Methyl Radical Initiated Kharasch and Related Reactions

Article abstract of DOI:10.1002/adsc.202001000

An improved procedure to run halogen atom and related chalcogen group transfer radical additions is reported. The procedure relies on the thermal decomposition of di-tert-butylhyponitrite (DTBHN), a safer alternative to the explosive diacetyl peroxide, to produce highly reactive methyl radicals that can initiate the chain process. This mode of initiation generates byproducts that are either gaseous (N₂) or volatile (acetone and methyl halide) thereby facilitating greatly product purification by either flash column chromatography or distillation. In addition, remarkably simple and mild reaction conditions (refluxing EtOAc during 30 minutes under normal atmosphere) and a low excess of the radical precursor reagent (2 equivalents) make this protocol particularly attractive for preparative synthetic applications. This initiation procedure has been demonstrated with a broad scope since it works efficiently to add a range of electrophilic radicals generated from iodides, bromides, selenides and xanthates over a range of unactivated terminal alkenes. A diverse set of radical trap substrates exemplifies a broad functional group tolerance. Finally, di-tert-butyl peroxyoxalate (DTBPO) is also demonstrated as alternative source of tert-butoxyl radicals to initiate these reactions under identical conditions which gives gaseous by-products (CO₂). (Figure presented.).

Full text of DOI:10.1002/adsc.202001000

Title: Methyl Radical Initiated Kharasch and Related Reactions
Authors: Nicholas D. C. Tappin and Philippe Renaud
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001000
Link to VoR: https://doi.org/10.1002/adsc.202001000

10.1002/adsc.202001000
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.202001000
Methyl Radical Initiated Kharasch and Related Reactions
Nicholas D. C. Tappin,a and Philippe Renauda*
a
University of Bern, Department of Chemistry and Biochemistry, Freiestrasse 3, 3012 Bern.
Email: philippe.renaud@dcb.unibe.ch
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. An improved procedure to run halogen atom and related chalcogen group transfer radical additions is reported.
The procedure relies on the thermal decomposition of di-tert-butylhyponitrite (DTBHN), a safer alternative to the
explosive diacetyl peroxide, to produce highly reactive methyl radicals that can initiate the chain process. This mode of
initiation generates byproducts that are either gaseous (N2) or volatile (acetone and methyl halide) thereby facilitating
greatly product purification by either flash column chromatography or distillation. In addition, remarkably simple and
mild reaction conditions (refluxing EtOAc during 30 minutes under normal atmosphere) and a low excess of the radical
precursor reagent (2.0 equivalents) make this protocol particularly attractive for preparative synthetic applications. This
initiation procedure has been demonstrated with a broad scope since it works efficiently to add a range of electrophilic
radicals generated from iodides, bromides, selenides and xanthates over a range of unactivated terminal alkenes. A
diverse set of radical trap substrates exemplifies a broad functional group tolerance. Finally, di-tert-butyl peroxyoxalate
(DTBPO) is also demonstrated as alternative source of tert-butoxyl radicals to initiate these reactions under identical
conditions which gives gaseous by-products (CO2).
Keywords: radical reaction; atom transfer; radical initiation; chain reaction; carbohalogenation; haloalkylation;
ATRA; alkene.
effectively solved this problem but led to product
contamination with tin residues.[11] Photoinitiation in
Introduction
the presence of a sensitizer such p-anisaldehyde was
found to work well with highly activated radical
precursors such as bromomalonate derivatives, CCl4,
and perfluorohexyl iodide.[12]
The atom transfer radical addition (ATRA) process
discovered by Kharasch in the 1940s is one of the most
attractive processes to create carbon–carbon bonds
under mild conditions and a theoretical perfect atom
economy (Scheme 1).[1–6] Theoretically too, such an
efficient chain reaction requires only a tiny amount of
a radical initiator when the process is favored by
thermodynamic and polar effects. In practice, the
initiation has proven to be a crucial element for the
success of this reaction. Scheme 1 summarizes three
commonplace strategies to initiate ATRA processes: A
carbon–halogen bond homolysis,
B
halogen
atom/chalcogen abstraction, and C reductive single
electron transfer. Curran has thoroughly demonstrated
that the more reactive halides such as α-iodocarbonyl
compounds are among the best substrates to conduct
ATRA reactions.[7–10] For such derivatives, initiation
using sun lamp irradiation was possible (strategy A).
