“This document is the Accepted Manuscript version of a Published Work that appeared in final form in Green Chemistry, copyright © The Royal
Society of Chemistry 2018 after peer review and technical editing by the publisher. To access the final edited and published work see:
https://pubs.rsc.org/en/content/articlelanding/2018/gc/c8gc01411f#!divAbstract “

Anodic Benzylic C(sp3)-H Amination: A Unified Access to Pyrrolidines and
Piperidines
Sebastian Herold,a Daniel Bafaluy,a Kilian Muñiz*a,b
www.rsc.org/
versions9 of classic amidyl radical chemistry.10 Despite the
impressive advance, no general environmentally benign
synthesis concept is currently available that would reach out for
both five- and six-membered ring formation in intramolecular
C-H amination.11
Conventional approaches:

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 an anodic C-H
activation to generate a benzylic cation, which is efficiently trapped
by the nitrogen nucleophile. The applicability of the process is
demonstrated for 40 examples comprising both 5- and 6membered ring formation.
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 CH 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 alkylnitrogen 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 limitation.8 Still, extended use of
precious metal promoters are considered problematic due to
removability of trace metal impurities or economic reasons.
Aliphatic C-H bond amination can also be achieved by catalytic

This journal is © The Royal Society of Chemistry 20xx

n

H
N [M]
N
H

N
H

piperidine
core

pyrrolidine
core

C-H insertion via
metal-nitrene

n

N
R

1,5/1,6-hydrogen
H atom transfer via
nitrogen centered radical

This work: uniform electrochemical C-H amination

-2e , -2H
N
X
R
piperidine

(n = 2)

n

-2e , -2H
X

(n = 1)
NH
R
X = electrophore

N
R

X

pyrrolidine

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 a notably
underdeveloped field.15
Initial experiments were carried out using similar conditions
reported in literature for the electrochemical generation of
nitrogen centred radicals.14a-c We rationalized that the anodic
formation of amidyl radicals should lead to a 1,5-H transfer8a,f
and subsequently to the desired pyrrolidines. Starting from
model compound 1a, optimization studies were performed in
an undivided cell, using a graphite rod anode and a platinum
cathode.16 A constant current of 5 mA and a charge of 2.2 F were
applied. Using methanol or mixtures of methanol and THF with

J. Name., 2013, 00, 1-3 | 1

LiClO4 as supporting electrolyte and sodium methoxide as base
the desired pyrrolidine 2a was only obtained in yields of up to
25% (Table 1, entries 1 and 2). Changing the supporting
electrolyte to Et4NOTs and Bu4NPF6 did not improve the yield
(Table 1, entries 3 and 4). We then altered the solvent to
1,1,1,3,3,3-hexafluoroisopropanol (HFIP). HFIP has proven
beneficial in electroorganic transformations due to its ability to
stabilize and enhance the lifetime of anodically generated
reactive intermediates such as radical cations.17, 18 To reduce
the fluorine footprint, HFIP can be redistilled.
Table 1 Optimization of electrolysis conditions.

graphite anode
platinum cathode
undivided cell
NHTs constant current
electrolysis (CCE)

H

investigated (Table 1, entries 14 and 15). The best yield (Table
1, entry 13) of the corresponding pyrrolidine 2a was obtained
by using a 0.1 M Bu4NBF4/HFIP electrolyte, a current of 2.5 mA
and 2.2 F. To test the robustness of the reaction, experiments
at 1 and 3 mmol scale of substrate 1a (0.33 g and 1 g,
respectively) were conducted without any change in reaction
conditions leading to 73-80% of isolated 2a (Table 1, entries 16
and 17). This demonstrates that the cyclization proceeds
equally efficient at higher substrate concentration.
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

Ts
N

H
1a

-2e , -2H

2a

R

NHSO2R'

