Radical cyanomethylation via vinyl azide cascade-fragmentation

Article abstract of DOI:10.1039/c9sc01370a

Herein, a novel methodology for radical cyanomethylation is described. The process is initiated by radical addition to the vinyl azide reagent 3-azido-2-methylbut-3-en-2-ol which triggers a cascade-fragmentation mechanism driven by the loss of dinitrogen and the stabilised 2-hydroxypropyl radical, ultimately effecting cyanomethylation. Cyanomethyl groups can be efficiently introduced into a range of substrates via trapping of α-carbonyl, heterobenzylic, alkyl, sulfonyl and aryl radicals, generated from a variety of functional groups under both photoredox catalysis and non-catalytic conditions. The value of this approach is exemplified by the late-stage cyanomethylation of pharmaceuticals.

Full text of DOI:10.1039/c9sc01370a

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DOI: 10.1039/C9SC01370A
ARTICLE
Radical cyanomethylation via vinyl azide cascade-fragmentation†
James R. Donald,* and Sophie L. Berrell
Received 00th January 20xx,
Accepted 00th January 20xx
Herein, a novel methodology for radical cyanomethylation is described. The process is initiated by radical addition to the
vinyl azide reagent 3-azido-2-methylbut-3-en-2-ol which triggers a cascade-fragmentation mechanism driven by the loss of
dinitrogen and the stabilised 2-hydroxypropyl radical, ultimately effecting cyanomethylation. Cyanomethyl groups can be
efficiently introduced into a range of substrates via trapping of α-carbonyl, heterobenzylic, alkyl, sulfonyl and aryl radicals,
generated from a variety of functional groups under both photoredox catalysis and non-catalytic conditions. The value of
DOI: 10.1039/x0xx00000x
this
approach
is
exemplified
by
the
late-stage
cyanomethylation
of
pharmaceuticals.
trifluoroborate salts, N-hydroxyphthalimido esters,6bc-e and
6
b
6
g,h
Introduction
carboxylic acids.
In contrast to cyanation and cyanoethylation, a method in
which radicals can be trapped in a cyanomethylation reaction
The recent renaissance of synthetic organic radical
chemistry has seen the development of several approaches for
the introduction of nitrile functionality into molecules through
the trapping of radical intermediates with a variety of closed-
shell reagents. These are valuable transformations given the
importance of nitriles, which are present within the structures
of a number of pharmaceuticals and bioactive natural
(i.e. a two-carbon homologation process) is not known. At
present, radical cyanomethylation can only be achieved via the
converse approach of adding an electrophilic cyanomethyl
radical to electron-rich substrates, limiting both substrate
7
scope and the sites at which cyanomethylation is possible.
Thus, to address this deficiency, we planned to develop a new
approach that would enable the facile introduction of useful
cyanomethyl groups into a broad range of substrates under
mild conditions, such as via the use of visible-light driven
1
products. Nitriles are also widely used as directing groups in
2
C–H activation chemistry and as versatile synthetic
3
intermediates, particularly as precursors to heterocycles and
4
functionality at the carboxylic acid oxidation level.
Modern methods to intercept radicals and directly install
cyano groups use a range of cyanating reagents and build upon
classical studies by Barton using tosyl cyanide and the
5
a
eponymous Barton esters (Scheme 1Ai). Alkyl examples
5
b
include photoredox-catalysed deboronative cyanation and -
heteroatom C–H cyanation with tosyl cyanide,5c and
decarboxylative
cyanobenziodoxolone (CBX). Enantioselective variants have
achieved cyanation at benzylic positions via C–H abstraction
cyanation
with
the
iodane
5
d
5
e
under asymmetric copper catalysis and decarboxylation of N-
hydroxyphthalimido esters under cooperative photoredox-
5
f
asymmetric Cu catalysis; both methods using TMSCN as the
cyanide source. The direct C–H cyanation of arenes has also
been performed under photoredox catalysis, using cyanide
5
g
generated from TMSCN to trap an aryl radical cation.