However, the generation of a small amount of iodine
resulting from the homolysis of the C–I bond was
found to inhibit ATRA chain propagation by
regenerating the starting radical precursor iodide
before the C–centered radical could add onto the
alkene. Adding hexamethylditin that reacts
spontaneously with elemental iodine to form Me3SnI
Scheme 1. Non-catalyzed ATRA process: mechanism and
key approaches for the initiation step
Kharasch in his seminal work used mainly strategy
B with diacetyl peroxide as a source of methyl
radicals.[5] However, this peroxide is explosive and
shock sensitive, and has therefore been generally
replaced by the more stable dilauroyl peroxide
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001000
Advanced Synthesis & Catalysis
(DLP).[13] The DLP approach has proven to be reliable
but the thermal decomposition products of DLP
including lauric acid, n-docosane and undecyl
laurate,[14] as well as lauroyl halide from productive
initiation, often contaminate the products and difficult
(sometimes multiple) purifications by column
chromatography are required to obtained analytically
pure ATRA products. This byproduct contamination
has also been observed when DLP was used to initiate
the highly efficient xanthate transfer reactions
developed over the last two decades by Zard and
coworkers.[15,16] One remarkably successful solution
has been to initiate with triethylborane and oxygen,
which works via transient ethyl radicals (strategy
B).[17–19] However the pyrophoric character of
triethylborane, and inherent incompatibility with -
halo- and -chalcoketones,[20,21] have made this
strategy less attractive. The use of transition metal
catalysis (Fe, Cu, Ru, Ni for instance) is also a popular
way of initiating (and often catalyzing) ATRA
processes,[22–28] this approach involves an initial inner-
sphere electron transfer (strategy C) and is particularly
suitable for reactions onto activated alkenes such as
styrene derivatives. More recently, visible light-
promoted electron transfers (strategy C) have been
reported in the presence of diverse, often expensive,
transition metal catalysts.[29–37] Despite all these
studies, the need of a simple and broadly applicable
method to run ATRA reactions remains highly needed.
Ideally, the reaction should work with a wide range of
reactive—and less reactive—substrates and reagents
under mild reaction conditions that avoid the use of
expensive or toxic metals and the formation of
byproducts which are difficult to remove.
constant of kf = 3.85–4.00 × 104 s–1 was measured for
this decomposition at 65 °C in isooctane.[41] β-
Fragmentation of the tert-butoxyl radical to acetone
and a methyl radical[38] takes place spontaneously and
quickly at ambient temperatures (kβ = 1.4 × 104 s–1 in
benzene at 22 °C),[43] and is sped up with heating (kβ
=1.1 × 105 s–1 in cumene at 60 °C).[44] Even more
interesting, this fragmentation is accelerated in polar
(kβ = 6.4 × 104 s–1 in acetonitrile at 22 °C) and protic
solvents (kβ = 1.4 × 106 s–1 in water at 22 °C).[43] Up to
now, most radical initiations using DTBHN involve
rapid reactions of tert-butoxyl radicals with oxophilic
species such as organoboron and ditin derivatives as
well as hydrogen atom donors such as tin hydrides and
silanes (Scheme 2, top, grey).[42] However, when no
such species is present in the reaction mixture,
DTBHN is expected to be a source of methyl radicals
and therefore a powerful system to initiate halogen /
chalcogen transfer processes from a variety of radical
precursors. To the best of our knowledge, the
DTBHN-methyl radical mediated initiation has only
been used by Trauner and coworkers for a conversion
of a xanthate to a bromide (Scheme 2, middle).[45,46]
Here, we report that DTBHN is an excellent general
initiator for ATRA processes under simple, mild, and
clean (only volatile initiator byproducts) reaction
conditions (Scheme 2, bottom). Here, only a small
excess of the radical precursor reagent (2.0 equiv)
relative to the substrate is employed avoiding the
frequently reported and wasteful excess (typically
>3.0 equiv).
Approaches A and C can provide very efficient
continuous solutions for the ATRA reaction. However,
based on their mechanism of action, they are not
expected to be applicable to a broad range of radical
precursors possessing different redox potentials and
photochemical properties. On the other hand, method
B involving classical halogen transfer processes is
expected to behave in a highly predictable manner and
its efficiency is governed by the difference of the C–X
bond dissociation energies between the radical
precursor and the halide or chalcogenide product
resulting from initiation. In order to maximize the
thermodynamic aspect of the initial atom transfer, the
use of the least stable alkyl radical, i.e. the methyl
radical, is an optimal choice insuring a fast halogen
transfer step with few chain-breaking events. Besides
fragmentation of diacetyl peroxide employed in
Kharasch’s seminal work, methyl radicals are also
generated by fragmentation of tert-butoxyl radicals.[38]
The use of di-tert-butyl peroxide was not considered
as an option since temperatures ≥120 °C are required
for its homolysis.[39,40] Interestingly, the thermal
homolytic scission of di-tert-butyl hyponitrite
(DTBHN)[41,42] takes place facilely at moderate
temperatures (40–70 °C; t1/2 = 29 min at 65 °C, neat)
to result in the simultaneous formation of two tert-
butoxyl radicals and extrusion of molecular nitrogen
(Scheme 2, top). A first order rate in [DTBHN] with
Scheme 2. Thermal decomposition of DTBHN as a source
of methyl radicals.
