The direct α-C(sp3)-H functionalisation of N-aryl tetrahydroisoquinolines via an iron-catalysed aerobic nitro-Mannich reaction and continuous flow processing

Article abstract of DOI:10.1039/c4cc07913b

An efficient nitro-Mannich type direct α-C(sp³)-H functionalisation of N-aryl-1,2,3,4-tetrahydroisoquinolines catalysed by simple iron salts in combination with O₂ as the terminal oxidant is described. The use of a Teflon AF-2400 mem

Full text of DOI:10.1039/c4cc07913b

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The direct a-C(sp3)–H functionalisation of N-aryl
tetrahydroisoquinolines via an iron-catalysed
aerobic nitro-Mannich reaction and continuous
flow processing†‡
Cite this: Chem. Commun., 2015,
51, 334
Received 10th October 2014,
Accepted 7th November 2014
Martin Brzozowski, Jose A. Forni, G. Paul Savage and Anastasios Polyzos*
DOI: 10.1039/c4cc07913b
www.rsc.org/chemcomm
An efficient nitro-Mannich type direct a-C(sp3)–H functionalisation increased catalyst loading, and elevated reaction tempera-
of N-aryl-1,2,3,4-tetrahydroisoquinolines catalysed by simple iron tures.9 Efficient iron-catalysed methodologies using O2 as the
salts in combination with O2 as the terminal oxidant is described. The use oxidant are thus relatively scarce.10
of a Teflon AF-2400 membrane Tube-in-Tube reactor under continuous
The relative abundance and low-toxicity of iron has led to
flow conditions allowed for considerable process intensification to our interest in exploring simple iron salts11 and O2 as a
be achieved relative to previous batch methods.
sustainable catalyst/oxidant combination for the nucleophilic
addition of nitroalkanes to imines (nitro-Mannich reaction).12
Transition metal-catalysed functionalisation of C–H bonds has The b-nitroamine products are valuable building blocks as they
emerged as a powerful strategy for the development of molecular contain a vicinal nitrogen motif that can be selectively manipulated
complexity.1,2 Compared to traditional cross-coupling methods, to gain access to 1,2-diamines (by nitro reduction) and a-amino-
this strategy removes the need for pre-functionalisation of the carbonyls (via the Nef reaction).
coupling partners and thus provides an atom economical and
Shirakawa et al. have reported the nitro-Mannich reaction of
an environmentally benign synthetic alternative.3 Due to the amines with FeCl3 and (t-BuO)2 and Li et al. have employed
ubiquitous nature of C–H bonds, site selective functionalisation magnetic Fe nanoparticles with O2 however a robust methodology
of one C–H bond in the presence of many others remains a exploiting inexpensive iron salts with O2 is currently lacking.13
considerable challenge.4
Recently Doyle and co-workers described the use of FeCl3 and
Heteroatom a-C(sp3)–H bonds exhibit innate reactivity as they O2 for the vinylogous Mannich reaction of N,N-dialkylanilines
can be selectively oxidised and subsequently reacted with nucleo- with siloxyfurans.10b These reaction conditions were extended
philes to give a-functionalised products.5 Oxidative functionalisa- to the nitro-Mannich reaction by performing the reaction in
tion of amine a-C(sp3)–H bonds has proven to be effective for a neat nitroalkane for 5–7 days.
range of C–C and C–X bond forming transformations.6 Oxidation is
The advantages of continuous flow processing in enhancing
typically achieved with a combination of transition metal catalyst7 chemical synthesis are well documented.14 We envisaged that a
and terminal oxidant. Although organic peroxides have by far been continuous flow method would allow us to overcome the poor
the most common oxidants employed, molecular O2 has also been efficiency observed in Fe/O2-mediated nitro-Mannich reactions
shown to be a mild oxidant and provides an attractive choice for the under batch conditions.
development of scalable, greener synthetic routes.8
Recently, the Ley group reported the development and use of a
Copper-catalysed amine a-C(sp3)–H functionalisation with O2 has Teflon AF-2400 membrane-based Tube-in-Tube gas–liquid reactor
been demonstrated to be a general approach, with a broad scope of that allowed for efficient gas delivery to a flow stream.15,16 This
nucleophilic partners exhibiting reactivity at room temperature.8b In reactor has been successfully applied to a range of transforma-
contrast, iron catalysts for amine a-C(sp3)–H functionalisation suffer tions employing gaseous reagents.17
from reduced reactivity, necessitating the use of peroxide oxidants,
Herein we report the Fe/O2-mediated nitro-Mannich reaction of
N-aryl tetrahydroisoquinolines facilitated by continuous flow pro-
cessing. The flow configuration consisted of a Vapourtec R2+/R4
module fitted with a Teflon AF-2400 Tube-in-Tube membrane
reactor (Scheme 1). A 75 psi back pressure regulator was placed
immediately after the gas–liquid reactor to preclude in-line
degassing. The reaction stream was then directed through
two 10 mL stainless steel heated reactor coils18 followed by a
CSIRO Manufacturing Flagship, Bayview Avenue, Clayton 3168, Victoria, Australia.