The cyanoethylation of radicals exploits the well-
established Giese reaction of radical conjugate addition to
6
a
acrylonitrile (Scheme 1Aii). Notable recent examples feature
6
f
nucleophilic alkyl and acyl radicals generated from enamines
Department of Chemistry, University of York, Heslington, York, YO10 5DD. Email:
james.donald@york.ac.uk
†
Electronic Supplementary Information (ESI) available: Experimental protocols,
cyclic voltammetry, quantum yield measurements and spectral data. See
DOI: 10.1039/x0xx00000x
Scheme 1 The cyanation, cyanoethylation and cyanomethylation of radicals.
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Journal Name
photoredox catalysis.
View Article Online
3 2 2
(Table 1, entries 1–3, see SI for full details). Ru(bpy) Cl .6H O
To this end, 3-azido-2-methylbut-3-en-2-ol (1)8 was was selected on grounds of cost and commercial availability,
DOI: 10.1039/C9SC01370A
1
considered ideally suited to achieve the cyanomethylation of providing nitrile 9 in 93% yield by H NMR, and 97% isolated
radicals because it encompasses two key design elements: i) a yield on a 1.0 mmol scale. Diphenyl bearing vinyl azide 7
vinyl azide which can act as a masked cyanomethyl group, and performed with similar efficacy in the radical
ii) a dimethylcarbinol as a latent radical leaving group (Scheme cyanomethylation process (92% yield) suggesting that a family
1
B). Following radical generation from a substrate e.g. via the of related structures might be viable reagents for this
oxidative quenching of an excited-state photoredox catalyst transformation. Given that the reaction by-products from
*
+1
(
PC → PC ), it was anticipated that reagent 1 would intercept reagent 1 are simply nitrogen and acetone, it was preferred
open-shell species to initiate a cascade process through radical over azide 7 which liberates benzophenone, for reasons of
9
addition to the olefin, affording adduct 2 which would readily atom-economy and purification. When run in CH
2
Cl
2
or DMF,
1
0
expel dinitrogen to produce iminyl radical 3. Subsequent the reaction proceeded with efficiency comparable to using
fragmentation of iminyl radical 3 through α-C–C bond cleavage MeCN as solvent (entries 5 and 6).
and ejection of the stabilised 2-hydroxypropyl radical 4 was
Control experiments confirmed that both photocatalyst
and light were necessary for product formation, and that the
1
1
envisaged to drive the formation of the nitrile functionality.
1
/2
Importantly, the low oxidation potential of radical 4 [퐸푂푥 = – yield was much lower in the absence of base – presumably due
1
2
0
.61 V vs saturated calomel electrode (SCE)]
would to the acid (HBr) promoted decomposition of vinyl azide 1
potentially make reagent 1 amenable to use both under (entries 7–9). Performing the reaction in the presence of
photoredox catalysis, where radical 4 could readily undergo TEMPO (2.0 eq.) completely suppressed the formation of
+
electron transfer to the oxidised form of a photocatalyst (PC ) product 9, and lowered the conversion of bromide 8, with 89%
to close a redox-neutral oxidative quenching cycle, and in remaining after 4 h; indicative of a radical mechanism (entry
other electron transfer processes such as to another molecule 10). Quantum yield measurements for the reactions with
of substrate R–X in a chain propagation (see proposed azides 1 and 7 (entries 1 and 4) determined values of Φ = 1.8
mechanism). Interestingly, azide 1 has previously been utilised and Φ = 0.6, respectively; suggesting that mechanistic
in the ionic cyanomethylation of stabilised p-quinone contributions from radical chain processes cannot be ruled out
1
3
16
methides, promoted by BF
3
·OEt
2
via a distinct mechanism. In (see SI for details).