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001000
Advanced Synthesis & Catalysis
Results and discussion
challenging radical precursors were then tested in a
systematic progression (Entries 1–8). Bromine atom
transfer from ethyl bromoacetate 2b[5,49] furnished 3b
in moderate 25% yield (Entry 2). The yield reached
33% by adding another 20 mol% of DTBHN
demonstrating that the chain reaction is inefficient
presumably due to the slow bromine atom transfer
propagation step. Phenylseleno group transfer reaction
behaved poorly for the ester precursor 2c (entry 3) but
xanthate group transfer performed well with the ester
2d (entry 4, 90%). A similar trend was observed for
the acetonitrile derivatives 2e–2h. The iodide 2e, a
typical iodine-ATRA radical precursor, gave an
anticipated good yield for iodide 3e (entry 5, 78%), as
did the bromoacetonitrile 2f to furnish 3f in 70% yield
under our standard conditions (entry 6).
Phenylselenoacetonitrile 2g gave 3g in low yield
(entry 7) and reaction of the xanthate 2h with 1a
delivered 3h in excellent yield (entry 8). Less reactive
iodides such as the pinacol boronic ester 2i[50] and the
sulfone 2j[51–53] afforded the ATRA products in
moderate to excellent yields (entries 9 and 10). The
unstable heat and light sensitive 2-iodoacetophenone
2k did not afford cleanly the iodide 3k (entry 11). On
the other hand, the corresponding bromoketone 2l[54,55]
did provide 3l in 50% yield (entry 12). Again, the
xanthate 2m added to 1a in a quantitative manner
(entry 13). The crude products of all reactions depicted
in Table 1 were easy to purify by column
chromatography, in sharp contrast to the same product
mixtures prepared using DLP as an initiator that are
contaminated by the aforementioned non-volatile
decomposition byproducts.[14,56–58]
Preliminary experiments with different radical
precursors. The methyl radical initiation was first
attempted for iodine atom transfer reactions which is a
high-performing manifold for the Kharasch reaction.
As polar solvents were expected to favor β-scission,[43]
we selected the environmentally benign EtOAc as a
solvent that has a reflux temperature matching a short
half-life of DTBHN.[41] DTBHN is readily synthesized
from tert-butylbromide and sodium hyponitrite, and
easily crystalized from pentane in modest yields (see
supplementary information).[41,47] Initial studies were
performed with 1-undecene 1a using a short reaction
time of 30 minutes. Reaction with two equivalents of
ethyl iodoacetate 2a gave ATRA product 3a in high
yields between 5–20 mol% loadings of DTBHN.
Reproducibility and yields were best for DTBHN
loadings over 10 mol% and had plateaued (and were
very slightly eroded) by 20 mol% (Table 1, Entry 1).
For the well-behaved iodine atom and xanthate group
transfer reactions, 10 mol% DTBHN was generally
sufficient or better (e.g. 4, Scheme 3). Nonetheless, in
order to unify the reaction conditions and maximize
reproducibility over all radical precursors, the
reactions were performed with 20 mol% DTBHN. The
rate constants for the halogen atom transfer from the
starting halide to a primary alkyl radical are also given
in Table 1,[48] to show that yields of 3 correlate well
with transfer rates from 2. The final column of Table 1
provides a point of reference for analogous reactions
initiated by alkyl radical generation (examples from
the literature with the same radical precursor but
different terminal alkenes are given). More
Table 1. Identification of radical precursor (2a–m) scope with 1-undecene 1a.[a]
Entry[a]
Radical Precursor
kT [M–1 s–1] Ref.
Product Yield[b]
Literature Analogies[f]
Yield Method
EWG
CO2Et
CO2Et
CO2Et
CO2Et
CN
X
I
Br
SePh
SC(S)OEt
I
[48]
1
2
3
4
5
6
7
8
2.6 × 107
83%, 87%[c]
93%
65%
DLP[13]
BEt3/O2
2a
2b
2c
2d
2e
2f
2g
2h
2i
3a
3b
3c
3d
3e
3f
[48]
[60]
7 × 104
25%, 33%[d]
<5%[e]
90%
[61]
1.0 × 105
~75% DLP[62]
[48]
1.7 × 109
78%
70%
[63]
CN
Br
3 × 106
[61]
CN
SePh
2.3 × 105
13%
87%
51%
3g
3h
3i
CN
SC(S)OEt
85%
~60% DLP[50]
DLP[64]
9
Bpin
SO2Ph
C(O)Ph
I
I
I
10
11
12
13
59%, 80%[d]
<10%[e]
41%, 50%[d]
94%
2j
2k
2l
3j
3k
3l
C(O)Ph Br
C(O)Ph SC(S)OEt
84%
DLP[65]
2m
3m
[a] All reactions were performed on 1.0 mmol of 1-undecene 1a, 2.0 mmol of the radical precursor 2a–m, and 0.2 mmol of
DTBHN (20 mol% with respect to 1a), and with technical grade EtOAc (3.3 mL) without any drying of solvents or reagents
under air atmosphere (no inert gas). The reaction mixture was heated under reflux for 30 min and concentrated in vacuo for
direct purification by silica-gel flash column chromatography. [b] Isolated yields. [c] 10 mol% DTBHN. [d] 2 × 20 mol%
DTBHN, 2 × 30 min reaction time. [e] Not characterized. [f] Analogous reactions involving a terminal alkene and initiation
via X-abstraction (Scheme 1, strategy B); only examples that employ no greater than a 3-fold excess of either radical
precursor or radical trap are given.
