Aminoxyl-Catalyzed Electrochemical Diazidation of Alkenes Mediated by a Metastable Charge-Transfer Complex

Article abstract of DOI:10.1021/jacs.8b13192

We report the development of a new aminoxyl radical catalyst, CHAMPO, for the electrochemical diazidation of alkenes. Mediated by an anodically generated charge-transfer complex in the form of CHAMPO-N₃, radical diazidation was achieved across a broad scope of alkenes without the need for a transition metal catalyst or a chemical oxidant. Mechanistic data support a dual catalytic role for the aminoxyl serving as both a single-electron oxidant and a radical group transfer agent.

Full text of DOI:10.1021/jacs.8b13192

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Communication
Aminoxyl-Catalyzed Electrochemical Diazidation of Alkenes
Mediated by a Metastable Charge-Transfer Complex
Juno C. Siu, Joseph B. Parry, and Song Lin
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 23 Jan 2019
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Aminoxyl-Catalyzed Electrochemical Diazidation of Alkenes Mediated by a Metastable Charge-
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Transfer Complex
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Juno C. Siu‡, Joseph B. Parry‡, Song Lin*
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States
Supporting Information Placeholder
oxyl catalysis in the development of metal-free
electrochemical diazidation of alkenes.
ABSTRACT: We report the development of a new aminoxyl
radical catalyst, CHAMPO, for the electrochemical
We previously reported a first-generation electrochemical
diazidation of alkenes. Mediated by an anodically generated
protocol for the diazidation of alkenes catalyzed by Mn
charge-transfer complex in the form of CHAMPO–N3,
(Scheme 1A, Eq 1).13 This work was built on foundational
radical diazidation was achieved across a broad scope of
contributions by Minisci,14 Magnus,15 Snider,16 Xu,17 and
alkenes without the need for a transition metal catalyst or a
others18 in alkene diazidation using conventional chemical
chemical oxidant. Mechanistic data support a dual catalytic
methods. These reactions provide 1,2-diazides in a single
role for the aminoxyl serving as both a single-electron
step from common alkenes, giving access to vicinally
oxidant and a radical group transfer agent.
dinitrogenated structures that are highly prevalent in
biomedically and synthetically relevant molecules.19
Nevertheless, all methods reported to date require the use of
a transition metal or a chemical oxidant, or both. These
reactive species often lead to environmentally deleterious
wastes and present an explosion hazard when used alongside
The discovery of reactions mediated by organic radicals
continues to provide solutions to challenging synthetic
problems in traditional two-electron chemistry.1 In this
context, design and implementation of new catalytic
strategies have both expanded the toolbox available for
accessing new synthetic targets and transformed the
fundamental understanding of reactions involving open-
shell pathways.2 For example, persistent aminoxyl radicals
[e.g., (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO)]
have been extensively explored in catalytic oxidation
reactions with both conventional chemical3 and
electrochemical techniques,4 which has given rise to
synthetically useful processes for small-molecule and
polymer syntheses.
–
N3 . Although our electrochemical protocol13 circumvents
the use of strong chemical oxidants, the need for a metal
catalyst and a Brønsted acid (HOAc) as the sacrificial
oxidant remains undesirable from a safety perspective.
Scheme 1. Mechanistic hypothesis for N-oxyl-catalyzed
alkene diazidation
(A) Background: Electrochemical diazidation and azidooxygenation
MnBr2 (cat.)
