Catalytic Carbocation Generation Enabled by the Mesolytic Cleavage of Alkoxyamine Radical Cations

Article abstract of DOI:10.1002/anie.201604619

A new catalytic method is described to access carbocation intermediates via the mesolytic cleavage of alkoxyamine radical cations. In this process, electron transfer between an excited state oxidant and a TEMPO-derived alkoxyamine substrate gives rise to a radical cation with a remarkably weak C?O bond. Spontaneous scission results in the formation of the stable nitroxyl radical TEMPO^.as well as a reactive carbocation intermediate that can be intercepted by a wide range of nucleophiles. Notably, this process occurs under neutral conditions and at comparatively mild potentials, enabling catalytic cation generation in the presence of both acid sensitive and easily oxidized nucleophilic partners.

Full text of DOI:10.1002/anie.201604619

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201604619
German Edition: DOI: 10.1002/ange.201604619
Radical Cations
Catalytic Carbocation Generation Enabled by the Mesolytic Cleavage
of Alkoxyamine Radical Cations
Qilei Zhu, Emily C. Gentry, and Robert R. Knowles*
Abstract: A new catalytic method is described to access
carbocation intermediates via the mesolytic cleavage of
alkoxyamine radical cations. In this process, electron transfer
between an excited state oxidant and a TEMPO-derived
alkoxyamine substrate gives rise to a radical cation with
and a carbocation. While pioneering studies from Arnold,[7]
Floreancig,[8] Mariano,[9] and Albini[10] have demonstrated the
feasibility and value of these methods, mesolytic cleavage-
based strategies for simple carbocation generation remain
underutilized.
À
a remarkably weak C O bond. Spontaneous scission results in
To design a practical system for cation generation, we first
sought to understand the molecular features that govern the
efficiency of mesolytic cleavage. Foremost, to enable bond
breaking, the strength of the scissile bond in the radical cation
must be reduced to near 0 kcalmolÀ1. The extent of bond
weakening associated with one electron oxidation of any
substrate can be readily calculated using the thermochemical
cycle shown in Scheme 1. In this process, the difference in
bond strengths between the neutral substrate and the radical
the formation of the stable nitroxyl radical TEMPOC as well as
a reactive carbocation intermediate that can be intercepted by
a wide range of nucleophiles. Notably, this process occurs
under neutral conditions and at comparatively mild potentials,
enabling catalytic cation generation in the presence of both
acid sensitive and easily oxidized nucleophilic partners.
T
hough carbocations are classical intermediates in synthetic
chemistry,[1] their applications in complex target synthesis and
asymmetric catalysis remain limited by the methods required
for their generation. Conventional approaches rely on the use
of either strong Lewis or Brønsted acids[2] or stoichiometric
silver reagents.[3] In turn, these methods place restrictions on
the scope of nucleophiles that can be successfully employed.
More recently, facilitated ionization mediated by thioureas
and other related hydrogen-bond donor catalysts have led to
tremendous advances in asymmetric carbocation reactivity.[4]
However, unstabilized carbocations are often difficult to
access using these methods. In light of these constraints, we
reasoned that new catalytic methods for the generation of
carbocations under neutral conditions might provide a signifi-
cant synthetic benefit, and enable more extensive use of these
versatile electrophiles in complex contexts. Herein we report
a novel method for the catalytic generation of simple benzylic
and tertiary alkyl carbocations based on the mesolytic
cleavage of TEMPO-derived alkoxyamine radical cations
and their efficient capture by a wide range of nucleophiles.
The design, development, and mechanistic features of this
procedure are described herein.
cation is equal to the potential difference between the (R X/
À
+
+
0
À
R X C) and (R /RC) couples (DBDFE = DE ). As the poten-
tial required for cation reduction is decoupled from the
identity of the dissociated radical fragment, the strength of
the scissile bond in the radical cation is principally a function
of two variables, namely the BDFE of the scissile bond in the
starting material and the potential required for generation of
the radical cation. From a synthetic perspective, we sought to
design a system in which substrate oxidation would occur at
a mild potential to ensure compatibility with more complex
substrates and a wide range of nucleophiles. However,
confining this couple to a less positive potential requires
Our interest in the mesolytic cleavage of radical cations
stems from the fact that bonds proximal to the unpaired
electron in these intermediates are dramatically destabi-
lized.[5,6] In certain cases these bonds are sufficiently weak-
ened such that they undergo spontaneous scission, resulting in
the formation of two new intermediates: a neutral free radical
[*] Q. Zhu, E. C. Gentry, Prof. R. R. Knowles
Department of Chemistry, Princeton University
Princeton, New Jersey 08544 (USA)
E-mail: rknowles@princeton.edu
Homepage: http://chemists.princeton.edu/knowles/
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201604619.