Ar

graphite anode
platinum cathode
undivided cell
CCE (I = 2.5 mA, 2.2 F)
0.1 M Bu4NBF4
(CF3)2CHOH
25 ºC, 280 min

1a-x

Entry

Electrolyte

Additive

Yield [%]
1a
2a

R
N

1

0.1 M LiClO4/MeOH

2

0.1 M LiClO4, 60%
MeOH/THF

3

0.1 M Et4NOTs/MeOH

4

0.1 M Bu4NPF6/MeOH

5
6[a]
7[b]
8[c]
9[d]

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
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

10[c]
11[c]
12[c]
13[c]
14[c]
15[c]

0.5 eq.
NaOMe
0.5 eq.
NaOMe
0.5 eq.
NaOMe
0.5 eq.
NaOMe
-

56

23

57

25

87

trace

n.d.
n.d.
n.d.
n.d.
trace

67
61
52
77
70

-

trace

24

-

n.d.
n.d.
n.d.
n.d.

65
53
85
68
70

16[c,e]

0.1 M Bu4NBF4/HFIP

-

n.d.

80

17[f]

0.1 M Bu4NBF4/HFIP

-

n.d.

2a (R = Ts): 85%
2b (R = 4-Ns): 51%
2c (R = Ms): 73%
2d (R = SES): 37%

The use of HFIP as solvent led to dramatically improved
yields of up to 67% of 2a (Table 1, entry 5). Having identified
HFIP as optimum solvent for this electrochemical
transformation, the amount of charge was varied in the range
of 2-2.4 F (Table 1, entries 6 and 7) as well as the applied current
(1.5-5 mA, Table 1, entries 5, 9 and 13). Furthermore, the effect
of the concentration of the supporting electrolyte was

2 | J. Name., 2012, 00, 1-3

R

N

Ph
2g (R = Ph): 65%
2h (R = CF3): 60%
Ts
N

Ts
N
R
2i (R = CH3): 84%
2j (R= F): 83%
2k (R = Cl): 52%

NTs

O
O
S
N

2l: 63%

NTs

R
2m (R = CH3): 77%
2n (R= Cl): 83%
2o (R = F): 56%
2p (R = CF3): 56%
2q (R = tBu): 62%

NTs
O
S
2s: 67%a

2r: 48%a
Ts
N

Ts
N

Ts
N

Ph

Ph
R

2t: 30%

2u: 87%

2v: 46%, 1.2:1 dr

73

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.

2a-x
O

Ph
R
R
2e [R2 = (CH2)5]: 89%
2f (R = H): 55%

trace

92

R

Ts
N
Ph

SO2R'
N
Ar

2w (R = CH3):
67%, 2.5:1 dr
2x (R = C2H5):
64%, 2:1 dr

pyrrolidines under mild conditions.
Figure 1 Electrochemical synthesis of pyrrolidines: scope. a With I = 1 mA.

OH

Ph
X
3a (X = H2)
3b (X = O)

graphite anode
platinum cathode
undivided cell
CCE (I = 2.5 mA, 2.2 F)
0.1 M Bu4NBF4
(CF3)2CHOH
25 ºC, 280 min

X
O
Ph
4a: 55%
4b: 83%

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 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 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-fused bicycle 6l. The stereochemistry
of the piperidine formation is comparable to the observations
from pyrrolidine formation. Amination under cyclic
stereocontrol proceeds with 100% selectivity as determined for
6m and 6n, while acyclic stereocontrol provides a slight
preference for the trans-diastereoisomer (6o,p). Although in

lower yield, the amination conditions could also be extended to
the synthesis of piperazine 6q.
Figure 2 Electrochemical synthesis of piperidines: scope.