The focus turned next to exploration of the nature of the
this paper, we report the successful implementation of vinyl
azide 1 as a new reagent for the direct cyanomethylation of a substrates and radical intermediates that could be
range of radicals generated from a broad variety of precursors cyanomethylated with vinyl azide 1. Cyanomethylation of
under both photoredox-catalysed and non-photocatalysed various electrophilic α-carbonyl alkyl radicals prepared from
radical generation.
the corresponding bromides was performed in high yield with
Known vinyl azide 1 and novel diphenyl analogue 7 were reagent 1, under photoredox catalysis (products 9–14, Scheme
III
II*
prepared from the corresponding alkynes via Bi’s Ag(I) 3). Exchanging Ru(bpy)
3
Cl
2
.6H
2
O [E1/2(Ru /Ru ) = −0.81 V vs
8
catalysed hydroazidation methodology (Scheme 2). Careful
Table 1 Reaction optimisationa
control of the equivalents of water and modification of the
work-up and purification procedures facilitated isolation of
photocatalyst (1.0 mol%)
2,6-lutidine (1.5 eq.)
O
1
4
O
N3
product 1 in 80% yield on a 60 mmol scale (6 g obtained, see
SI for details). The cyclic voltammogram of azide 1 exhibited a
single reduction process with a peak current at –1.68 V vs SCE.
The relatively large magnitude of this value suggests that
direct reduction of 1 via single-electron transfer is unlikely to
be competitive with the proposed reaction mechanism.
Br
+
R
R
N
OH
solvent, blue LEDs, rt, 4 h
(
1.0 eq.)
8
(1.5 eq.)
R = Me (1), R = Ph (7)
9
Entry
Azide
1
Photocatalyst
Solvent.
Yield of 9 (%)
93, 97b
1
2
3
4
5
6
7
8
9
1
Ru(bpy)
fac-Ir(ppy)
4CZIPN
3
Cl
2
·6H
2
O
MeCN
MeCN
MeCN
MeCN
CH
DMF
Reaction development commenced with the evaluation of
1
1
7
1
1
1
1
1
1
3
97
95
92
93
93
0
0
7
0
vinyl azide
1
in the cyanomethylation of 2-
1
/2
bromoacetophenone [퐸푟푒푑 = –1.13 V vs SCE]15 in the presence
of 2,6-lutidine and a range of photocatalysts (1.0 mol%) with
strongly reducing photoexcited-states capable of inducing
radical formation via spin-centre shift. All of the catalysts
tested afforded cyanomethylated product 9 in high efficiency
Ru(bpy)
Ru(bpy)
Ru(bpy)
3
Cl
3
Cl
3
Cl
2
·6H
2
·6H
2
·6H
2
O
2
O
2
O
2
Cl
2
-
MeCN
MeCN
MeCN
MeCN
c
Ru(bpy) Cl ·6H O
3
3
3
2
2
2
2
2
2
d
Ru(bpy)
Ru(bpy)
Cl
Cl
·6H
·6H
O
O
Ag2CO3 (10 mol%)
N3
TMSN3 (1.5 eq.), H2O (1.0 eq.)
0e
R
R
R
R
DMSO, 80 ºC
OH
a
1
OH
Reactions performed on a 0.2 mmol scale. Yields were determined by H NMR
b
R = Me (1), 80%a
integration against 1,3-benzodioxole as an internal standard. Isolated yield on a
1.0 mmol scale.
R = Me (5)
R = Ph (6)
R = Ph (7), 52%b
c
d
e
No light.
No 2,6-lutidine.
With TEMPO [(2,2,6,6-
tetramethylpiperidin-1-yl)oxyl] (2.0 eq.).
a
b
Scheme 2 Reagent synthesis. Reaction time 2h, 6 h.