Scheme 1. Reaction design and thermochemistry of bond weakening in
radical cations. BDFE=bond dissociation free energy in kcalmolÀ1
.
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
that the strength of the scissile bond in the starting material be
weak, a feature which could potentially result in substrate
instability.
In seeking to balance these competing requirements, we
were drawn to the idea that alkoxyamines derived from
TEMPO might be ideal substrates for mesolytic cleavage. As
furnish product 3 and a silyl–TEMPO derivative, and return
the active form of the redox catalyst. Notably, direct outer
sphere electron transfer to reduce TEMPOC to TEMPO anion
is very challenging (E1/2 = À1.95 V vs. Fc/Fc+ in MeCN).[15]
However, it is well-known that in the presence of protons this
reduction step can occur via a PCET process at potentials that
are significantly less negative.[16] We reasoned that the silyl
group may play a similar role, with silyl-coupled ET to
TEMPOC resulting in direct formation of neutral closed shell
À
a result of the high stability of TEMPO radical, the C O bond
strengths in these compounds are unusually weak. For
À
example, the benzylic C O BDFE in the TEMPO adduct of
isopropyl benzene is only 26 kcalmolÀ1 [11]
,
in comparison to
TEMPO SiR3.
À
À1
À
a C O BDFE of 81 kcalmol for the corresponding tertiary
benzylic alcohol.[12] However, these adducts are also relatively
robust and can typically be chromatographed and stored at
room temperature for extended periods without decomposi-
tion. Moreover, the lone pair on nitrogen in these compounds
can be oxidized at potentials significantly less positive (Ep/2
ꢀ 0.7 V vs. Fc/Fc+ in MeCN) than those of many common
nucleophiles, providing a possible mechanism for selective
carbocation generation in their presence. These alkoxyamines
are well known and have been extensively studied in the
context of atom-transfer radical polymerization, but their use
as cation precursors is, to the best of our knowledge,
unprecedented.[13]
Preliminary experiments demonstrated that use of [Ru-
(bpy)3](PF6)2 did not provide any product, consistent with the
fact that its excited state reduction potential is 320 mV less
positive than that of substrate 1 (Table 1, entry 1). Gratify-
ingly, the use of more oxidizing photocatalysts, such as
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6 or [Ru(bpz)3](BArF)2 proved
more effective, with the latter furnishing the desired product 3
in 73% yield (entries 2,3). Further improvements were
realized through use of [Ir(dF(CF3)ppy)2(d(CF3)bpy)]PF6
which provided 3 in 78% yield (entry 5). A further evaluation
of reaction solvents with [Ir(dF(CF3)ppy)2(d(CF3)bpy)]PF6
demonstrated that nitromethane was optimal, generating 3
To evaluate these ideas, we elected to explore the
mesolytic cleavage of alkoxylamine 1 in the presence of silyl
enol ether nucleophile 2 and a variety of visible light
photoredox catalysts. In this process (Scheme 2), we imagined
that the excited state of the catalyst would remove an electron
Table 1: Optimization studies.
from the nitrogen lone pair of 1, resulting in the formation of
+
À
a radical cation 1 C. As outlined above, the C O bond strength
in 1+C is expected to be weak,[14] resulting in facile mesolytic
cleavage to furnish a benzylic carbocation and TEMPO
radical. Importantly, the cation and neutral radical are not
expected to remain electrostatically associated in solution,
which may increase both the lifetime and reactivity of the
nascent electrophile. Trapping of the cation by 2 would follow,
Entry Photocatalyst
E0 (V vs.