blank

1,4

H
Ar

graphite anode

NHTs
platinum cathode

1,2

j / mA cm-2

Furthermore, it is possible to perform the transformation
with modified backbone (2e) and without any substitution in
the alkyl backbone (2f), demonstrating that a Thorpe-Ingold
effect is not required, although in this case the isolated yield is
slightly lower (55%) compared to the similar substrates 2a and
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 monosubstitution in the alkyl chain, acyclic stereocontrol with a
diastereomeric excess of up to 2.5:1 for the trans:cis-ratio 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
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

undivided cell
CCE (I = 2.5 mA, 2.2 F)

1f

R

1,0

NHSO2R'
7a

0,8 5a-q
7b

0,6

R
R 0,4 NTs

NHTs

0.1 M Bu4NBF4
(CF3)2CHOH
25 ºC, 280 min
O O Br
S
N

Ar
6a-q

NTs

-2

j
Phlim. = 0.1 mA cm Ph

0,2

6c: 49%

6a (R 0,0 3): 53%
= CH
6b [R2 = (CH2)5]: 39%
-0,2
-0,4

NSO2R'

R

NTs

NTs
1

2

6d (R = tBu): 59%
6e (R = Ph): 69%
6f (R = Cl): 49%
6g (R = F): 64%
3
6h (R = OBz): 29%

R

E / V vs. Ag/AgNO3
6j: 44%

6i: 50%
NTs

NTs

Ph

TsN

n
6m (n = 1): 54%
6n (n = 2): 48%

6l (X-ray)

6l: 40%

6k: 81%
R

NTs

NNs
TfN

Ph
6o (R = CH3): 59%, 1.7:1 dr
6p (R = C2H5): 49%, 1.5:1 dr

Ph
6q: 24%

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.

In order to study the mechanistic aspects of the process, we
performed cyclic voltammetric studies of model compounds 1f
(Figure 3, red line), 7a (Figure 3, blue line) and 7b (Figure 3,
green line) in 0.1 M Bu4NBF4/HFIP. Each solution contained a
concentration of 3 mM of the corresponding substrate. By
comparing the oxidation potentials of the three model
substrates 1f, 7a and 7b it should be possible to determine
whether the amine functionality or the aromatic core is oxidized
first. Initially, the CV of the blank electrolyte 0.1 M
Bu4NBF4/HFIP (black line) was measured demonstrating the
outstanding stability of HFIP based electrolytes towards anodic
oxidation.20 Significant degradation of the electrolyte 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 1f bearing
both the aromatic core and the amino functionality is
irreversibly oxidized at a potential of 1.79 V vs. Ag/AgNO3. The
oxidation for tosylamide 7a without the aromatic core is 230 mV
higher at 2.02 V vs. Ag/AgNO3 whereas the oxidation of model
compound 7b takes place at 1.77 V vs. Ag/AgNO3. 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

J. Name., 2013, 00, 1-3 | 3

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).

OH
Ph
8

graphite anode
platinum cathode
undivided cell
NHTs CCE (I = 2.5 mA, 2.2 F)
0.1 M Bu4NBF4
(CF3)2CHOH
25 ºC, 280 min

Ts
N

CF3
O

CF3

9 (40%)

R-MgBr
Et2O, -78 to 25 ºC

NHTs
Ts
N

1a
-e
NHTs
H2

A
-H

+2e
NHTs

2H

B
-e

TsHN

TsN
-H
C

2a

9 (X-ray)

10a (R = CH3): 90%
10b (R = C2H ): 65%
R 10c (R = n-C 5 ): 61%
6H14
10d (R = allyl): 94%

Conclusions
To conclude, we have developed a mild and atomeconomical 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.