N3
(Eq 1)
N3
Diazidation
R
NaN3
via [MnIII]–N3
R
electrolysis
OTMP
N3
TEMPO
(Eq 2)
Despite significant advances, we contend that the scope of
TEMPO chemistry remains to be fully explored. TEMPO
and related N-oxyl radicals can undergo one-electron redox
processes, granting access to three discrete oxidation states.4
This feature distinguishes these radicals from common
organic compounds and likens them to many transition metal
complexes. In this fashion, TEMPO has been shown to
enable single-electron oxidation events in an inner-sphere
manner via the formation of metastable closed-shell
intermediates.5,6 Nevertheless, the systematic use of the
“metallic” character of N-oxyls in catalyst development
remains meager.7 To date, reactions catalyzed by N-oxyls
are largely confined to oxidations of alcohols,8 aldehydes,9
amines,10 (thio)amides,11 and peroxyl radicals.12 In these
transformations, the persistent radical is used primarily in
two capacities—as a single/two-electron oxidant or an H
atom abstractor. In this report, we expand the scope of N-
Azidooxygenation
R
via TEMPO–N3
TMP = 2,2,6,6-
tetramethylpiperidyl
For seminal developments in chemical diazidation, see refs. 14–18.
For seminal developments in chemical azidooxygenation, see ref. 20b.
(B) Working mechanistic hypothesis for aminoxyl (NO•)-catalyzed
alkene diazidation
e–
OTMP
N3
NO•
R
TEMPO
N3
–
•
N3
N3
R
R
via:
(I)
Azidooxygenation
(undesired; TEMPO
is consumed)
ref. 20a
N
N
N
TEMPO–N3
R
N
O
N3
–TEMPO
N3
R
N3
Diazidation (desired;
catalytic in TEMPO)
TEMPO–N3 CTC
While studying the electrochemical alkene diazidation, we
discovered new electrochemical method for the
a
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azidooxygenation of alkenes mediated by TEMPO (Scheme
1A, Eq 2).20 Detailed mechanistic investigation showed that
TEMPO plays two roles in this reaction. Aside from being a
radical trap, TEMPO also promotes the single-electron
1
2
3
4
5
6
–
● 21
oxidation of N3 to N3 . This process is mediated by a
metastable charge-transfer complex (CTC) formed between
–
anodically generated TEMPO+ and N3 . Upon azidyl
addition, the nascent carbon-centered radical I rapidly
combines with TEMPO to deliver the masked vicinal
aminoalcohol (Scheme 1B, black-red pathway).
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We
envisioned
that
the
TEMPO-consuming
azidooxygenation reaction could be engineered into a
TEMPO-catalyzed alkene diazidation if intermediate I was
terminated by an N3 equivalent instead of directly by
TEMPO (Scheme 1B, black-blue pathway). Specifically, we
hypothesize that the TEMPO–N3 adduct may behave as an
azidyl group transfer agent akin to the function of a redox-
active transition metal complex (e.g., [MnIII]–N3). This
operation will furnish the desired vicinal diazide while
returning the aminoxyl from an oxoammonium ion to a
neutral radical oxidation state.
●
We investigated the plausibility of N-oxyl-catalyzed
electrochemical diazidation (Table 1). In our alkene
azidooxygenation, diazidation products were occasionally
observed in small quantities when sterically encumbered
alkenes were used. The diazide formation was more
pronounced at a higher applied voltage and using less
TEMPO. Under these conditions, the [TEMPO+]/[TEMPO]
ratio is maximized to favor the formation of the CTC and
mitigate the undesired azidooxygenation. For example, the
electrolysis of alkene 1a, NaN3, and 1 equiv TEMPO in
MeCN/H2O at a cell voltage of 2.7 V22 yielded 36% 1,2-
diazide 2a in addition to 45% 3a (entry 1). Decreasing
TEMPO loading to a catalytic amount still provided
encouragingly 11% 2a alongside 7% 3a (entry 2). However,
the catalyst was unproductively consumed in the
azidooxygenation pathway, which was also indicated by the
color change of the reaction medium. Upon starting
electrolysis, the solution turned dark red, which is
characteristic of the TEMPO–N3 CTC. This color
disappeared after a mere 10 minutes as a result of TEMPO
depletion. This visual indicator thus provided a convenient
readout for reaction optimization.
We reasoned that heating the reaction would promote
homolysis of the C–O bond in byproduct 3a, thus returning
both TEMPO and the carbon-centered radical to the catalytic
cycle.23 Counterintuitively, this operation led to rapid
decomposition of the CTC and suppressed diazidation.