Solvent Yield
[%][b]
Fc)[a]
1
2
3
4
[Ru(bpy)3](PF6)2
[Ir(dF-CF3-ppy)2(dtbbpy)]PF6
[Ru(bpz)3](BArF)2
+0.39
+0.28
+1.07
+1.92
CH2Cl2
CH2Cl2 19
CH2Cl2 73
0
À
resulting in C C bond formation. Reduction of TEMPOC by
the reduced form of the photocatalyst and silyl transfer would
2,4,6-triphenylpyrilium
CH2Cl2
7
5
6
7
8
9
10
11
[Ir(dF(CF3)ppy)2(d(CF3)bpy)]PF6 +0.98
[Ir(dF(CF3)ppy)2(d(CF3)bpy)]PF6 +1.26
[Ir(dF(CF3)ppy)2(d(CF3)bpy)]PF6 +1.26
[Ir(dF(CF3)ppy)2(d(CF3)bpy)]PF6 +1.26
[Ir(dF(CF3)ppy)2(d(CF3)bpy)]PF6 +1.26
[Ir(dF(CF3)ppy)2(d(CF3)bpy)]PF6 +1.26
[Ir(dF(CF3)ppy)2(d(CF3)bpy)]PF6 +1.26
CH2Cl2 78
C6H6
dioxane
DME
TFE
0
4
21
40
MeCN 43
MeNO2 95
Entry Change from best conditions (Entry 10) Solvent Yield [%][b]
12
no light
MeNO2
MeNO2
MeNO2
MeNO2
0
0
0
7
13
no photocatalyst
HBF4·OEt2 (50 mol%)
TMSOTf (50 mol%)
14[c]
15[c]
[a] Reduction potentials of Mn*/MnÀ1 redox couple in MeCN [b] Yields
determined by GC analysis using internal standard Ph2O. [c] No
photocatalyst, no light.
Scheme 2. Proposed catalytic cycle.
2
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 2: Nucleophile scope.
in 95% yield after 12 hours at room temperature (entry 11).
In control reactions lacking either the Ir photocatalyst or
visible light irradiation no product formation was observed
(entries 12,13). We also questioned whether silyl cations or
Brønsted acids generated in situ during the course of the
reaction might catalyze cation formation. However, addition
of 50 mol% of either TMSOTf or HBF4·Et2O to the reaction
in the absence of photocatalyst resulted in 7% and 0% yields
of product 3, respectively (entries 14,15).
Nucleophile
Product
Nucleophile
Product
With these optimized conditions in hand, we next
explored the scope of this process. Using alkoxyamine 1 as
a
model electrophile, together with 2 mol% [Ir(dF-
(CF3)ppy)2(d(CF3)bpy)]PF6 in MeNO2 solution, we evaluated
a diverse range of nucleophiles (Table 2). Along with 2,
numerous other silyl enol ethers and allyl silanes could be
accommodated, furnishing alkylation products in good yields
(5–13, 68–89% yield). Similarly, a vinyl trifluoroborate salt
À
was coupled successfully to furnish C C coupled product 15
(61% yield). Direct Friedel–Crafts arylation with an indole
nucleophile was also successful (17, 82% yield). Notably,
within this set of carbon nucleophiles, three different electro-
philes (silicon, boron, and proton) were all competent to
facilitate TEMPO reduction and enable catalytic turnover.
Turning our attention to heteroatom nucleophiles, we found
that a variety of nitrogen groups could be introduced
efficiently, including azide, methyl carbamate, and sulfona-
mide derivatives (19, 21, 23; 58–85% yield). Also, aniline and
diphenylamine nucleophiles reacted to furnish N-alkylated
products 25 and 27 (67% and 65% yield), respectively.
Alcohol nucleophiles were also examined with both cyclo-
À
hexanol and tert-butanol providing C O coupled compounds
in good yields (29 and 31, 77% and 82% yield). Hindered
ethers such as these are often challenging to form by classical
methods, and suggest that this method may prove useful in the
À
production of congested C O linkages. Finally, we found that
the reaction can also be adapted for use in intramolecular
settings, as demonstrated by the etherification and arylation
reactions leading to products 33 and 35.
Next, we evaluated the scope of carbocations that can be
generated using this method. Under the optimal conditions,
a variety of cyclic and acyclic benzylic cations could be
formed and subsequently alkylated with 2 (Table 3), furnish-
ing products in good yields. In the acyclic series, both
secondary and tertiary cations could be alkylated, as could
a variety of substituted phenyl derivatives (37–57, 67–93%
yield). Perhaps unsurprisingly, arenes bearing strong electron-
withdrawing groups were not amenable to carbocation
formation using this procedure, though halogen substituents
were readily accommodated. Allylic cations and oxocarbe-
nium ions could also be generated and alkylated in good
yields (59 and 61; 83% and 55% yield). Gratifyingly, even
tertiary alkyl cations could be accessed using this method, as
evidenced by the alkylation of both adamantyl and tert-butyl
derived substrates, though the yield of the latter is likely
diminished by competitive deprotonation of the cation
intermediate (63 and 65; 85% and 21% yield). With respect
to limitations, this method is currently unable to generate
unstabilized secondary carbocations, such as the cyclohexyl
cation, as their alkoxyamine precursors exhibit significantly
[a] Reaction run on 0.5 mmol scale. Yields and diastereoselectivity are
determined for isolated material following chromatography and are the
average of two runs. [b] With electrophile 42. [c] 6.0 equivalents of tert-
butanol.