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 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, deprotonation occurs readily
leading to benzylic radical B. Such benzylic radicals are as a rule
oxidized at lower potentials than the corresponding neutral
substrate 1a.23 Further SET generates a benzylic cation C, which
is efficiently trapped by the nucleophilic tosylamide. The
formation and trapping of a benzylic cation is further supported
by our observation of diastereomeric excesses in the cases of
acyclic stereocontrol with compounds 1u-w, 5o,p. In contrast,
C-N bond formation involving radical pathways provides equal
mixtures of diastereomers.9
Finally, electrochemical oxidation of alcohol 8 leads to C-C
cleavage and provides the 2-alkoxylated pyrrolidine 9.16 The
same compound can be accessed through a Shono oxidation24
of N-tosyl pyrrolidine in the presence of HFIP (52% yield).
Compound 9 serves as a versatile synthon for Grignard addition
to provide access to pyrrolidines with elusive 2-substitution
outside the aryl motif (Scheme 3).25
Scheme 3 Electrochemical access to 2-substituted pyrrolidines.

Conflicts of interest
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).

Notes and references
1

2
3
4

5
6
7

4 | J. Name., 2012, 00, 1-3

(a) E. Fattorusso and O. Taglialatela-Scafati, Modern Alkaloids,
(Eds.: E. Fattorusso, O. Taglialatela-Scafati) Wiley-VCH,
Weinheim, 2007. (b) D. O’Hagan, Nat. Prod. Rep., 2000, 17,
435.
E. Vitaku, D. T. Smith and J. T. Njardarson, J. Med. Chem.,
2014, 57, 10257.
(a) F. Lovering, J. Bikkert and C. Humblet, J. Med. Chem., 2009,
52, 6752. (b) F. Lovering, Med. Chem. Commun., 2013, 4, 515.
(a) T. Brückl, R. D. Baxter, Y. Ishihara and P. S. Baran, Acc.
Chem. Res., 2012, 45, 826. (b) B. G. Hashiguchi, S. M. Bischof,
M. M. Konnick and R. A. Periana, Acc. Chem. Res., 2012, 45,
885. (c) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110,
1147. (d) J. L. Jeffrey and R. Sarpong, Chem. Sci., 2013, 4, 4092.
(a) H. M. L. Davies and M. S. Long, Angew. Chem. Int. Ed., 2005,
44, 3518. (b) R. Hili and A. K. Yudin, Nature Chem. Biol., 2006,
2, 284.
(a) T. A. Ramirez, B. Zhao and Y. Shi, Chem. Soc. Rev., 2012, 41,
931. (b) A. McNally, B. Haffemayer, B. S. L. Collins and M. J.
Gaunt, Nature, 2014, 510, 129.
(a) J. L. Roizen, M. E. Harvey and J. DuBois, Acc. Chem. Res.,
2012, 45, 911. (b) F. Collet, C. Lescot and P. Dauban, Chem.