2
| J. Name., 2012, 00, 1-3
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SCE] for the more strongly reducing photoexcited-state previously been applied in a Barton-McCombie deoxygenation
View Article Online
18 DOI: 10.1039/C9SC01370A
IV+ III*
catalyst fac-Ir(ppy)
3
[E1/2(Ir /Ir ) = −1.73 V vs SCE] and reaction under photoredox catalysis. Lactic acid derivatives
increasing the reaction time afforded improved yields for the 15 and 16 underwent deoxygenative cyanomethylation via
1
7
more challenging substrates 10, 11 and 14. Particularly interception of the intermediate α-carbonyl radicals. This
pleasing was the formation of β-acetoxy ketone 10 in 88% approach was also successfully applied to the trapping of
isolated yield, without any obvious trace of elimination under heterobenzylic radicals to afford β-heteroarylpropionitriles 17
the reaction conditions, highlighting the advantages of an and 18 in 66% and 60% yields respectively.
approach which avoids the strong base mediated
functionalization of MeCN.
Next, to provide a new one-carbon homologation strategy
from carboxylic acids to cyanomethyl groups, the
To expand the substrate scope, we sought to utilise cyanomethylation of electronically unactivated alkyl radicals
imidazolyl thiocarbamates as radical precursors, which have
generated
investigated.
from
N-hydroxyphthalimido
esters
was
6
c,d,19
The best results were obtained with the
IV+ III*
3
highly reducing photocatalyst Ir(5-Fppy) [E1/2(Ir /Ir ) = −1.91
III III–
20
V; E1/2(Ir /Ir ) = −2.18 V vs SCE] in conjunction with (+)-
sodium L-ascorbate, producing products 19–24 resulting from
primary radicals in 48–74% yields. The addition of (+)-sodium
L-ascorbate was detrimental to the formation of phosphonate
product 25, likely due the lability of the β-phosphonato N-
2
1
hydroxyphthalimido ester. Excitingly, azide 1 was also
competent in intercepting secondary alkyl radicals, e.g. to
produce cyanomethyl compounds 26–28, and even afforded
product 29 derived from trapping of the electron-rich N-Boc
pyrrolidinyl radical intermediate, albeit in a modest yield.
Sulfonyl radicals were also efficiently trapped by reagent 1
(products 30–34), providing a direct access to α-sulfonyl
acetonitriles from sulfonyl chlorides and obviating the typical
synthetic procedure involving reduction to the intermediate
sulfinate followed by alkylation with a halo-acetonitrile
2
2
reagent. Resubjection of iodo-α-sulfonyl acetonitrile 34 to
the reaction in the presence of Ir(5-Fppy) and (+)-sodium L-
3
ascorbate afforded the di-cyanomethylated product 35 in 46%
yield. This result highlighted that aryl radicals can participate in
2
3
the cyanomethylation reaction to afford arylacetonitriles,
which are valuable synthetic precursors to heterocyclic
3
e
structures, and that sequential radical cyanomethylation is
possible, with radical formation gated by the redox potentials
2
4
of the functional groups involved.
To further scope the trapping of aryl radicals with vinyl
azide 1, aryl diazonium salts were explored as radical
2
5
precursors.
tetrafluoroborate with reagent 1 revealed that the addition of
,6-lutidine alone was sufficient to produce aryl radical
Reaction screening of phenyldiazonium
2
2
6
intermediates, affording phenylacetonitrile in 52% yield. The
conditions provided convenient access to substituted
arylacetonitriles 36–39 under mild conditions from the
corresponding aryldiazonium tetrafluoroborates.
Finally, to demonstrate the cyanomethylation of radicals in
more complex settings, the late stage functionalisation of
pharmaceutical
agents
was
undertaken.