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 3: Electrophile scope.
Subsequent experiments demonstrated that this current
feature occurs at an identical potential as the TEMPOC/
oxoammonium redox couple,[15] suggesting that TEMPOC is
generated in solution during the oxidative sweep. Together
these results are consistent with a process wherein oxidatively
À
induced mesolytic cleavage of the C O bond occurs following
Electrophile
Product
Electrophile
Product
single-electron oxidation of 1. In support of this reasoning, the
+
À1
À
C O BDE of 1 C is calculated to be only 10 kcalmol using
the thermochemical cycle presented in Scheme 1. We also
determined the quantum yield for the reaction of 1 with
enolsilane 2 to be 0.43.
In conclusion, we have described a new photocatalytic
method for accessing carbocation intermediates via the
mesolytic cleavage of alkoxyamine radical cations. This
process occurs under mild, Brønsted-neutral catalytic con-
ditions and enables efficient alkylation reactions of a wide
variety of nucleophiles. We are optimistic that this work will
find use in complex settings that are not amenable to
traditional cation generation processes, as well as lead to
the rational design of new mesolytic cleavage partners with an
expanded substrate scope.
Acknowledgements
We gratefully acknowledge the NIH (R01 GM120530) for
support of this work. We also acknowledge Ryan Evans
(Princeton) for the original synthesis of the Ir catalyst used in
this work.
Keywords: alkoxyamines · carbocations · mesolytic cleavage ·
photoredox catalysis · radical cations
[1] a) G. A. Olah, G. K. S. Prakash, Carbocation Chemistry, Wiley,
Hoboken, 2004; b) R. R. Naredla, D. A. Klumpp, Chem. Rev.
2013, 113, 6905 – 6948.
[a] Reaction run on 0.5 mmol scale. Yields are determined for isolated
material following chromatography and are the average of two runs.
[b] GC yield.
[2] a) K. Mori, S. Sueoka, T. Akiyama, J. Am. Chem. Soc. 2011, 133,
2424 – 2426; b) H. Li, W. Li, W. Liu, Z. He, Z. Li, Angew. Chem.
Int. Ed. 2011, 50, 2975 – 2978; Angew. Chem. 2011, 123, 3031 –
3034; c) J. Lv, Q. Zhang, X. Zhong, S. Luo, J. Am. Chem. Soc.
2015, 137, 15576 – 15583; d) F. Zhang, S. Das, A. J. Walkinshaw,
A. Casitas, M. Taylor, M. G. Suero, M. J. Gaunt, J. Am. Chem.
Soc. 2014, 136, 8851 – 8854; e) D. Nitsch, S. M. Huber, A. Pꢀthig,
A. Narayanan, G. A. Olah, G. K. S. Prakash, T. Bach, J. Am.
Chem. Soc. 2014, 136, 2851 – 2857; f) M. Rueping, U. Uria, M.-Y.
Lin, I. Atodiresei, J. Am. Chem. Soc. 2011, 133, 3732 – 3735.
[3] For a remarkable recent example, see: R. P. Loach, O. S. Fenton,
M. Movassaghi, J. Am. Chem. Soc. 2016, 138, 1057 – 1064.
[4] a) K. Brak, E. N. Jacobsen, Angew. Chem. Int. Ed. 2013, 52, 534 –
561; Angew. Chem. 2013, 125, 558 – 588; b) M. Mahlau, B. List,
Angew. Chem. Int. Ed. 2013, 52, 518 – 533; Angew. Chem. 2013,
125, 540 – 556; c) R. J. Phipps, G. L. Hamilton, F. D. Toste, Nat.
Chem. 2012, 4, 603 – 614; d) N. Mittal, K. M. Lippert, C. Kant-
a De, E. G. Klauber, T. J. Emge, P. R. Schreiner, D. Seidel, J. Am.
Chem. Soc. 2015, 137, 5748 – 5758.
[11b]
À
stronger C O bonds.
Efforts to address this limitation
through variation of the key properties discussed above are
currently ongoing.
To better understand the details of the oxidatively induced
mesolytic cleavage step, we evaluated both of its constituent
elementary steps. First, luminescence-quenching assays
revealed concentration-dependent quenching of the excited
state of [Ir(dF(CF3)ppy)2(d(CF3)bpy)]PF6 by alkoxyamine 1,
consistent with single-electron oxidation (KSV=86 LmolÀ1).