E-mail: tash.polyzos@csiro.au
† Part of this research was undertaken on the MX1 beamline at the Australian
Synchrotron, Victoria, Australia.
‡ Electronic supplementary information (ESI) available: Experimental procedures
and product characterisation. CCDC 1027557. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c4cc07913b
334 | Chem. Commun., 2015, 51, 334--337
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The conditions from entry 3 were selected as optimal for further
investigation and under these conditions the nitro-Mannich adduct
2a was isolated in 72% yield after column chromatography.
This result established a considerable reduction in reaction
time in comparison to the previously reported Fe/O2-mediated
nitro-Mannich batch reaction of 1ab, which required a reaction
time of 5 days for full conversion.10b
In order to demonstrate the scope and utility of the iron-
catalysed aerobic nitro-Mannich flow reaction, a series of sub-
stituted tetrahydroisoquinolines were coupled with nitroalkanes
using the developed reaction conditions (Table 2).
Scheme 1 Flow configuration for the aerobic nitro-Mannich reaction of
N-aryl tetrahydroisoquinolines.
Initial attempts to access nitro-Mannich adducts other than 2a
gave disappointingly poor isolated yields (o30%) despite full
consumption of the starting amine. Slow turnover of the nitro-
alkane to the nitronate anion was hypothesised to be a limiting
factor and consistent with the work of Todd19 and Doyle,10b
Table 1 Selected optimisation screening of the aerobic nitro-Mannich
reaction of N-phenyl tetrahydroisoquinoline 1a in flowa
Table 2 Scope of continuous flow iron-catalysed aerobic nitro-Mannich
reactiona,b
Cat. loading
(mol%)
Temp.
(1C)
O2 pressure
(bar)
Conv.b
(%)
Entry
1
2
3
4
5
6
7
8
9
10
10
10
1
2
5
10
10
10
50
70
90
90
90
90
90
90
90
7
7
7
7
7
7
1
3
5
37
87
100
11
26
40
18
36
72
a
Reaction conditions: 1a (0.1 mmol), FeCl2, MeNO2 (5 equiv.), MeOH
(2 mL), O2, TR = 1 h. Determined by 1H NMR.
b
250 psi back pressure regulator. We began our investigation by
optimising the processing parameters for the aerobic nitro-
Mannich reaction of N-phenyl tetrahydroisoquinoline 1ab with
nitromethane catalysed by iron(II) chloride (Table 1).
Methanol was chosen as the solvent as it has been previously
shown to assist the reaction by forming a hemiaminal inter-
mediate that provides a reservoir for the reactive iminium
species8a and also due to its effective solvation of the reaction
components, which improved the compatibility with flow
synthesis through the furnishing of a homogeneous reaction
mixture. The optimisation data showed that the reaction exhibited
an approximately linear dependence on temperature, with full
conversion observed at 90 1C (entry 3, Table 1). Comparable results
were obtained with Fe(III) and Cu(II) salts (see ESI‡). Decreases in
the catalyst loading, or O2 pressure were not tolerated and led to a
reduction in conversion (entries 4–9, Table 1). In addition, reducing
the equivalents of nitromethane led to a corresponding reduction
in conversion. Although 5 equivalents of the pronucleophile was
necessary to furnish acceptable conversion to the nitro-Mannich
a
Reaction conditions: 1 (0.5–1.0 mmol), FeCl2 (10 mol%), RCH2NO2
adduct, this represents a considerably low concentration and (5 equiv.), MeOH (0.05 M), O2 (7 bar), 90 1C, TR = 2 h unless otherwise
b
stated. All reactions quenched with 2 equiv. Et3N. Isolated yields after
the safety implications are instructive. It should be noted that
c
d
column chromatography. Residence time of 1.5 h. 11.7 mmol scale.
e
f
the reaction was found to be very clean in all cases, with no side
Loaded onto sample loop in 9 : 1 MeOH/THF. Based on recovered
starting material.
