Anodic benzylic C(sp3)-H amination: Unified access to pyrrolidines and piperidines

Article abstract of DOI:10.1039/c8gc01411f

An electrochemical aliphatic C-H amination strategy was developed to access the important heterocyclic motifs of pyrrolidines and piperidines within a uniform reaction protocol. The mechanism of this unprecedented C-H amination strategy involves anodic C-H activation to generate a benzylic cation, which is efficiently trapped by a nitrogen nucleophile. The applicability of the process is demonstrated for 40 examples comprising both 5- and 6-membered ring formations.

Full text of DOI:10.1039/c8gc01411f

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Anodic Benzylic C(sp3)-H Amination: A Unified Access to
Pyrrolidines and Piperidines
Sebastian Herold,a Daniel Bafaluy,a Kilian Muñiz*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An electrochemical aliphatic C-H amination strategy was limitation.8 Still, extended use of precious metal promoters are
developed to access the important heterocyclic motifs of considered problematic due to removability of trace metal
pyrrolidines and piperidines within a uniform reaction protocol. impurities or economic reasons. Aliphatic C-H bond amination
The mechanism of this unprecedented C-H amination strategy can also be achieved by catalytic versions9 of classic amidyl
involves an anodic C-H activation to generate a benzylic cation, radical chemistry.10 Despite the impressive advance, no
which is efficiently trapped by the nitrogen nucleophile. The general environmentally benign synthesis concept is currently
applicability of the process is demonstrated for 40 examples available that would reach out for both five- and six-
comprising both 5- and 6-membered ring formation.
membered ring formation in intramolecular C-H amination.11
Pyrrolidines and piperidines are among the most significant
saturated nitrogen heterocycles in Nature, being present in
numerous natural products.1 They also exhibit essential
pharmacophoric properties and thus constitute prominent
molecular components in pharmaceutical structure
development.2 Their nature as saturated aminated
heterocycles renders them ideal representatives of the
“escape from flatland” concept.3 The quest for new accesses
towards this class of compounds has been a constant source
for synthetic innovation. Recently, the direct functionalization
of aliphatic C-H bonds has been identified as a logical strategy
for the formation of such higher-functionalized molecules.4
Within this context, molecular catalysts have demonstrated
conceptual utility for certain intramolecular C-H amination
reactions, which have been developed to an impressive extent
based on transition metal catalysis.5 Therein, the formation of
new alkyl-nitrogen bonds is predominantly based on
nucleophilic nitrogen groups6 and metal nitrene insertions7
into aliphatic hydrocarbon bonds. Despite high levels of
efficiency, such metal-catalysed reactions commonly rely on
non-carbon spacer units activating and/or stabilizing the
nitrogen atom involved in the C-H amination reaction. This
generates heterocycles that differ from naturally occurring
cycloamines. Recent advances in the area have overcome this
Scheme 1 Aliphatic C-H amination
We have now envisioned an electrochemical strategy to
selectively and sustainably access pyrrolidines and piperidines
within a unified protocol. This approach employs a suitably
positioned electrophoric group to direct C-H amination within
electrochemical oxidation. Synthetic organic electrochemistry
has recently attracted a lot of attention and is recognized as an
environmentally benign methodology in the tool kit of the
organic chemist.12,13 While the formation of pyrrolidines and