Thermodynamically, this electron transfer process is exer-
À
gonic by 550 mV. Next, we studied the feasibility of C O
cleavage following one-electron oxidation using voltammetric
techniques. Specifically, initial CV scans of substrate 1 in
MeCN revealed an irreversible oxidation event at 0.71 V vs.
Fc/Fc+, which was assigned to the oxidation of the nitrogen
lone pair of 1. However, the return scan in the reducing
direction also exhibited a new peak at 0.21 V vs. Fc/Fc+.
[5] A. D. McNaught, A. Wilkinson, IUPAC. Compendium of
Chemical Terminology, 2nd ed., Blackwell Scientific Publica-
tions, Oxford, 1997.
4
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
[6] a) M. Schmittel, A. Burghart, Angew. Chem. Int. Ed. Engl. 1997,
2012, 124, 8705 – 8708; c) E. Fasani, M. Mella, A. Alibini, J.
36, 2550 – 2589; Angew. Chem. 1997, 109, 2658 – 2699; b) E. R.
Gaillard, D. G. Whitten, Acc. Chem. Res. 1996, 29, 292 – 297; c) P.
Maslak, J. N. Narvaez, Angew. Chem. Int. Ed. Engl. 1990, 29,
283 – 285; Angew. Chem. 1990, 102, 302 – 304; d) E. Baciocchi,
M. Bietti, O. Lanzalunga, Acc. Chem. Res. 2000, 33, 243 – 251;
e) M. Fagnoni, D. Dondi, D. Ravelli, A. Albini, Chem. Rev. 2007,
107, 2725 – 2756.
Chem. Soc. Perkin Trans. 2 1995, 449 – 452.
[11] a) T. Kothe, S. Marque, R. Martschke, M. Popov, H. Fischer, J.
Chem. Soc. Perkin Trans. 2 1998, 1553 – 1560; b) P. Marsal, M.
Roche, P. Tordo, P. de Sante Claire, J. Phys. Chem. A 1999, 103,
2899 – 2905.
[12] Y.-R. Luo, Comprehensive Handbook of Chemical Bond Ener-
gies, CRC Press, Boca Raton, 2007, pp. 323.
[7] a) R. M. Borg, D. R. Arnold, T. S. Cameron, Can. J. Chem. 1984,
62, 1785 – 1802; b) R. Popielarz, D. R. Arnold, J. Am. Chem. Soc.
1990, 112, 3068 – 3082.
[8] a) V. S. Kumar, P. E. Floreancig, J. Am. Chem. Soc. 2001, 123,
3842 – 3843; b) P. E. Floreancig, Synlett 2007, 2, 0191 – 0203; c) L.
Wang, J. R. Seiders, P. E. Floreancig, J. Am. Chem. Soc. 2004,
126, 12596 – 12603.
[13] C. J. Hawker, A. W. Bosman, E. Harth, Chem. Rev. 2001, 101,
3661 – 3688.
À
[14] C O Bond strength calculated from the equation in Scheme 1,
oxidative potential of radical to cation from: D. D. M. Wayner,
D. J. McPhee, D. Griller, J. Am. Chem. Soc. 1988, 110, 132 – 137.
[15] J. J. Warren, T. A. Tronic, J. M. Mayer, Chem. Rev. 2010, 110,
6961 – 7001.
[9] a) S. H. Lim, K. Nahm, C. S. Ra, D. W. Cho, U. C. Yoon, J. A.
Latham, D. Dunaway-Mariano, P. S. Mariano, J. Org. Chem.
2013, 78, 9431 – 9443; b) D. W. Cho, U. C. Yoon, P. S. Mariano,
Acc. Chem. Res. 2011, 44, 204 – 215.
[16] J. J. Warren, J. M. Mayer, J. Am. Chem. Soc. 2011, 133, 8544 –
8551.
[10] a) M. Fagnoni, A. Albini, Acc. Chem. Res. 2005, 38, 713 – 721;
b) S. Protti, D. Ravelli, B. Mannucci, A. Albini, M. Fagnoni,
Angew. Chem. Int. Ed. 2012, 51, 8577 – 8580; Angew. Chem.
Received: May 11, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Radical Cations
Q. Zhu, E. C. Gentry,
R. R. Knowles*
&&&& — &&&&
Carbocation intermediates can be
accessed by mesolytic cleavage of
alkoxyamine radical cations with
the stable nitroxyl radical TEMPOC and the
reactive carbocation intermediate that
can be intercepted by a wide range of
nucleophiles.
Catalytic Carbocation Generation Enabled
by the Mesolytic Cleavage of Alkoxyamine
Radical Cations
À
a remarkably weak C O bond. Sponta-
neous scission results in the formation of
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!