1
products observed by TLC or H NMR.
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we found that by quenching the reaction with base (2 equivalents
of Et3N), the desired nitro-Mannich adducts were obtained in
consistently good yields.
Reactions employing nitroethane (2b, 2d) were discernibly
slower than those with nitromethane, with o85% conversion
typically obtained after 1 h. Thus, the residence time for all
couplings was increased to 2 h to allow for full conversion.
Electron-rich tetrahydroisoquinolines with alkyl or ether
substituted N-aryl groups reacted smoothly, giving the nitro-
Mannich products in good yields (2c–i). N-Naphthyl substrate
1n reacted cleanly, albeit slowly due to steric hinderance at the C1
oxidation site. Substrates bearing mildly electron-withdrawing
substituents were well tolerated (2j–l), although ortho-fluorine
substitution of the N-aryl ring (2m) significantly slowed the
reaction and also gave an unidentified side product. More strongly
electron-withdrawing substitution caused the reaction to fail com-
pletely,20 consistent with our mechanistic hypothesis of a single
electron transfer (SET) oxidation. Notably, the 6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline scaffold, which is a common
structural motif in bioactive compounds, was amenable to
the reaction conditions (2o).
Scheme 2 Proposed mechanism for Fe-catalysed aerobic nitro-Mannich
reaction.
We next attempted to obtain evidence of an iminium inter-
mediate (3). In the absence of nitroalkane, stoichiometric Fe(II)
gave quantitative conversion to the iminium trichloroferrate(II)
salt [3]+[FeCl3]À, which was observed by ESI MS (entry 4, Table 3).
Upon standing, crystals grew from the reaction mixture that were
characterised by X-ray crystallography (XRD) as the (m-oxo)bis[tri-
chloroferrate(II)] salt 2[3]+[Fe2OCl6]2À
.
On the basis of these considerations we tentatively propose a
potential mechanism (Scheme 2). The process is initiated by a
single electron transfer (SET) from the amine substrate to Fe(III)
to give the amine radical cation 4, which can undergo hydrogen
atom abstraction and a second SET step in an analogous
fashion to the non-classical Polonovski reaction. Nucleophilic
attack on the resulting iminium intermediate 3 by a nitronate
anion yields the a-alkylated product 2, with regeneration of the
Fe(III) catalyst by molecular oxygen.
In summary, we have reported the efficient aerobic nitro-
Mannich reaction of N-aryl tetrahydroisoquinolines using simple Fe
salts and molecular O2. The use of continuous flow processing
allowed for significant process intensification to be achieved relative
to batch methodology. Preliminary studies have shown some
success with other nucleophilic partners and further investiga-
tions to expand the reaction scope are currently underway.
The authors would like to acknowledge Dr David Turner,
School of Chemistry, Monash University, Clayton 3168, Victoria,
Australia for providing XRD crystallography data.
To demonstrate the scalability of the flow protocol to preparative
quantities,21 a gram scale run was performed. Pleasingly, 11.7 mmol
of substrate 1ab was processed continuously to provide 2a in
68% isolated yield (2.13 g) after purification, consistent with
yields achieved on smaller scale.
Doyle and Klussmann both have postulated the initiation
step in transition metal-catalysed aerobic a-functionalisation of
amines to be a single electron oxidation to yield an amine
cation radical that is then further oxidised to an iminium
species.8b,10b To probe the reaction mechanism several control
experiments were performed. Purging the reaction with nitrogen
afforded trace amounts of the nitro-Mannich product (entry 1,
Table 3). Furthermore, when the reaction was conducted under
nitrogen with 10 mol% Fe(III), a 9% yield of product was observed
(entry 2, Table 3), indicating that Fe(III) may be the catalytically
relevant oxidation state of iron. Addition of BHT as a radical
trapping agent resulted in a reduction of product yield to 33%
(entry 3, Table 3), suggesting that the reaction plausibly pro-
ceeds through a radical pathway.
Notes and references
Table 3 Control experiments to probe reaction mechanisma
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Changes from standard conditions
Yield 2ab (%)
1
2
3
4
Under N2
Under N2, FeCl3 (10 mol%)
BHT (1 equiv.)
—
9
33
No MeNO2, FeCl2 (2 equiv.)
Quant. (3)
a
Reaction conditions: 1a (0.1 mmol), MeNO2 (5 equiv.), MeOH (1 mL),
2 h, flow rate = 0.167 mL minÀ1
.
Determined by 1H NMR.
b
336 | Chem. Commun., 2015, 51, 334--337
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