N-Hydroxyphthalimide-Mediated Electrochemical Iodination of Methylarenes and Comparison to Electron-Transfer-Initiated C-H Functionalization

Article abstract of DOI:10.1021/jacs.7b09744

An electrochemical method has been developed for selective benzylic iodination of methylarenes. The reactions feature the first use of N-hydroxyphthalimide as an electrochemical mediator for C-H oxidation to nonoxygenated products. The method provides the basis for direct (in situ) or sequential benzylation of diverse nucleophiles using methylarenes as the alkylating agent. The hydrogen-atom transfer mechanism for C-H iodination allows C-H oxidation to proceed with minimal dependence on the substrate electronic properties and at electrode potentials 0.5-1.2 V lower than that of direct electrochemical C-H oxidation.

Full text of DOI:10.1021/jacs.7b09744

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Communication
NHPI-Mediated Electrochemical Iodination of Methylarenes and
Comparison to Electron-Transfer-Initiated C–H Functionalization
Mohammad Rafiee, Fei Wang, Damian P. Hruszkewycz, and Shannon S. Stahl
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 08 Dec 2017
Downloaded from http://pubs.acs.org on December 8, 2017
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Upon addition of 4-tBu-toluene (1a, 20 mM) to the solution,
the CV exhibits an increase in the anodic current, reflecting
regeneration of NHPI on the CV timescale via PINO-mediated
HAT from 1a (Figure 1d). No cathodic current is present in
the reverse scan, as is expected if PINO is consumed by
reaction with the substrate.
Table 1. Optimization of preparative electrolysis reactions.
1
2
3
4
PINO
CH3
+
I
NHPI
I• (= 1/2 I2)
Electrolyte
Base
10 mL MeCN
R
R
1 mmol
4-tBu (2a)
3-OMe (2b)
4-tBu (1a)
3-OMe (1b)
R =
R =
5
6
7
8
In order to extend these observations from voltammetry to
synthetic bulk-electrolysis, we sought a suitable trap to
functionalize the in situ-generated benzylic radical.
Preliminary tests probed the reactivity of 4-tBu-toluene in the
presence of NHPI (2.5 mol% with respect to 1a) and different
trapping agents, including PhS–SPh, TsCN, TsC!CPh, CuCl2
and I2 (10:1 ratio of 1a:trap).12,13 A divided cell configuration
was used to avoid reduction of the trap (e.g., I2, CuCl2) at the
cathode. No productive reactivity was observed, however,
except with iodine, which led to the benzyl iodide product in
quantitative yield with respect to I• (both iodine atoms of I2 are
used) (Table 1, entry 1). Successful benzylic C–H iodination
presumably reflects the rapid reaction of I2 with radicals
relative to other traps.14 The reaction of PINO with benzylic
C–H bonds is nearly thermoneutral,15 and inefficient trapping
of the organic radical could prevent product formation due to
the inevitable degradation of PINO during the electrolysis.16
The synthetic utility of electrochemical methods of this type
will ultimately require the methylarene to be used as the
limiting reagent. Various reaction conditions were tested in an
effort to optimize the product yield with respect to the
methylarene.12 Increasing the NHPI loading and optimization
of the base and electrolyte composition led to a 57% yield of
4-tBu-benzyl iodide (2a) (Table 1, entry 3) (see Supporting
Information for full optimization data). The combination of
lutidine/lutidinium supplies the base and the supporting
electrolyte for the reaction, while lutidinium provides a proton
source to facilitate production of H2 at the counter electrode.
Overoxidation and side reactions of the product 2a limited the
accessible yield, and use of excess equivalents of I• did not
improve the outcome (entry 4). An improved yield of benzyl
iodide was obtained with 3-methoxytoluene (1b) (83%; entry
5) owing to the increased stability of the benzyl iodide 2b
under the reaction conditions.