The
N-
hydroxyphthalimido ester derivative of the nonsteroidal anti-
2
7a
inflammatory (NSAID) oxaprozin (40) was subjected to a
decarboxylative cyanomethylation, yielding homologated
nitrile 41 in 63% isolated yield (47% from oxaprozin, Scheme
4
i). Secondly, the sulfonyl chloride derivative of the diuretic
Scheme 3 Cyanomethylation of radicals. Reaction conditions: all reactions run on a 1.0
2
7b
mmol scale; a Ru(bpy) O; b fac-Ir(ppy) ; c 24 h, d no 2,6-lutidine; e Ir(5-Fppy)
meticrane (42)
chlorosulfonic acid; this isolated intermediate was efficiently
was readily prepared by heating in
3
Cl .6H , (+)-
2
2
3
3
sodium L-ascorbate (1.5 eq.); f no (+)-sodium L-ascorbate; g 8 h; h no photocatalyst, no
LEDs.
cyanomethylated with reagent 1 under photoredox catalysis,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Journal Name
There are no conflicts to declare.
View Article Online
DOI: 10.1039/C9SC01370A
Acknowledgements
We wish to thank Elsevier (J.R.D.) and the EPSRC Dial-a-
Molecule Network (EP/P007589/1) for financial support, and
Prof. Richard J. K. Taylor (University of York) for insightful
discussions.
Notes and references
1
For reviews, see: a) F. F. Fleming, Nat. Prod. Rep., 1999, 16,
5
97–606, b) F. F. Fleming, L. Yao, P. C. Ravikumar, L. Funk
and B. C. Shook, J. Med. Chem., 2010, 53, 7902–7917.
2
3
For a review, see: a) Y. Ping, L. Wang, Q. Ding and Y. Peng,
Adv. Synth. Catal., 2017, 359, 3274–3291.
Scheme 4 Late-stage cyanomethylation of pharmaceuticals. Reaction conditions:
For selected reviews, see: a) Z. Rappoport, Chemistry of the
Cyano Group, Wiley, London, 1970; b) B. Heller and M.
Hapke, Chem. Soc. Rev., 2007, 36, 1085–1094; c) M. D. Hill,
Chem. Eur. J., 2010, 16, 12052–12062; tetrazole synthesis: d)
J. Roh, K. Vávrová and A. Hrabálek, Eur. J. Org. Chem., 2012,
6101–6118; e) P. J. Lindsay-Scott and P. T. Gallagher,
Tetrahedron Lett., 2017, 58, 2629–2635.
a
2 2
Cl
, rt, 16 h; b N-hydroxyphthalimido ester
oxaprozin (40), PhthNOH, DCC, DMAP, CH
(0.01 mmol), DMSO (0.2 M), blue LEDs, rt, 24 h; c
H, 100 °C, 2 h; d sulfonyl chloride (1.0 mmol), 1 (1.5 mmol), 2,6-
lutidine (1.5 mmol), Ru(bpy) Cl .6H
O (0.01 mmol), MeCN (0.2 M), blue LEDs, rt, 4 h; e
aminoglutethimide (44), NaNO , aq. HBF , H
O, 0 °C, 30 min; f Diazonium salt (1.0
(1.0 mmol.), 1 (1.5 mmol), Ir(5-Fppy)
3
meticrane (42), ClSO
3
3
2
2
2
4
2
mmol), 1 (1.5 mmol), 2,6-lutidine (1.5 mmol), MeCN (0.2 M), rt, 4 h.
4
5
For selected reviews see: a) R. C. Larock, Comprehensive
Organic Transformations: A Guide to Functional Group
Preparations, VCH, New York, 1989; b) A. Y. Kukushkin and A.
J. L. Pombeiro, Inorg. Chim. Acta, 2005, 358, 1–21.
a) D. H. R. Barton, J. C. Jaszberenyi and E. A. Theodorakis,
Tetrahedron, 1992, 48, 2613–2626; b) J.-J. Dai, W.-M. Zhang,
Y.-J. Shu, Y.-Y. Sun, J. Xu, Y. S. Feng and H. J. Xu, Chem.
Commun., 2016, 52, 6793–6796; c) T. Wakaki, K. Sakai, T.