Instead, cooling the reaction improved the yield to 46% at 0
°C and 61% at –10 °C (entries 3, 4). However, the color of
the CTC decayed after 2 h with concomitant formation of 3a
(ca. 5%).
Studies by Bobbitt,8k Minteer/Sigman24, and Stahl25
showed that the distal C4 substituent of the aminoxyl has a
profound influence on its reactivity in alcohol oxidation.
Accordingly, we surveyed various catalysts26 and found that
4-acetamido-TEMPO (ACT) proved the most promising,
furnishing 71% 2a and <5% 3a (entry 4). However, the CTC
decayed after ca. 3 h. We hypothesized that catalyst
degradation could also occur via β-H+ elimination of the
corresponding oxoammonium ion27 in a manner akin to the
Hofmann elimination.
We reasoned that increasing the steric encumbrance about
the N-oxyl center should disfavor catalyst consumption via
azidooxygenation28 and β-elimination.29 Accordingly, we
synthesized cyclohexane-substituted (4-acetamidopiperidin-
1-yl)oxyl (CHAMPO).27,30 With CHAMPO as the
electrocatalyst, the lifetime of the CTC significantly
improved and the color of the solution persisted upon full
conversion of the alkene (4 h).31 Diazide 2a was obtained in
97% isolated yield with complete elimination of the N-oxyl
trapping product (entry 5). Importantly, exclusion of catalyst
led to olefin consumption but negligible diazide formation
(entry 6).32 In addition, common single-electron oxidants in
lieu of electricity did not provide appreciable diazide.33 We
observed the same catalyst trend using trisubstituted alkene
1b: from TEMPO to ACT to CHAMPO, improvement in
product yield and catalyst stability was evident (entries 7–
9).
Table 1. Reaction optimizationa
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We subsequently explored the scope of this new
CHAMPO (10 mol%)
NaN3 (1.5 equiv per C–N)
N3
2
1
2
3
4
5
6
7
8
N3
electrochemical diazidation (Table 2). A broad range of
alkenes with diverse structures and electronic properties
underwent the desired transformation with high efficiency
(2c–p). Unactivated monosubstituted alkenes were less
R
R
LiClO4 (0.1 M), H2O/MeCN (1:12)
C(+)/Pt(–), Ecell = 2.7 V, –10°C
1
O
N3
O
PhO
N3
N3
N3
N3
N3
N3
●
N3
N
reactive toward N3 addition and more prone to
OMe
N3
Ph
8
N3
azidooxygenation due to reduced steric hindrance.20a,34
Therefore, 15 mol% CHAMPO was used to ensure
synthetically useful yields (2c, d).
2c, 70%b
2d, 49%b
2e, 68%
2f, 85%
N3
N3
N3
O
N3
Me
N3 Me
Me
N3
N3
9
Alkenes with a catalog of labile functional groups
underwent electrochemical diazidation smoothly (2q–y).
For example, electrophiles prone to nucleophilic
N
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MeO
O
Ph
2h, 88% 2i, 72%, dr = 11:1
2g, 79%b
2j, 82%
–
displacement by N3 , such as alkyl bromide and epoxide
Me
O
groups,
remained
intact.