Testing of other imidoxyl mediators did not improve the
results. Ph4NHPI has been reported to be more stable than
NHPI,17 but no improvement in mediator stability or product
yield was observed with this mediator (entry 6). Cl4NHPI and
NHSI have stronger O–H bonds and, therefore, the
corresponding imidoxyl species should undergo more rapid
reaction with the methylarene. However, these imidoxyl
species undergo more rapid degradation and result in lower
product yields (entries 7 and 8).
Good reactivity was observed with a range of methylarenes
under these electrochemical iodination conditions (Table 2).
The method tolerates various functional groups, including
halide, methoxy, phenoxy, acetyl and acetoxy groups.
Reactions with some electron-deficient substrates (e.g., 1e, 1k)
revealed significant amounts of competing iodination of the
benzylic methyl groups of lutidine, but improved yields could
be obtained by using 2,6-di-tert-butylpyridine/pyridinium
(DTBP)/DTBP-H+ as the buffering electrolyte. In contrast,
substrates with electron-donating groups (e.g., 1a) are
susceptible to facile displacement of the iodide. In these cases,
replacement of lutidine by DTBP did not improve the yield.
The in situ nucleophilic substitution of iodide has potential
synthetic utility. Use of pyridine/pyridinium as the electrolyte
led to efficient displacement of iodide by pyridine, leading
I•
NHPI
(mol%)
Base
(equiv)
% yield
entry
R
Electrolyte
KPF6
vs ArCH3 (vs I•)
(equiv)
Lut, KHCO3
(0.1, 1.1)
1
2.5%
4 5
" Bu
0.1
10 (100)
Lut, KHCO3
(0.1, 3.3)
9
5Bu
1.0
38 (38)
KPF6
2
15%
4
"
10
11
12
13
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'
"
"
5,6
5,6
/65$ %#)!
1/65.2-40(
%#$
3
&$+
)*$ )*!
4
&$+
4
/65$ %#)!
1/65.2-40(
%#)
4
5
)&$ ')!
Lut (1.5)
[LutH]ClO4
1.0
+'$ +'!
20%
3-OMe
20%
Cl4NHPI
Lut (1.5)
Lut (1.5)
[LutH]ClO4
[LutH]ClO4
[LutH]ClO4
71 (71)
54 (54)
78 (78)
6
7
8
3"
3"
3"
OMe
OMe
OMe
1.0
1.0
1.0
20%
NHSI
20%
Ph4NHPI
Lut (1.5)
O
Cl
O
Ph
O
Cl
Cl
Ph
N
OH
N
OH
N
OH
N
N
H
Ph
O
O
O
2,6-Lutidine 2,6-Lutidinium
(Lut)
(LutH+)
Cl
Cl4NHPI
Ph
Ph4NHPI
NHSI
Table 2. Electrochemical iodination of methylarenes mediated by
NHPI.a
CH3
20 mol% NHPI, 50 mol% I2
I
A: Lutidine/LutH+ClO4- or
B: 2,6-di-tBuPy/2,6-di-tBuPyH+ClO4
-
R
1
2
R
MeO
Ph
I
I
I
I
I
tBu
I
2c, 71% (A)
2d, 69% (A)
2a, 57% (A)
2b, 83% (78%) (A)
O
I
I
O
I
Ph
F
Br
2f, 68% (62%) (B) 2g, 69% (68%) (B)
2e, 57% (B)
2h, 70% (67%) (B)
I
O
I
I
I
O
Cl
F3C
2i, 40% (36%) (A)
2j, 77% (A)
2l, 67% (B)
2k, 39% (A)
a
+
!
A: 0.1 M 1, 20 mol% NHPI, 50 mol% I2, 0.2 M Lut/0.1 M LutH ClO4 ,
10 mL MeCN, 5 mA. B: 0.1 M substrate 1, 20 mol% NHPI, 50 mol% I2,
0.2 M 2,6-di-tBuPy, 0.1 M 2,6-di-tBuPyH ClO4 , 10 mL MeCN, 5 mA. H
12
NMR yields (isolated yields in parentheses).
+
!