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001000
Advanced Synthesis & Catalysis
Scope of the method. Having established that a
Finally, challenging xanthate transfer reactions
involving the formation of tertiary xanthates were
attempted with cyclic exo-methylene radical traps and
α-ester and α-ketone xanthates 2d and 2m. The tertiary
xanthates 14 and 15 were obtained in moderate 48%
and 49% yields. Zard has reported a similar yield for
the DLP-initiated xanthate transfer onto N-Boc
protected 4-exo-methylenepiperidine.[66]
wide range of radical precursors could be added over
unfunctionalized 1-substituted alkenes. More
functionalized alkenes as well as different radical
precursors were also tested. The wealth of examples
presented in Scheme 3 demonstrates the generality of
this method. Alcohols protected as esters, Weinreb
amides, and 1,2-cis-alkenes all underwent iodine-
ATRA with high yields (Scheme 3, 4–8) except for
ICH2Bpin which furnished 5 in a modest 43% yield.
Bromine-ATRA with dimethyl 2-bromomalonate 2p
and BrCH2CN 2f provided 9 and 10 in excellent yields.
The 2-methylated bromomalonate 2q was allowed to
react with the bromide 1d affording 11 in 30% yield
along with 43% of recovered 1d. The low yield is
unlikely to be due to steric hindrance of the radical
generated from 2q since other groups have reported
good results with this radical precursor.[12] Conversion
became high and yield increased to 44% with 2×20
mol% DTBHN. The analogous selenomalonate 2r,
reacted with 1d and 1g to give 12 and 13 in improved
75% and 62% yields, respectively. The efficacy of the
selenophenyl group transfer reaction with 2q relative
to the monoester and nitrile derivatives 2c and 2g
(Table 1, entries 3 and 7) is rationalized by the faster
group transfer process (kT = 8 × 105 M–1s–1).[61]
Preparation of tertiary iodides and lactones. Due
to the instability of tertiary iodides under most
reactions conditions reported for ATRA reactions
(light, heat), iodine ATRA-reactions involving the
formation of a tertiary iodides have so far only been
achieved at room temperature using triethylborane[67–
69]
[70]
and Mn2(CO)10 initiation. Surprisingly, running
reaction between the protected 4-
the
methylenepiperidine 1h and ethyl 2-iodoacetate 2a
under our mild DTBHN conditions afforded the
tertiary iodide 16 in an excellent 91% yield (Scheme 4,
eq. a). Its structure was confirmed by single crystal X-
ray crystallography. When the same reaction was
performed with methylenecyclohexane derivatives 1i–
k, the intermediate tertiary iodides were spontaneously
converted into the lactones 17i–k with respectable 76–
81% yields (Scheme 4, eq. b). The reaction of
methylenecyclohexane 5i with 2a was scaled up to 10
mmol without yield depreciation for the formation of
17i (79%) after distillation. Such lactonization
processes were already observed by Kharasch in his
seminal work on bromine ATRA but requires heating
at ≥160 °C,[5] by Kraus and Landgrebe using
iodostannylester,[71] and by Curran with iodoesters and
iodomalonate derivatives.[7,10,72] This radical-ionic
sequence has also been reported for ethyl
iodoacetate[73–75] and iodoacetic acid[76] metal-
catalyzed ATRA processes.
2a (2 equiv)
DTBHN (20 mol%)
I
EtO2C
(a)
NTs
EtOAc, reflux, 30 min
NTs
16, 91%
1h
2a (2 equiv)
DTBHN (20 mol%)
O
(b)
O
EtOAc, reflux, 30 min
R
R
1i–k
17i (R = H), 79% (10 mmol scale)
17j (R = Ph), 76% (dr = 59:41)
17k (R = t-Bu), 81% (dr = 59:41)
Scheme 4. Iodine ATRA reaction leading to tertiary iodides
and lactones.
Scheme 3. Scope of the DTBHN initiated ATRA reactions.
All reactions were performed as described in Table 1.
Isolated yields are reported. [a] With 10 mol% DTBHN. [b]
Yield of major diastereoisomer; the two diastereoisomers
were easily separated by flash column chromatography, (see
SI for details). [c] 2 × 20 mol% DTBHN, 2 × 30 min reaction
time.
Radical cyclizations. In order to further showcase
this initiation method, the iodine atom transfer
cyclizations depicted in Scheme 5 were investigated.
Iodoacetate 18 could be converted in good yield to the
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001000
Advanced Synthesis & Catalysis
lactone 19 in agreement with light-ditin,[72] and DLP
procedures.[13] An intermolecular radical addition-
cyclization sequence with a perfluoroalkyl iodide 2s
was employed to convert 20 to the cyclopentane 21 in
94% yield (cis/trans ∼80:20). The observed
diastereoselectivity matches expectations for such a
radical process[77] and the yield compares well with
reported procedures[77–79] including the ones requiring
photoredox catalysis.[80–82]
The formation of acetone resulting from the
fragmentation of the intermediate tert-butoxyl radical
could also be observed at 1.61 ppm[83] in the 1H-NMR
spectrum of the reaction.