piperidines by intramolecular electrochemical amination of
electron-rich alkenes is well known and has been extensively
studied,14 until now the corresponding anodic amination of
unfunctionalised aliphatic C-H bonds remains
underdeveloped field.15
a notably
Initial experiments were carried out using similar
conditions reported in literature for the electrochemical
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generation of nitrogen centred radicals.14a-c We rationalized
The use of HFIP as solvent led to dramatically improved
that the anodic formation of amidyl radicals should lead to a yields of up to 67% of 2a (Table 1, entry 5). Having identified
1,5-H transfer8a,f and subsequently to the desired pyrrolidines. HFIP as optimum solvent for this electrochemical
Starting from model compound 1a, optimization studies were transformation, the amount of charge was varied in the range
performed in an undivided cell, using a graphite rod anode and of 2-2.4 F (Table 1, entries 6 and 7) as well as the applied
a platinum cathode.16 A constant current of 5 mA and a charge current (1.5-5 mA, Table 1, entries 5, 9 and 13). Furthermore,
of 2.2 F were applied. Using methanol or mixtures of methanol the effect of the concentration of the supporting electrolyte
and THF with LiClO4 as supporting electrolyte and sodium was investigated (Table 1, entries 14 and 15). The best yield
methoxide as base the desired pyrrolidine 2a was only (Table 1, entry 13) of the corresponding pyrrolidine 2a was
obtained in yields of up to 25% (Table 1, entries 1 and 2). obtained by using a 0.1 M Bu4NBF4/HFIP electrolyte, a current
Changing the supporting electrolyte to Et4NOTs and Bu4NPF6 of 2.5 mA and 2.2 F. To test the robustness of the reaction,
did not improve the yield (Table 1, entries 3 and 4). We then experiments at 1 and 3 mmol scale of substrate 1a (0.33 g and
altered the solvent to 1,1,1,3,3,3-hexafluoroisopropanol 1 g, respectively) were conducted without any change in
(HFIP). HFIP has proven beneficial in electroorganic reaction conditions leading to 73-80% of isolated 2a (Table 1,
transformations due to its ability to stabilize and enhance the entries 16 and 17). This demonstrates that the cyclization
lifetime of anodically generated reactive intermediates such as proceeds equally efficient at higher substrate concentration.
radical cations.17, 18 To reduce the fluorine footprint, HFIP can
be redistilled.
With the optimized electrolysis conditions in hand, we
explored the scope of the reaction (Figure 1). Different
sulphonyl protecting groups on the nitrogen are tolerated
including 4-nosyl, mesyl and SES (2a-d). The possible use of SES
and Ns is important in order to access the corresponding free
pyrrolidines under mild conditions.
Table 1 Optimization of electrolysis conditions.
Yield [%]
Entry Electrolyte
Additive
1a
2a
0.5 eq.
1
2
3
4
0.1 M LiClO4/MeOH
56
23
NaOMe
0.1 M LiClO4, 60%
MeOH/THF
0.5 eq.
57
87
92
25
NaOMe
0.5 eq.
0.1 M Et4NOTs/MeOH
0.1 M Bu4NPF6/MeOH
trace
trace
NaOMe
0.5 eq.
NaOMe
5
0.1 M Bu4NPF6/HFIP
0.1 M Bu4NPF6/HFIP
0.1 M Bu4NPF6/HFIP
0.1 M Bu4NPF6/HFIP
0.1 M Bu4NPF6/HFIP
0.1 M Bu4NPF6, 50%
CH3CN/HFIP
-
-
-
-
-
n.d.
n.d.
n.d.
n.d.
67
61
52
77
6[a]
7[b]
8[c]
9[d]
trace 70
10[c]
-
trace 24
11[c]
12[c]
13[c]
14[c]
15[c]
0.05 M Bu4NPF6/HFIP
0.1 M Et4NOTs/HFIP
0.1 M Bu4NBF4/HFIP
0.05 M Bu4NBF4/HFIP
0.2 M Bu4NBF4/HFIP
-
-
-
-
-
n.d.
-
65
53
85
68
70
n.d.
n.d.
n.d.
16[c,e] 0.1 M Bu4NBF4/HFIP
17[f]
0.1 M Bu4NBF4/HFIP
-
-
n.d.
n.d.
80
73
Figure 1 Electrochemical synthesis of pyrrolidines: scope. a With I = 1 mA.
Isolated yields. 0.2 mmol substrate; I = 5 mA, 2.2 F; [a] 2.0 F; [b] 2.4 F; [c] I = 2.5
mA; [d] I = 1.5 mA; [e] 1.0 mmol substrate scope; [f] 3.0 mmol substrate scope;
n.d. = not determined.