1
to diverse benzyl pyridinium products under the iodination
electrolysis conditions (Table 3). Generation of iodide in the
nucleophilic substitution step has the benefit of allowing
reoxidation of iodide to iodine at the anode, and permitting
these reactions to be performed with catalytic quantities of
iodine (20 mol%). Benzyl pyridinium derivatives of this type
have been used in a number of synthetic methods, such as
[3+2] cycloadditions, to access valuable heterocyclic
compounds. 18 It is worth noting that the yields of these
reactions are generally significantly higher than those from the
iodination reactions (e.g., 89% yield of 3 vs. 57% yield of 2a
from the reaction of 1a) owing to the enhanced product
stability relative to benzyl iodides. In addition to in situ
functionalization, the electrochemical iodination protocol may
be employed in sequential iodination/alkylation. This concept
is illustrated by the facile preparation of the three key
pharmaceutically important target molecules 11-13 (Scheme
3).19 Together, these in situ and sequential protocols illustrate
an appealing strategy for the use of methylarene derivatives as
alkylating agents.
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ASSOCIATED CONTENT
Supporting Information
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2
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Gambarotti, C.; Paganelli, R.; Pedulli, G. F.; Fontana, F. Tetrahedron
Lett. 2004, 5, 1607. (d) Kiyokawa, K.; Takemoto, K.; Minakata, S.
Chem. Commun., 2016, 52, 13082.
Additional electrochemical data, experimental details and product
characterization data; this material is available free of charge via
the Internet at http://pubs.acs.org.
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Pharm. Bull. 1987, 35, 1372. (b) Gorgy, K.; Lepretre, J.-C.; Saint-
Aman, E.; Einhorn, C.; Einhorn, J.; Marcadal, C.; Pierre, J.-L.
Electrochim. Acta 1998, 44, 385. (c) Kishioka, S.; Yamada, A. J.
Electroanal. Chem. 2005, 578, 71.
5
6
7
8
AUTHOR INFORMATION
Corresponding Author
*stahl@chem.wisc.edu
12. See Supporting Information for details.
13. For other applications of these reagents as radical traps, see: (a)
Crossley, S. W. M.; Obradors, C.; Martinez, R. M.; Shenvi, R. A.
Chem. Rev. 2016, 116, 8912. (b) Yi, H.; Zhang, G.; Wang, H.; Huang,
Z.; Wang, J.; Singh, A. K.; Lei, A. Chem. Rev. 2017, 117, 9016.
14. Iodine has even been shown to be a more efficient trap than O2.
See ref. 10b and the following: Hook, S. C. W.; Saville, B. J. Chem.
Soc. Perkin Trans. II 1975, 589.
15. The BDE of toluene derivatives typically ranges from 88 to 90
kcal/mol, and the BDE of NHPI is 88 kcal/mol. (a) Fox, T.; Kollman,
P. A. J. Phys. Chem. 1996, 100, 2950. (b) Bean, G. P. Tetrahedron
2002, 58, 9941. (c) Pratt, D. A.; DiLabio, G. A.; Mulder, P.; Ingold,
K. U. Acc. Chem. Res. 2004, 37, 334–340. (c) Xue, X.-S. Ji, P.; Zhou,
B.; Cheng, J.-P. Chem. Rev. 2017, 117, 8622. (d) Hirai, N; Sawatari,
N.; Nakamura, N.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2003, 68,
6587.
16. Both bimolecular and unimolecular pathways have been
reported for decomposition of PINO. See ref. 11a, c.
17. Nechab, M.; Einhorn, C.; Einhorn, J. Chem. Commun., 2004,
1500.R
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Chem. Soc. Jpn. 1985, 58, 3547. (c) Liu, Y; Hu, H.;
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9
ACKNOWLEDGMENT
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Financial support for this project was provided by Merck
Research Laboratories. Additional support was provided by an
SIOC fellowship (for FW) and the NIH (R01 GM100143 for
SSS,
F32
GM113399
for
DPH).
Spectroscopic
instrumentation was partially supported by the NIH (S10
OD020022) and the NSF (CHE-1048642).
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