Initiation with di-tert-butyl peroxyoxalate. Since
DTBHN is prepared from expensive sodium trans-
hyponitirite (ca. 48 euros/g), a cheaper alternative was
sought. Di-tert-butylperoxyoxalate (DTBPO), easily
prepared from oxalyl chloride and tert-butyl
hydroperoxide, is well-known for low temperature
generation of tert-butoxyl radicals.[84,85] This
compound has been recently used in our group for
efficient
initiation
of
reactions
involving
organoborane precursors.[86,87] Its decomposition as
well as the initiation process is also expected to
provide exclusively gaseous (CO2) and volatile (MeI,
acetone) byproducts (Scheme 7, top). When used in
place of DTBHN for the iodine-ATRA reaction
between 2a and the unsaturated benzoate 1b, I-ATRA
product 22 was obtained in 70% yield (Scheme 7,
bottom) in full accordance with the DTBHN initiated
processes seen in Table 1 and Scheme 3.
Scheme 5. DTBHN initiated iodine atom transfer radical
cyclization (ATRC).
Mechanistic investigation. At the beginning of this
project, we hypothesized that the initiation with
DTBHN will involve the highly reactive methyl
radical. In order to get insight into the mechanism and
to confirm the involvement of methyl radicals, the
reaction was monitored by NMR. The reaction
between 2a and 1a was performed in a sealed tube with
C6D6 as a solvent. NMR analysis of an aliquot revealed
a 13C-NMR signal at –24.4 ppm corresponding to MeI
Scheme 7. DTBPO initiated iodine-ATRA reaction:
Another clean initiation procedure.
1
(see SI). In the H-NMR, a singlet at 1.51 ppm was
present. Upon addition of commercial MeI to the
reaction aliquot, a growth in intensity of the peak at
1.51 ppm was observed confirming the formation of
methyliodide.
Conclusion
A simple, mild and generally applicable procedure
for halogen ATRA and related reactions has been
developed. This procedure is suitable to run non-
catalyzed ATRA favored by thermodynamic and polar
effects and is not intended to run challenging ATRA
that require a catalyst involved in the reaction chain
process to overcome kinetically or thermodynamically
difficult steps.[22–28] The use of DTBHN (or DTBPO)
allows efficient initiation involving atom/group
transfer processes, mediated by methyl radicals, at
moderate temperature. The main advantage of this
approach is the absence of product contamination
caused by the initiation thus greatly facilitating
product purification. Indeed, the byproducts of
initiation are either gaseous (N2 or CO2) or volatile
(acetone, methyl iodide). Under these conditions,
efficient and clean radical chain reactions can occur
without the assistance of either toxic or expensive
metal additives. In contrast to photoinitiated processes,
thermal initiation with DTBHN is easily scalable as
demonstrated by running the reaction on 10 mmol
scale without the need to modify the reaction
conditions. Finally, we have shown that DTPBO
functions as a cheaper and otherwise entirely
equivalent alternative, although stricter safety
1
Scheme 6. Mechanism of the initiation process. H-NMR
evidence for the formation of MeI and acetone during the
reaction.
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001000
Advanced Synthesis & Catalysis
precautions are necessary. We believe that the
simplicity of this method will make it attractive for
application of ATRA reactions in a broad of organic
synthesis such as the synthesis of natural and
biologically active products, preparation of novel
material, and even construction of all kinds of
molecular devices. In all these types of applications,
purification is often a major problem for the delivery
of high-quality material.
[6] J. Byers, in Radicals in Organic Synthesis And (Eds.:
M.P. Sibi, P. Renaud), Wiley, 2008, pp. 72–89.
[7] D. P. Curran, in Free Radicals in Synthesis and
Biology (Ed.: F. Minisci), Springer, Dordrecht, 1989,
pp. 37–51.
[8] D. P. Curran, Synthesis 1988, 1988, 489–513.
[9] D. P. Curran, M. H. Chen, E. Spletzer, C. M. Seong,
C. T. Chang, J. Am. Chem. Soc. 1989, 111, 8872–
8878.
[10] D. P. Curran, C. M. Seong, J Am Chem Soc 1990, 112,
9401–9403.
[11] D. P. Curran, M. H. Chen, D. Kim, J. Am. Chem. Soc.
1989, 111, 6265–6276.
[12] E. Arceo, E. Montroni, P. Melchiorre, Angew. Chem.
Int. Edit. 2014, 53, 12064–12068.
[13] C. Ollivier, T. Bark, P. Renaud, Synthesis 2000, 2000,
1598–1602.
[14] B. B. Noble, P. Nesvadba, M. L. Coote, J. Org. Chem.
2020, 85, 2338–2346.
[15] B. Quiclet-Sire, S. Z. Zard, in Topics in Current
Chemistry. Radicals in Synthesis II (Ed.: A.