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Furthermore, it is possible to perform the transformation 100% selectivity as determined for 6m and 6n, while acyclic
with modified backbone (2e) and without any substitution in stereocontrol provides a slight preference for the trans
the alkyl backbone (2f), demonstrating that a Thorpe-Ingold diastereoisomer (6o ). Although in lower yield, the amination
effect is not required, although in this case the isolated yield is conditions could also be extended to the synthesis of
-
,
p
slightly lower (55%) compared to the similar substrates 2a and piperazine 6q
2e. Not only sulphonyl but also carbonyl substituents at the
nitrogen functionality can be employed to yield the
corresponding amides in good yields (2g,h). Typical organic
substituents including methyl, chloro and fluoro groups are
.
well tolerated on the arene as demonstrated for derivatives 2i
-
k. The C-H amination scope also includes substrates with a
phenyl backbone. The corresponding isoindolines 2m-2q are
formed in very good yields tolerating chloro, fluoro, alkyl as
well as trifluoromethyl substitution in the 4-position of the aryl
moiety. For the case of heteroarene substitution, 2r and 2s are
formed in considerable yields tolerating the electron-rich
thiophene and benzofurane cores, respectively. In addition,
transannular cyclisations are possible as demonstrated for 2t
.
Diastereomerically pure pyrrolidine 2u was obtained as a
result of cyclic stereocontrol. In the case of substrates bearing
mono-substitution in the alkyl chain, acyclic stereocontrol with
a diastereomeric excess of up to 2.5:1 for the trans
was observed (2v 2x). These latter experiments provided a
first indication that the cyclization most likely occurs through a
planarised benzylic cation allowing for minor
:cis-ratio
-
diastereoselection. Besides the main interest in amination
reactions, the possibility to include oxygen nucleophiles to trap
the anodically generated benzylic cation was briefly explored
(Scheme 2). Under standard conditions, cyclization of 4-phenyl
butanol 3a was straightforward to provide 2-phenyl
tetrahydrofurane 4a. In the same manner, 4-phenyl butanoic
acid 3b generated the 5-membered lactone 4b in high yield.19
Figure 2 Electrochemical synthesis of piperidines: scope.
blank
1,4
1,2
1,0
0,8
0,6
0,4
Scheme 2 Electrochemical oxygenative cyclization.
The scope of the C-H amination reaction could be directly
expanded to the formation of piperidines 6a-q. Figure 2
displays several examples of such
a 6-membered ring
0,2
0,0
jlim. = 0.1 mA cm-2
formation under the mild and operational simple
electrochemical conditions. The cyclization proceeds well for
tosylamides 5a,b with different backbone substitution and for
5c with a functionalized benzenesulfonamide. As expected,
common functional groups are well tolerated as substituents
at the 4- and the 3-position of the arene group demonstrating
-0,2
-0,4
1
2
3
E / V vs. Ag/AgNO3
the broad scope of the transformation (6d-6j). A substrate
with a phenyl backbone efficiently yielded the corresponding
tetrahydroisoquinoline 6k in excellent yield of 81%. The
reaction could also be applied to generate the new benzo-
Figure 3 Cyclic voltammetry of 1f (3 mM, red line), 7a (3 mM, blue line) and 7b (3 mM,
green line). The voltammogram for the blank electrolyte is shown for comparison
(black line). Working electrode: glassy carbon; counter electrode: platinum wire;
reference electrode: Ag/0.01 M AgNO3 in 0.1 M Bu4NClO4; scan rate: 50 mV s-1
.
fused bicycle 6l
. The stereochemistry of the piperidine
formation is comparable to the observations from pyrrolidine
formation. Amination under cyclic stereocontrol proceeds with
In order to study the mechanistic aspects of the process,
we performed cyclic voltammetric studies of model
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compounds 1f (Figure 3, red line), 7a (Figure 3, blue line) and deprotonation occurs readily leading to benzylic radical
7b (Figure 3, green line) in 0.1 M Bu4NBF4/HFIP. Each solution Such benzylic radicals are as a rule oxidized at lower potentials
contained a concentration of 3 mM of the corresponding than the corresponding neutral substrate 1a 23
Further SET
substrate. By comparing the oxidation potentials of the three generates a benzylic cation , which is efficiently trapped by
model substrates 1f 7a and 7b it should be possible to the nucleophilic tosylamide. The formation and trapping of a
B.
