichiometric copperandamineligandswith asinglephotoredox
catalyst resulted in easier reaction workup1d,7 with particular
significance for reaction scale-up. To demonstrate this, we
performed a 10.0 mmol scale reaction under the identical
continuous flow condition (Scheme 3). The desired product was
obtained simply by acid−base extraction in 62% crude yield with
only trace amounts of tin residue. Further purification by
precipitation with 4 M HCl in dioxane gave the pure oxazepane
salt 9a·HCl in 41% yield.
Interestingly, a few substrates were reluctant to participate in
cyclizations under these conditions for uncertain reasons. In
particular, attempts to use naphthyl aldehydes failed to give any
desiredproducts, despitethefactthatsuchaldehydesareexcellent
substrates for Cu-promoted SnAP chemistry. UV−vis spectro-
scopic experiments suggested that naphthylimine absorbs light in
the region where photoredox catalyst 1 was excited under blue
LEDs source, which could lead to the depletion of catalyst’s
quantum yield (see Supporting Information, Figure S3).
Likewise, more elaborate SnAP reagents, such as SnAP-2-Spiro-
(4-Pip) M, gave only trace amounts of the desired product; an
C
DOI: 10.1021/acs.orglett.8b00611
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Scheme 3. Gram-Scale Synthesis of Saturated N-Heterocycles
with Continuous Flow Photochemistry
ACKNOWLEDGMENTS
■
Financial support was provided by the Royal Thai Government
Scholarship and the European Research Council (ERC Starting
Grant 306793−CASAA). We thank the LOC Mass Spectrometry
Service and the LOC NMR Service of ETH Zurich. We also
express our gratitude to Dr. Benedikt Wanner (ETH Zurich) and
̈
̈
Dr. Anastasios Polyzos (University of Melbourne) for the
construction of the photoflow-reactor, and Dr. Michael Luescher,
Dr. Tuo Jiang, Moritz Jackl, and Yayi Wang (ETH Zurich) for
̈
helpful discussions.
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Corresponding Author
*E-mail: bode@chem.ethz.ch.
ORCID
Jeffrey W. Bode: 0000-0001-8394-8910
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.8b00611
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(17)Residencetime=reactorvolume/flowrate;inthiscase, ourreactor
volume is 1.7 mL, which gives a residence time of 7−9 min for the flow
rate of 0.20−0.25 mL/min.
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DOI: 10.1021/acs.orglett.8b00611
Org. Lett. XXXX, XXX, XXX−XXX