Gansäuer), Springer, Berlin, Heidelberg, 2006, pp.
201–236.
Experimental Section
Precautions: The preparation and manipulation of
DTBHN[42] and DTBPO[88] must be conducted behind a
blast shield. DTBHN has been reported to be insensitive to
scratching and is considered as handleable.[41] DTBPO is
sensitive to scratching and shock:[89] Ear defenders, face
shield, and thick leather gloves should be mandatory, in
addition to standard PPE, as well as restrictions in quantities.
Once in solution peroxides are safer: during this work no
explosions occurred. For more information on working with
peroxides consult the appropriate literature.[90]
See the SI for full experimental details. A representative
procedure is given below.
Preparation of 3a. Under air atmosphere (no inert gas
protection required), 1-undecene 1a (0.21 mL, 1.0 mmol),
ethyl 2-iodoacetate 2a (0.24 mL, 2.0 mmol), and EtOAc
(technical grade, 3.3 mL, 0.3 M) were loaded into a 10 mL,
1-neck, round bottom flask equipped with a cold finger.
DTBHN (35 mg, 20 mol%) was added in one portion to the
flask which was then plunged into a 90 °C pre-heated oil
bath. The reaction was heated under reflux for 30 min. After
concentration in vacuo, to the crude residue was purified by
flash column chromatography to afford 3a as a clear oil (306
mg, 0.831 mmol, 83%). Rf = 0.45 (8% EtOAc/heptanes). 1H
NMR (300 MHz, CDCl3): δ 4.14 (q, J = 7.1 Hz, 2H), 2.74 –
2.33 (m, 2H), 2.19 – 2.00 (m, 2H), 1.98 – 1.79 (m, 1H), 1.71
(ddt, J = 14.5, 10.2, 5.1 Hz, 1H), 1.55 – 1.46 (m, 1H), 1.46
– 1.36 (m, 1H), 1.36 – 1.20 (m, 15H), 0.91 – 0.85 (m, 3H).
13C NMR (75 MHz, CDCl3): δ 172.7 (Cq), 60.5 (CH2), 40.8
(CH2), 38.4 (CH), 35.5 (CH2), 34.4 (CH2), 31.9 (CH2), 29.52
(CH2), 29.48 (CH2), 29.45 (CH2), 29.3 (CH2), 28.8 (CH2),
[16] S. Z. Zard, Helv. Chim. Acta 2019, 102, e1900134.
[17] T. Nakamura, H. Yorimitsu, H. Shinokubo, K.
Oshima, Synlett 1998, 1998, 1351–1352.
[18] H. Yorimitsu, T. Nakamura, H. Shinokubo, K.
Oshima, J. Org. Chem. 1998, 63, 8604–8605.
[19] H. Yorimitsu, T. Nakamura, H. Shinokubo, K.
Oshima, K. Omoto, H. Fujimoto, J. Am. Chem. Soc.
2000, 122, 11041–11047.
[20] K. Nozaki, K. Oshima, K. Utimoto, Tetrahedron Lett.
1988, 29, 1041–1044.
[21] H. Yorimitsu, K. Oshima, in Radicals in Organic
Synthesis (Eds.: P. Renaud, M.P. Sibi), Wiley-VCH
Verlag GmbH, Weinheim, Germany, 2001, pp. 11–27.
[22] D. Bellus, Pure Appl. Chem. 1985, 57, 1827–1838.
[23] T. Pintauer, K. Matyjaszewski, Chem. Soc. Rev. 2008,
37, 1087–1097.
22.7 (CH2), 14.2 (CH3), 14.1 (CH3). IR (thin film): max
=
1733 (s) cm–1. Only the characteristic carbonyl stretch of the
acyclic ester is reported. HRMS (ESI): Calculated for
C15H30O2I [M+H]+: 369.1285. Found: 369.1284.
[24] T. Pintauer, Eur. J. Inorg. Chem. 2010, 2010, 2449–
2460.
Acknowledgements
[25] J. M. Muñoz-Molina, T. R. Belderrain, P. J. Pérez,
Eur. J. Inorg. Chem. 2011, 2011, 3155–3164.
[26] K. Severin, CHIMIA 2012, 66, 386–388.
[27] W. Pu, D. Sun, W. Fan, W. Pan, Q. Chai, X. Wang,
Y. Lv, Chem. Commun. 2019, 55, 4821–4824.
[28] W. T. Eckenhoff, T. Pintauer, Dalton Trans. 2011, 40,
4909–4917.
We thank the Swiss National Science Foundation (grant
200020_172621) for financial support. We thank the group of
Chemical Crystallography of the University of Bern (Dr. Simon
Grabowsky and Dr. Michal Andrzejewski) for solving the X-ray
crystal structure.
[29] T. Chatterjee, N. Iqbal, Y. You, E. J. Cho, Acc. Chem.
Res. 2016, 49, 2284–2294.
References
[30] J. D. Nguyen, J. W. Tucker, M. D. Konieczynska, C.
R. J. Stephenson, J. Am. Chem. Soc. 2011, 133, 4160–
4163.