8

9
10

11
12

13

14

15

16

Soc. Rev., 2011, 40, 1926. (c) P. Dauban and R. H. Dodd,
Synlett, 2003, 11, 1571. (d) M. M. Díaz-Requejo, A. Caballero,
M. R. Fructos and P. J. Pérez, Catalysis by Metal Complexes
Vol. 38 (Ed. P. J. Pérez), Springer, Berlin, 2012, Chapter 6, Pp.
229-264.
(a) J. C. K. Chu and T. Rovis, Angew. Chem. Int. Ed., 2018, 57,
62. (b) I. T. Alt, C. Guttrof and B. Plietker, Angew. Chem. Int.
Ed., 2017, 56, 10582. (c) D. A. Iovan and T. A. Betley, J. Am.
Chem. Soc., 2016, 138, 1983. (d) D. A. Iovan, M. J. T. Wilding,
Y. Baek, E. T. Hennessy and T. A. Betley, Angew. Chem. Int. Ed.,
2017, 56, 15599. (e) O. Villanueva, N. M. Weldy, S. B. Blakey
and C. E. MacBeth, Chem. Sci., 2015, 6, 6672. (f) L. M.
Stateman, K. M. Nakafuku and D. A. Nagib, Synthesis, 2018,
50, 1569.
(a) C. Martínez and K. Muñiz, Angew. Chem. Int. Ed., 2015, 54,
8287. (b) P. Becker, T. Duhamel, J. C. Stein, M. Reiher and K.
Muñiz, Angew. Chem. Int. Ed., 2017, 56, 8004.
(a) M. D. Kärkäs, ACS Catal., 2017, 7, 4999. (b) T. Xiong and Q.
Zhang, Chem. Soc. Rev., 2016, 45, 3069. (c) J.-R. Chen, X.-Q.
Hu, L.-Q. Lu and W.-J. Xiao, Chem. Soc. Rev., 2016, 45, 2044.
(d) L. Q. Nguyen and R. R. Knowles, ACS Catalysis, 2016, 6,
2894.
For the case of catalytic amidyl radicals: H. Zhang and K.
Muñiz, ACS Catal., 2017, 7, 4122.
For recent reviews on electroorganic synthesis, see: (a) B. A.
Frontana-Uribe, R. D. Little, J. G. Ibanez, A. Palma and R.
Vasquez-Medrano, Green Chem., 2010, 12, 2099. (b) M. Yan,
Y. Kawamata and P. S. Baran, Chem. Rev., 2017, 117, 13230.
(c) J.-i. Yoshida, K. Kataoka, R. Horcajada and A. Nagaki, Chem.
Rev., 2008, 108, 2265. (d) E. J. Horn, B. R. Rosen and P. S.
Baran, ACS Cent. Sci., 2016, 2, 302. (e) Y. Jiang, K. Xu and C.
Zeng, Chem. Rev., 2018, 118, 4485. (f) A. Wiebe, T. Gieshoff,
S. Möhle, E. Rodrigo, M. Zirbes and S. R. Waldvogel, Angew.
Chem. Int. Ed., 2018, 57, 5594. (g) S. Möhle, M. Zirbes, E.
Rodrigo, T. Gieshoff, A. Wiebe and S. R. Waldvogel, Angew.
Chem. Int. Ed., 2018, 57, 6018. (h) R. Francke and R. D. Little,
Chem. Soc. Rev., 2014, 43, 2492. (i) Y.-i. Yoshida, A. Shimizu
and R. Hayashi, Chem. Rev., 2018, 118, 4702.
For selected recent examples of synthetic organic
electrochemistry, see: (a) A. Wiebe, B. Riehl, S. Lips, R. Franke
and S. R. Waldvogel, Sci. Adv., 2017, 3, eaao3920/1–7. (b) T.
Broese and R. Francke, Org. Lett., 2016, 18, 5896. (c) B. Schille,
N. O. Giltzau and R. Francke, Angew. Chem. Int. Ed., 2018, 57,
422. (d) Y. Kawamata, M. Yan, Z. Liu, D.-H. Bao, J. Chen, J. T.
Starr and P. S. Baran, J. Am. Chem. Soc., 2017, 139, 7448. (e)
R. Hayashi, A. Shimizu and J.-i. Yoshida, J. Am. Chem. Soc.,
2016, 138, 8400. (f) H.-B. Zhao, A.-J. Liu, J. Song and H.-C. Xu,
Angew. Chem. Int. Ed., 2017, 56, 12732. (g) A. A. FolgueirasAmador, K. Philipps, S. Guilbaud, J. Poelakker and T. Wirth,
Angew. Chem. Int. Ed., 2017, 56, 15446.
(a) H.-C. Xu and K. D. Moeller, J. Am. Chem. Soc., 2008, 130,
13542. (b) H.-C. Xu and K. D. Moeller, J. Am. Chem. Soc., 2010,
132, 2839. (c) J. M. Campbell, H.-C. Xu and K. D. Moeller, J.
Am. Chem. Soc., 2012, 134, 18338. (d) Y. Ashikari, T. Nokami
and J.-i. Yoshida, Org. Biomol. Chem., 2013, 11, 3322. (e) S.
Liang, C.-C. Zeng, X.-G. Luo, F.-z. Ren, H.-Y. Tian, B.-G. Sun and
R. D. Little, Green Chem., 2016, 18, 2222. (f) M. Tokuda, T.
Miyamoto, H. Fujita and H. Suginome, Tetrahedron, 1991, 47,
747. (g) S. Karady, E. G. Corley, N. L. Abramson, J. S. Amato
and L. M. Weinstock, Tetrahedron, 1991, 47, 757.
(a) R. Hayashi, A. Shimizu, Y. Song, Y. Ashikari, T. Nokami and
J.-i. Yoshida, Chem. Eur. J., 2017, 23, 61. (b) T. Morofuji, A.
Shimizu and J.-i. Yoshida, J. Am. Chem. Soc., 2014, 136, 4496.
(c) T. Fuchigami, T. Sato and T. Nonaka, J. Org. Chem., 1986,
51, 366. For C(sp3)-H amination via anodic Ritter-type
reaction, see: (d) O. Hammerich and J. H. P. Utley, in Organic
Electrochemistry, 5th Ed., (Eds.: O Hammerich, B. Speiser), CRC
Press, Boca Raton, 2016, Pp. 781-783.
See Supporting Information for details.