.
C
,
determine whether the amine functionality or the aromatic benzylic cation is further supported by our observation of
core is oxidized first. Initially, the CV of the blank electrolyte diastereomeric excesses in the cases of acyclic stereocontrol
0.1 M Bu4NBF4/HFIP (black line) was measured demonstrating with compounds 1u-w, 5o,p. In contrast, C-N bond formation
the outstanding stability of HFIP based electrolytes towards involving radical pathways provides equal mixtures of
anodic oxidation.20 Significant degradation of the electrolyte diastereomers.9
only starts at 2.80 V vs. Ag/AgNO3 with a cut-off current
density for oxidation defined as jlim. = 0.1 mA cm-2. Compound cleavage and provides the 2-alkoxylated pyrrolidine 9 16
1f bearing both the aromatic core and the amino functionality same compound can be accessed through a Shono oxidation24
is irreversibly oxidized at a potential of 1.79 V vs. Ag/AgNO3. of -tosyl pyrrolidine in the presence of HFIP (52% yield).
The oxidation for tosylamide 7a without the aromatic core is Compound serves as a versatile synthon for Grignard
Finally, electrochemical oxidation of alcohol
8
leads to C-C
.
The
N
9
230 mV higher at 2.02 V vs. Ag/AgNO3 whereas the oxidation addition to provide access to pyrrolidines with elusive 2-
of model compound 7b takes place at 1.77 V vs. Ag/AgNO3. substitution outside the aryl motif (Scheme 3).25
Furthermore, the CV of pyrrolidine product 2f was measured,16
which reveals that oxidation of 2f takes place at 1.88 V vs.
Ag/AgNO3. This is 90 mV above the oxidation of substrate 1f
thus ensuring clean product formation. Although not
investigated at present, redox mediators may allow for
additional selectivity increase for electron-rich substrates.12h
The results depicted in Figure 3 allow for a conclusion
regarding the mechanism of the electrochemical
intramolecular C-H amination (Figure 4).
Scheme 3 Electrochemical access to 2-substituted pyrrolidines.
Conclusions
To conclude, we have developed a mild and atom-
economical intramolecular C(sp3)-H amination to access
pyrrolidine and piperidine scaffolds under uniform reaction
conditions. This unprecedented C-N bond formation has been
enabled by use of an anodic C(sp3)-H bond activation. The
resulting straightforward heterocycle synthesis provides an
attractive green alternative to existing protocols and is
compatible with a diverse range of functional groups.
Figure 4 Proposed mechanism with 1a as representative substrate.
Conflicts of interest
Interpreting the data from cyclic voltammetry, the
aromatic core was identified as the functional group, which is
engaging in the initial oxidation. This is evidenced by the
comparable oxidation potentials of phenyl-containing
compounds 1f and 7b, while oxidation of the aliphatic
tosylamide 7a occurs at significantly higher potentials.21 This
concludes that from the involved aryl and tosylamide
functional groups the former one acts as electrophore at the
outset of the reaction. Upon single electron transfer (SET), an
There are no conflicts to declare.
Acknowledgements
We thank the Spanish Ministry for Economy and Competitiveness
and FEDER (CTQ2017-88496R grant to K. M., Severo Ochoa
Excellence Accreditation 2014-2018 to ICIQ, SEV-2013-0319) for
financial support. The authors are grateful to the CERCA
Programme of the Government of Catalonia and to COST
Action CA15106 “C-H Activation in Organic Synthesis”
(CHAOS).
aromatic radical cation
A is thus formed. Because of the
positive charge, the acidity of the benzylic hydrogens is
dramatically increased by several magnitudes of order.22 Thus,
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An electrochemical C-H amination process enables the
sustainable unified access to the heterocyclic classes of
pyrrolidines and piperidines.
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