[31] C.-J. Wallentin, J. D. Nguyen, P. Finkbeiner, C. R. J.
Stephenson, J. Am. Chem. Soc. 2012, 134, 8875–8884.
[32] S. Paria, M. Pirtsch, V. Kais, O. Reiser, Synthesis
2013, 45, 2689–2698.
[1] M. S. Kharasch, E. V. Jensen, W. H. Urry, Science
1945, 102, 128–128.
[2] M. S. Kharasch, W. H. Urry, E. V. Jensen, J. Am.
Chem. Soc. 1945, 67, 1626–1626.
[3] M. S. Kharasch, E. V. Jensen, W. H. Urry, J. Am.
Chem. Soc. 1946, 68, 154–155.
[4] M. S. Kharasch, O. Reinmuth, W. H. Urry, J. Am.
Chem. Soc. 1947, 69, 1105–1110.
[33] M. A. Cismesia, T. P. Yoon, Chem. Sci. 2015, 6,
5426–5434.
[5] M. S. Kharasch, P. S. Skell, P. Fisher, J. Am. Chem.
Soc. 1948, 70, 1055–1059.
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001000
Advanced Synthesis & Catalysis
[34] P. Riente, M. A. Pericàs, ChemSusChem 2015, 8,
1841–1844.
[62] Z. Liu, L. Qin, S. Z. Zard, Org. Lett. 2012, 14, 5976–
5979.
[35] T. Courant, G. Masson, J. Org. Chem. 2016, 81,
6945–6952.
[63] Y. Gonen, L. A. Rajbenbach, A. Horowitz, Int. J.
Chem. Kin. 1977, 9, 361–369.
[36] G. Magagnano, A. Gualandi, M. Marchini, L.
Mengozzi, P. Ceroni, P. G. Cozzi, Chem. Commun.
2017, 53, 1591–1594.
[37] L.-L. Mao, H. Cong, ChemSusChem 2017, 10, 4461–
4464.
[38] J. K. Kochi, J. Am. Chem. Soc. 1962, 84, 1193–1197.
[39] T. V. RajanBabu, N. S. Simpkins, T. V. RajanBabu,
Encyclopedia of Reagents for Organic Synthesis 2005,
DOI: 10.1002/047084289X.rd066.pub2.
[40] J. Lalevée, J. P. Fouassier, Encyclopedia of Radicals
in Chemistry, Biology and Materials 2012, DOI:
10.1002/9780470971253.rad003.
[64] F. Barbier, F. Pautrat, B. Quiclet-Sire, S. Z. Zard,
Synlett 2002, 2002, 811–813.
[65] M. Lusinchi, T. V. Stanbury, S. Z. Zard, Chem.
Commun. 2002, 1532–1533.
[66] L. Anthore-Dalion, Q. Liu, S. Z. Zard, J. Am. Chem.
Soc. 2016, 138, 8404–8407.
[67] J. Maury, L. Feray, M. P. Bertrand, A. Kapat, P.
Renaud, Tetrahedron 2012, 68, 9606–9611.
[68] V. Soulard, G. Villa, D. P. Vollmar, P. Renaud, J. Am.
Chem. Soc. 2018, 140, 155–158.
[69] D. Meyer, E. Vin, B. Wyler, G. Lapointe, P. Renaud,
Synlett 2015, 27, 745–748.
[41] H. Kiefer, T. G. Traylor, Tetrahedron Lett. 1966, 7,
6163–6168.
[70] Y.-X. Ji, L.-J. Wang, W.-S. Guo, Q. Bi, B. Zhang, Adv.
Synth. Catal. 2020, 362, 1131–1137.
[42] J. Boukouvalas, S. Cren, P. Renaud, Encyclopedia of
Reagents for Organic Synthesis 2007, DOI:
10.1002/047084289X.rd062.pub2.
[43] Y. P. Tsentalovich, L. V. Kulik, N. P. Gritsan, A. V.
Yurkovskaya, J. Phys. Chem. A 1998, 102, 7975–
7980.
[71] G. A. Kraus, K. Landgrebe, Tetrahedron Lett. 1984,
25, 3939–3942.
[72] D. P. Curran, C. T. Chang, J. Org. Chem. 1989, 54,
3140–3157.
[73] J. O. Metzger, R. Mahler, Angew. Chem. Int. Ed. Engl.
1995, 34, 902–904.
[44] T. Nakamura, W. K. Busfield, I. D. Jenkins, E.
Rizzardo, S. H. Thang, S. Suyama, J. Org. Chem.
2000, 65, 16–23.
[45] R. Meier, D. Trauner, Angew. Chem. Int. Ed. 2016, 55,
11251–11255.
[46] B. S. Matsuura, P. Kölle, D. Trauner, R. de Vivie-
Riedle, R. Meier, ACS Cent. Sci. 2017, 3, 39–46.
[47] S. S. Zlotskii, Izv. Vyssh. Uchebn. Zaved., Khim.
Khim. Tekhnol. 2010, 53, 123–125.