Enomoto, M. Kondo, S. Masaoka, K. Oisaki and M. Kanai,
Chem. Eur. J., 2018, 24, 8051–8055; d) F. Le Vaillant, M. D.
Wodrich and J. Waser, Chem. Sci., 2017, 8, 1790–1800; e) W.
Zhang, F. Wang, S. D. McCann, D. Wang, P. Chen, S. S. Stahl
and G. Liu, Science, 2016, 353, 1014–1018, f) D. Wang, N.
Zhu, P. Chen, Z. Lin and G. Liu, J. Am. Chem. Soc., 2017, 139,
affording sulfonylacetonitrile 43 in 80% yield (Scheme 4ii).
Lastly, the aniline bearing aminoglutethimide (44) was selected
for modification, a compound that acts as a steriodogenesis
2
7c
inhibitor used for the treatment of Cushing’s syndrome,
2
7d
seizures and a number of cancers. Following diazotization,
the isolated salt was efficiently cyanomethylated under the
mild reaction conditions (Scheme 4iii). These examples help to
highlight the diversity of functional groups widely found within
medicinally relevant compounds that after activation, can be
employed as substrates for the radical cyanomethylation
procedure.
1
5632–15635; g) J. B. McManus and D. A. Nicewicz, J. Am.
Chem. Soc., 2017, 139, 2880–2883.
6
a) B. Giese, J. A. González-Gómez and T. Witzel, Angew.
Chem. Int. Ed. Engl., 1984, 23, 69–70; b) Y. Yasu, T. Koike and
M. Akita, Adv. Synth. Catal., 2012, 354, 3414–3420; c) G. L.
Lackner, K. W. Quasdorf and L. E. Overman, J. Am. Chem.
Soc., 2013, 135, 15342–15345; d) Y. Slutskyy and L. E.
Overman, Org. Lett., 2016, 18, 2564–2567; e) T. Qin, L. R.
Malins, J. T. Edwards, R. R. Merchant, A. J. E. Novak, J. Z.
Zhong, R. B. Mills, M. Yan, C. Yuan, M. D. Eastgate and P. S.
Baran, Angew. Chem. Int. Ed., 2017, 56, 260–265; f) J. A.
Terrett, M. D. Clift and D. W. C. MacMillan, J. Am. Chem.
Soc., 2014, 136, 6858–6861; g) A. Millett, Q. Lefebvre and M.
Rueping, Chem. Eur. J., 2016, 22, 13464–13468; h) G.-Z.
Wang, R. Shang, W.-M. Cheng and Y. Fu, Org. Lett., 2015, 17,
4830–4833.
Conclusions
In conclusion, by exploiting the radical decomposition of
functionalised vinyl azide 1 via loss of dinitrogen and
fragmentation of the resultant iminyl radical, a cascade-
fragmentation approach towards the cyanomethylation of
radicals has been developed. Reagent 1 is readily prepared on
scale and can be used to intercept α-carbonyl, heterobenzylic,
alkyl, sulfonyl and aryl radicals prepared from a range of
precursors under both photoredox catalysis and more classical
radical generation. This methodology facilitates access to
synthetically versatile cyanomethyl groups without the need
for cyanide or strong base, under mild conditions, making it
amenable to the derivatisation of more complex substrates as
demonstrated in the late-stage cyanomethylation of
pharmaceutical agents. Further exploration of this reactivity
pattern in the design of reagents with which to trap radicals is
on-going and will be reported in due course.
7
For examples of generation of the electrophilic cyanomethyl
radical from bromoacetronitrile and addition to electron-rich
closed-shell substrates see: a) E. R. Welin, A. A. Warkentin, J.
C. Conrad and D. W. C. MacMillan, Angew. Chem. Int. Ed.,
2
015, 54, 9668–9672; b) Q. Chang, Z. Liu, P. Liu, L. Yu and P.