Oxidatively
sensitive
N3 Me
Me N3
Me N3
functionalities, such as enolizable ketone, aldehyde, sulfide,
and ferrocene groups, also were tolerated. Intriguingly, a
primary alcohol-derived alkene was converted to the
corresponding diazide in 60% yield with traces of aldehyde
byproducts. Chemoselectivity between various C=C bonds
Me
O
N3
N3
Ph
TBSO
BocN
NHFmoc
2a, 97%
2k, >99%
2l, 81% (dr = 1:1)
N3 N3
Me N3
Me N3
N3
Me
Me
Ph
N3
N3
was
observed
with
carvone
or
N-allyl-N-
Me N3
MeO
2n, 55% (dr = 5:1)
prenyltoluenesulfonamide as substrate. Owing to the
electrophilic nature of N3 , the more electron-releasing
alkene was preferentially diazidated.35
2m, 79%
2o, 92%b (dr = 1:1)
2p, >99%
●
O
Reactive functional groups:
2
1
Me
Me Me
N3
Me
Me Me
Me
H
9
Table 2. Substrate scopea
O
N3
Br
N3
N3
2s, 54% (dr = 1:1)
Me N3
2r, 77% (dr = 1:1 at C9)c
N3
2q, 82% (dr = 1:1)
O
Me Me
N3
N3
N3 Me
N3
N3
Fe
Me
N3
Me
N3
HO
PhS
N3
2b, 87%
2t, 43%b
2u, 60%d
2v, 97%
O
N
N3
Me
Me
N3
Ts
N
N3
N3
Me
N3
N
Me
Me
H
N3
2x, 90% (dr = 1:1)
2w, 84%
2y, 70%
Product derivatization:
NH3OTs
Me N3
5, 52%f
Me NHBoc
NHBoc
NHAc
NH3OTs
Fe
Me
Ph
TBSO
4, 72%e
6, 63%g
aConditions: 1 (0.2 mmol, 1 equiv), CHAMPO (10 mol%), NaN3 (3 equiv), LiClO4
(1.8 equiv), MeCN/H2O (3.8 mL, 12:1). b15 mol% CHAMPO. cLimonene-1,2-oxide
(1r) was purchased as a pair of diastereomers at C1,2. dDetermined by 1H NMR
owing to the volatility of the product. eConditions: 2v, PPh3, H2O/THF, reflux; then
pTSA. fConditions: 2k, PPh3, H2O/THF, reflux; then Ac2O, NEt3, DCM, 0 °C.
gConditions: 2a, H2, Pd/C, EtOAc, Boc2O.
The 1,2-diazide products can be readily reduced to the
corresponding vicinal diamines using Staudinger reduction
or catalytic hydrogenation. Notably, the different steric
environments of the two azido groups in 2k enabled
chemoselective reduction to form β-azidoamide 5. The
diazides could also be readily converted to bistriazoles or
1,2-dinitro compounds,36 which are common structures in
energetic materials.
Compared with our first-generation Mn-catalyzed alkene
diazidation, the new protocol presents several practical
advances. For example, replacing the transition metal
catalyst with an organocatalyst and the protic acid (HOAc)
with H2O eliminates the generation of hazardous metal
azides and hydrazoic acid. These features make the diazide
synthesis safer and more amenable to practical applications.
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(A) Cationic pathway I: Direct oxidation of carbon-centered radical I
We conducted further experiments to exemplify the user
friendliness of the protocol (Table 3). Using inexpensive Ni
foam as the cathode instead of Pt only marginally decreased
product yield (entry 2). Using carbon as both cathode and
anode did not provide 2k in appreciable amounts. To make
the reaction system metal-free, we carried out electrolysis in
a divided cell that completely separates the diazidation from
the cathodic proton reduction on Pt (entry 3). The
electrolysis was also successfully performed using
commercial ElectraSyn 2.037 or AA batteries as the power
source (entries 4, 5). Electrolyte choice proved unimportant
(entry 6). In fact, given the ionic nature of NaN3, electrolysis
in the absence of an additional electrolyte yielded 2k
–
CHAMPO+ or anode
N3
1
N3
N3
N3
N3
R
R
2
R
single-electron oxidation
(I)
(II)
3
(B) Cationic pathway II: Oxidation of the azidooxygenation product 3
4
5
N(R’)2
–
N3
O
anode
N3
N3
N3
N3
R
6
R
R
oxidation–mesolytic
cleavage
(II)
3
7
8
9
(C) Radical pathway
2H2O
2e–
–
N3
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H2
+ 2OH– cathode
substrate
CHAMPO+
CHAMPO–N3
quantitatively (entry 7). Finally, diazidation on
a
R
Innersphere
SET cycle
synthetically relevant scale resulted in a promising isolated
yield of 69% (entry 8).