[48] D. P. Curran, E. Bosch, J. Kaplan, M. Newcomb, J.
Org. Chem. 1989, 54, 1826–1831.
[74] M. Iwasaki, N. Miki, Y. Ikemoto, Y. Ura, Y.
Nishihara, Org. Lett. 2018, 20, 3848–3852.
[75] J. O. Metzger, R. Mahler, G. Francke, Liebigs Ann.
1997, 1997, 2303–2313.
[76] I. Triandafillidi, M. G. Kokotou, C. G. Kokotos, Org.
Lett. 2018, 20, 36–39.
[77] W.-Y. Huang, G. Zhao, Y. Ding, J. Chem. Soc.,
Perkin Trans. 1 1995, 1729–1731.
[78] N. O. Brace, J. Org. Chem. 1969, 34, 2441–2445.
[79] G. Zhao, J. Yang, W. Huang, J. Fluor. Chem. 1997,
86, 89–97.
[49] H. Yorimitsu, H. Shinokubo, S. Matsubara, K.
Oshima, K. Omoto, H. Fujimoto, J. Org. Chem. 2001,
66, 7776–7785.
[50] N. D. C. Tappin, W. Michalska, S. Rohrbach, P.
Renaud, Angew. Chem. Int. Ed. 2019, 58, 14240–
14244.
[51] M. Masnyk, Tetrahedron Lett. 1991, 32, 3259–3262.
[52] Millius, Lapointe, Renaud, Molecules 2019, 24, 4184.
[53] G. Povie, S. R. Suravarapu, M. P. Bircher, M. M.
Mojzes, S. Rieder, P. Renaud, Science Adv. 2018, 4,
eaat6031.
[80] L.-L. Mao, H. Cong, ChemSusChem 2017, 10, 4461–
4464.
[81] T. Rawner, E. Lutsker, C. A. Kaiser, O. Reiser, ACS
Catal. 2018, 8, 3950–3956.
[82] L. Helmecke, M. Spittler, K. Baumgarten, C.
Czekelius, Org. Lett. 2019, 21, 7823–7827.
[83] G. R. Fulmer, A. J. M. Miller, N. H. Sherden, H. E.
Gottlieb, A. Nudelman, B. M. Stoltz, J. E. Bercaw, K.
I. Goldberg, Organometallics 2010, 29, 2176–2179.
[84] P. D. Bartlett, E. P. Benzing, R. E. Pincock, J. Am.
Chem. Soc. 1960, 82, 1762–1768.
[54] M. Pirtsch, S. Paria, T. Matsuno, H. Isobe, O. Reiser,
Chem. Eur. J. 2012, 18, 7336–7340.
[55] S. Engl, O. Reiser, Eur. J. Org. Chem. 2020, 2020,
1523–1533.
[56] L. R. Ryzhkov, J. Org. Chem. 1996, 61, 2801–2808.
[57] A. Fraind, R. Turncliff, T. Fox, J. Sodano, L. R.
Ryzhkov, J. Phys. Org. Chem. 2011, n/a-n/a.
[58] M. Feldhues, H. J. Schäfer, Tetrahedron 1986, 42,
1285–1290.
[59] C. H. Cho, S. Kim, Can. J. Chem. 2005, 83, 917–921.
[60] E. Baciocchi, E. Muraglia, Tetrahedron Lett. 1994, 35,
2763–2766.
[85] D. Abdallah, M. A. A. Ghani, M. F. Cunningham, P.
M. Kazmaier, B. Keoshkerian, E. Buncel, Can. J.
Chem. 2004, 82, 1393–1402.
[86] L. Gnägi, S. V. Martz, D. Meyer, R. M. Schärer, P.
Renaud, Chem. Eur. J. 2019, 25, 11646–11649.
[87] D. Meyer, H. Jangra, F. Walther, H. Zipse, P. Renaud,
Nat. Commun. 2018, 9, 4888.
[88] J. Boukouvalas, J. M. Tanko, Encyclopedia of
Reagents for Organic Synthesis 2007, DOI:
10.1002/047084289X.rd067.pub2.
[89] J. L. Courtneidge, M. Bush, J. Chem. Soc., Perkin
Trans. 1 1992, 1531–1538.
[61] D. P. Curran, A. A. Martin-Esker, S. B. Ko, M.
Newcomb, J. Org. Chem. 1993, 58, 4691–4695.
[90] D. Swern, Ed. , Organic Peroxides, Wiley, New York,
1970.
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001000
Advanced Synthesis & Catalysis
UPDATE
X
DTBHN
Methyl Radical Initiated Kharasch and Related
Reactions
+
X
R
EWG
EWG
R
X = I, Br, SePh, SC(S)OEt
Adv. Synth. Catal. Year, Volume, Page – Page
Ot-Bu
Me
Me
Me
Δ
N N
t-BuO
DTBHN
Nicholas D. C. Tappin, and Philippe Renaud*
O
N2
acetone
EWG
MeX
X
Me•
EWG
enters the
radical chain
volatile
byproducts
8
This article is protected by copyright. All rights reserved.