Sun, J. Org. Chem., 2017, 82, 5391–5397; c) C. J. O’Brien, D.
G. Droege, A. Y. Jiu, S. S. Ghandi, N. A. Paras, S. H. Olson and
J. Conrad, J. Org. Chem., 2018, 83, 8926–8935; for a review
of radical cyanomethylation initiated by C–H abstraction
from acetonitrile, see: d) X.-Q. Chu, D. Ge, Z.-L. Xhen and T.-
P. Loh, ACS Catal., 2018, 8, 258.
Conflicts of interest
4
| J. Name., 2012, 00, 1-3
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8
9
Z. Liu, J. Liu, L. Zhang, P. Liao, J. Song and X. Bi, Angew. Chem.
Int. Ed., 2014, 53, 5305–5309.
Downham, W. Farnaby, A. Goldby, D. HannahV,ieDw.ArHticalerrOinsloinne
and H. Willems (Takeda), WO 198045 A1, 2015.
DOI: 10.1039/C9SC01370A
For examples of our own work featuring radical cascades, 23 For selected recent approaches to arylacetonitriles, see: a) J.
see: a) W. F. Petersen, R. J. K. Taylor and J. R. Donald, Org.
Lett., 2017, 19, 874–877; b) W. F. Petersen, R. J. K. Taylor and
J. R. Donald, Org. Biomol. Chem., 2017, 15, 5831–5845.
0 For the original example of this reactivity, see: a) A. Suzuki,
M. Tabata and M. Ueda, Tetrahedron Lett., 1975, 2195– 24 As determined by cyclic voltammetry, 2-Iodobenzenesulfonyl
Velcicky, A. Soicke, R. Steiner and H.-G. Schmalz, J. Am.
Chem. Soc., 2011, 133, 6948–6951; b) P. J. Lindsay-Scott, A.
Clarke and J. Richardson, Org. Lett., 2015, 17, 476–479; c) Y.
Satoh and Y. Obora, RSC Adv., 2014, 4, 15736–15739.
1
1
2
198; for elucidation of the mechanism, see: b) A. F.
Bamford, M. D. Cook and B. P. Roberts, Tetrahedron Lett.,
983, 3779–3782; for reviews, see: c) B. Hu and S. G.
chloride is reduced at –0.66 V vs SCE, this reactivity is
attributed to the sulfonyl chloride and lies within the ‘redox
III
II*
1
3 2 2
window’ of Ru(bpy) Cl .6H O [E1/2(Ru /Ru ) = −0.81 V vs
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IV+ III*
III III–
4
6, 7208–7228.
3
Ir(5-Fppy) [E1/2(Ir /Ir ) = −1.91 V; E1/2(Ir /Ir ) = −2.18 V
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were measured vs Ag/AgCl (3.0 M KCl) and converted to vs
SCE (see SI for details).
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4 Whilst low molecular weight organic azides can potentially
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heated on an aluminium block. After melting at 33 °C, the
material appeared stable in the liquid state with no visible
decomposition up to ca 100 °C, whereupon it had
evaporated.
1
1
1
5 E. D. Nacsa and D. W. C. MacMillan, J. Am. Chem. Soc., 2018,
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1
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0 Data for Ir(5-Fppy) : K. Teegardin, J. I. Day, J. Chan and J.
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Weaver, Org. Process Res. Dev., 2016, 20, 1156–1163.
1 31% yield with (+)-sodium L-ascorbate (1.5 eq.), 61% yield
1
without, as determined by H NMR analysis against 1,3-
benzodioxole as an internal standard.
2
2 For recent examples, see: a) J. Kim, J. Kwon, D. Lee, S. Jo, D.-
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Chemical Science
Page 6 of 6
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DOI: 10.1039/C9SC01370A
The cyanomethylation of radicals with a vinyl azide reagent is described, via a
cascade-fragmentation mechanism.