17 Selected references for the use of HFIP in synthetic organic
electrochemistry, see: (a) B. Elsler, D. Schollmeyer, K. M.
Dyballa, R. Franke and S. R. Waldvogel, Angew. Chem. Int. Ed.,
2014, 53, 5210. (b) A. Wiebe, D. Schollmeyer, K. M. Dyballa, R.
Franke and S. R. Waldvogel, Angew. Chem. Int. Ed., 2016, 55,
11801. (c) T. Gieshoff, D. Schollmeyer and S. R. Waldvogel,
Angew. Chem. Int. Ed., 2016, 55, 9437.
18 Stabilization effects of HFIP on radical cations, see: (a) L.
Eberson, M. P. Hartshorn and O. Persson, J. Chem. Soc., Perkin
Trans 2, 1995, 1735. (b) L. Eberson, O. Persson and M. P.
Hartshorn, Angew. Chem. Int. Ed. Engl., 1995, 34, 2268.
19 While conducting our studies, a report was published,
describing such an electrochemical lactone formation.
However, under our conditions a higher yield of the phenyl
substituted lactone 4b was obtained, see: S. Zhang, L. Li, H.
Wang, Q. Li, W. Liu, K. Xu and C. Zeng, Org. Lett., 2018, 20,
252.
20 F. Francke, D. Cericola, D. Weingarth, R. Kötz and S. R.
Waldvogel, Electrochim. Acta, 2012, 62, 372.
21 In line with this observation, a pyridine-containing substrate
undergoes sulphonamide oxidation prior to oxidation of the
electron-poor arene core.16
22 The estimated pKa of a toluene radical-cation in acetonitrile is
between -9 and -13 thus making it an extremely strong acid
that deprotonates readily even in moderately acidic media: A.
M. P. Nicholas and D. R. Arnold, Can. J. Chem., 1982, 60, 2165.
23 (a) D. D. M. Wayner, D. J. McPhee and D. Griller, J. Am. Chem.
Soc., 1988, 110, 132. (b) O. Hammerich, in Organic
Electrochemistry, 5th Ed., (Eds.: O. Hammerich, B. Speiser),
CRC Press, Boca Raton, 2016, Pp. 892-894 and 907-909.
24 T. Shono, Tetrahedron, 1984, 40, 811.
25 (a) T. Shono, Y. Matsumura and K. Tsubata, J. Am. Chem. Soc.,
1981, 103, 1172. (b) A. M. Jones and C. E. Banks, Beilstein J.
Org. Chem., 2014, 10, 3056.

J. Name., 2013, 00, 1-3 | 5

Table of contents:
An electrochemical C-H amination process enables the
sustainable unified access to the heterocyclic classes of
pyrrolidines and piperidines.

6 | J. Name., 2012, 00, 1-3