slow
–e–
•
N3
Table 3. Optimization of the electrolysis setupa
CHAMPO
CHAMPO
“Standard conditions”:
CHAMPO (10 mol%)
NaN3 (1.5 equiv per C–N)
Me
Me N3
N3
N3
R
N3
(I)
Ph
Ph
LiClO4 (0.1 M), MeCN/H2O (12:1)
1k
C(+)/Pt(–), Ecell = 2.7 V, –10 °C
2k
fast
–e–
Group transfer
cycle
Entry
Variation from “standard conditions”
Yield (%)
N3
R
CHAMPO+
CHAMPO–N3
1
2
3
None
>99
92
product
Ni(–) instead of Pt(–)
Divided cell, constant current of 8 mA
81
–
N3
anode
4
5
6
7
8
ElectraSyn 2.0 as power source, 0.3 mmol 1k
AA batteries (x2) as power source
Using TBAPF6 instead of LiClO4
No LiClO4, Ecell = 3.4 Vb
82
Experimental evidence (Scheme 3) is consistent with our
original mechanistic proposal in which the aminoxyl–N3
adduct mediates the radical diazidation, whereas for certain
types of substrates, carbocation pathway I also might
operate. Reactions with radical clocks showed that
cyclopropane 7 and bisallylamine 9/10 underwent radical-
induced ring rupture or 5-exo-trig cyclization, respectively.
In all cases, no direct alkene diazidation was observed. In
principle, upon radical ring opening or cyclization, the
resultant carbon-centered radical could be further oxidized
to the cation before nucleophilic azidation; however, these
carbocations, either highly electron-deficient or at a primary
carbon, would be rather unstable. We also carried out
diazidation of amide 13, which—if operating via a
carbocation mechanism—would cyclize to furnish
oxazoline 15.39 However, electrolysis produced diazide 14
cleanly as the only observable product. Together, these data
strongly support the radical mechanism.
89
95
>99
69c
1 mmol scale
aReaction conditions: see Table 1, entry 5. bA higher cell voltage
is applied to compensate for the increased solution resistance
between cathode and anode. cIsolated yield; reaction was
carried out at a higher substrate concentration (see SI);
Aside from the radical pathway in our initial working
mechanistic hypothesis (see Scheme 1B), two additional
reaction pathways may be plausible to account for
diazidation reactivity. Carbon-centered radical I may
undergo single-electron oxidation, either directly on the
anode or by CHAMPO+, to generate the corresponding
carbocation (II; Scheme 2A). The cation would
–
subsequently react with N3 to form the diazide.
Alternatively, azidooxygenated product 3 could be an
intermediate en route to the diazide via oxidation and
mesolytic cleavage38 to form II (Scheme 2B).
Scheme 3. Mechanistic probes. Structures in purple are
expected products if the second C–N3 formation were via a
cationic pathway.
Scheme 2. Plausible mechanistic pathways
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●
– 21
accessing N3 from N3 . In light of our new mechanistic
information, we conclude that the CHAMPO–N3 CTC plays
two key roles—promoting the generation of free N3 and
1
2
3
4
5
6
7
8
●
mediating the second azidation through a putative radical
group transfer event. Preliminary data suggest that the CTC
is the resting state of the catalyst under a sufficient anodic
potential. The first C–N3 bond formation is slower than the
second owing to the relatively slow, endergonic
●
fragmentation of the CTC to CHAMPO and N3 . This rate
9
difference allows the two distinct radical addition events to
take place successively with high chemoselectivity toward
diazidation over side pathways that unproductively
consumes I. In this mechanistic hypothesis, the metal-like
behavior of N-oxyl radicals in the alkene diazidation is
particularly intriguing. Our ongoing efforts will be devoted
to further evaluating the mechanistic proposal and using the
knowledge to guide the discovery of other synthetically
useful transformations.
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ASSOCIATED CONTENT
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website,
including experimental procedures and characterization data
(PDF) and crystallographic data for CHAMPO
(CCDC1881714) (CIF).
AUTHOR INFORMATION
We further studied alkene substrates that would lead to
resonance-stabilized carbocation intermediates (Scheme 3C)
and observed radical-to-carbocation oxidation. For example,
camphor-derived alkene 16 was converted to 11% diazide
17 in addition to 42% 1,3-azidoalcohol 18 via carbocation
rearrangement. We reasoned that the norbornyl structure
selectively stabilizes carbocation (II) but not its radical
precursor (I), thus favoring the oxidation of I to II. Notably,
neither rearrangement-azidation (19) or direct 1,2-
azidohydroxylation products were observed. This result
strongly supports the hypothesis that the alkene diazidation
undergoes predominantly a radical pathway,17b,40 whereas
the azidohydroxylation adopts a cationic pathway that
triggers the rearrangement.41 Furthermore, 4-methoxy-α-
methylstyrene (1g) was converted to diazide 2g (major) and
azidoalcohol 20 (minor). A key finding from these
experiments is that if a carbocation is formed, its capture by
H2O is inevitable. Importantly, the majority of the substrates
we investigated (see Table 2) produced no appreciable
amounts of azidoalcohol products. This piece of information
lends further support for the radical mechanism involving N-
oxyl-mediated azidyl transfer.
Corresponding Author
*songlin@cornell.edu
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support was provided by Cornell University and
NIGMS (R01GM130928). S.L. thanks the ONR for a Young
Investigator Award which supports the synthesis of
energetic materials. This study made use of the NMR facility
supported by the NSF (CHE-1531632) and the ESR facility
supported by NIGMS (P41GM103521). We thank IKA for
the donation of ElectraSyn 2.0, Dr. Samantha MacMillan for
help with X-ray crystallography analysis, Drs. Ivan
Keresztes and Frank Schroeder for help with NMR spectral
analysis, Yifan Shen for reproducing experimental results,
and Dean Kim for experimental assistance.
Finally, we conducted a control experiment using
azidooxygenated product 21 instead of the alkene as the
substrate for electrolysis and observed no diazide formation.
This result excluded the possibility that N-oxyl adducts are
key intermediates in the alkene diazidation (see Scheme 2B).
REFERENCES
Accordingly, we propose a CHAMPO–N3-mediated
electrocatalytic cycle (Scheme 2C). We previously showed
that N-oxyl radicals trigger an inner-sphere oxidation
pathway that substantially lowers the potential required for
1. (a) Renaud, P.; Sibi, M. P. Radicals in Organic Synthesis;
Wiley-VCH: Weinhein, 2001. (b) Yan, M.; Lo, J. C.; Edwards, J. T.;
Baran, P. S. Radicals: Reactive Intermediates with Translational
Potential. J. Am. Chem. Soc. 2016, 138, 12692. (c) Ischay, M. A.; Yoon,
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Azide Reagent Combination. Direct α- and β-Azido Functionalization
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See ref 20a.
28. This strategy has been employed in nitroxide-mediated
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temperature needed to maintain chain growth. See ref. 23.
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ACT as the catalyst.
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22. This corresponds to ca. 0.7 V anodic potential vs. Fc/Fc+
(ferrocene/ferrocenium).
23. Studer, A.; Harms, K.; Knoop, C.; Müller, C.; Schulte, T. New
Sterically Hindered Nitroxides for the Living Free Radical
Polymerization:ꢀ X-ray Structure of an α-H-Bearing Nitroxide.
Macromolecules 2004, 37, 27.
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25. (a) Gerken, J.; Pang, Y.; Lauber, M.; Stahl, S. Structural Effects
on the pH-Dependent Redox Properties of Organic Nitroxyls: Pourbaix
Diagrams for TEMPO, ABNO, and Three TEMPO Analogs. J. Org.
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26. For a full list of catalysts surveyed, see SI.
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Innersphere
SET cycle
Group
transfer cycle
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Key intermediate
(CHAMPO–N3)
Representative product derivatization
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Me NHBoc
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NH3OTs
NH3OTs
NHBoc
TBSO
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Ph
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