Radical hydroxymethylation of alkyl iodides using formaldehyde as a C1 synthon

Article abstract of DOI:10.1039/d1sc03083c

Radical hydroxymethylation using formaldehyde as a C1 synthon is challenging due to the reversible and endothermic nature of the addition process. Here we report a strategy that couples alkyl iodide building blocks with formaldehyde through the use of photocatalysis and a phosphine additive. Halogen-atom transfer (XAT) from α-aminoalkyl radicals is leveraged to convert the iodide into the corresponding open-shell species, while its following addition to formaldehyde is rendered irreversible by trapping the transient O-radical with PPh₃. This event delivers a phosphoranyl radical that re-generates the alkyl radical and provides the hydroxymethylated product.

Full text of DOI:10.1039/d1sc03083c

Chemical
Science
View Article Online
View Journal | View Issue
EDGE ARTICLE
Radical hydroxymethylation of alkyl iodides using
formaldehyde as a C1 synthon†
Cite this: Chem. Sci., 2021, 12, 10448
a
a
a
James J. Douglas,b
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Lewis Caiger,
Conar Sinton,
Timothee Constantin,
´
and Daniele Leonori
Nadeem S. Sheikh,c Fabio Julia
a
a
*
´
Radical hydroxymethylation using formaldehyde as a C1 synthon is challenging due to the reversible and
endothermic nature of the addition process. Here we report a strategy that couples alkyl iodide building
blocks with formaldehyde through the use of photocatalysis and a phosphine additive. Halogen-atom
transfer (XAT) from a-aminoalkyl radicals is leveraged to convert the iodide into the corresponding
open-shell species, while its following addition to formaldehyde is rendered irreversible by trapping the
transient O-radical with PPh3. This event delivers a phosphoranyl radical that re-generates the alkyl
radical and provides the hydroxymethylated product.
Received 7th June 2021
Accepted 6th July 2021
DOI: 10.1039/d1sc03083c
rsc.li/chemical-science
thus requires a subsequent stoichiometric hydride reduction
step (Scheme 1B, path b).9
Introduction
The difficulties in using formaldehyde as a C1 synthon for
radical hydroxymethylation (Scheme 1B, path c) come from the
reversible nature of the addition process.9a,10 According to our
computational studies, the reaction between cyclohexyl radicals
and HCHO (B) is kinetically accelerated compared to the reac-
tion with CO (A) but, crucially, endothermic with a later tran-
sition state character (as determined by comparison of the
respective d(C–C) values) (Scheme 1C).11 This means that the
back reaction, involving b-scission of the primary O-radical C, is
a fast process which hampers reaction development. Overall,
this mechanistic challenge has impacted the practical ways we
conduct hydroxymethylation with HCHO, which is generally
achieved using Grignard or organolithium reagents that might
limit functional group compatibility (Scheme 1B, path d).12
We have recently demonstrated that alkyl radicals can be
conveniently accessed from the corresponding halides using
halogen-atom transfer (XAT) with a-aminoalkyl radicals
(Scheme 1D).13 These open-shell species can be generated from
the corresponding amines by SET (single-electron transfer)
oxidation14 and deprotonation15 and display an abstracting
prole similar to that of tin radicals in the homolytic activation
of organic halides. This reactivity mode benets from a polar-
ised transition state13,16 with signicant charge-transfer char-
acter and can be used in redox-neutral photoredox manifolds
and also as an initiation mechanism in transformation based
on radical-chain propagations.13b
Hydroxymethyl motifs are frequently encountered in the core
structure of natural products and drugs and commonly used as
handles for further derivatisation (Scheme 1A).1 This structural
and practical relevance makes the development of methods able
to introduce the “CH2OH” fragment onto advanced building
blocks impactful to the discovery and development of high-
value materials.2
Retrosynthetically, the most direct approach to achieve
programmable small-molecule hydroxymethylation is through
the formation of a sp3–sp3 C–C bond with an oxygenated C1
synthon.3 Within the realm of radical chemistry, a-hydrox-
ymethyl radicals, which are easily generated from MeOH via
HAT (H-atom transfer), have been successfully applied to the
functionalisation of Giese4 and Minisci5 acceptors (Scheme 1B,
path a). A signicantly less explored avenue is the development
of methodologies where C-radicals react with C1 SOMOphiles.6
Considering the three most atom-economic and abundant
oxygenated C1 synthons – CO2, CO and HCHO – CO is the
most used in radical strategies. Indeed, while radical
addition to CO2 is endothermic,7 reaction with CO is both
kinetically and thermodynamically facile and, as demonstrated
by the pioneering work of Ryu, also compatible for application
in radical chain propagations.8 This approach however,
provides the aldehyde as the product of the radical process and
aDepartment of Chemistry, University of Manchester, Manchester M13 9PL, UK.
E-mail: daniele.leonori@manchester.ac.uk; Web: https://leonorigroup.com
bEarly Chemical Development, Pharmaceuticals Sciences, R&D, AstraZeneca,
Maccleseld, UK
We recently became interested in benchmarking XAT reac-
tivity with the aim of enabling radical couplings between alkyl
halides and HCHO. Here we demonstrate the realisation of this
goal and report the development of a practical approach for
direct radical hydroxymethylation (Scheme 1E). The process
sequentially exploits XAT to generate an alkyl radical and then
cDepartment of Chemistry, College of Science, King Faisal University, P. O. Box 400, Al-
Ahsa 31982, Saudi Arabia
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1sc03083c
10448 | Chem. Sci., 2021, 12, 10448–10454
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Edge Article
Chemical Science
Scheme 1 (A) Examples of natural products and therapeutic agents containing the hydroxymethyl motif. (B) Overview of the main methods to
install a hydroxymethyl motif using radical chemistry. (C) Radical addition to CO is possible while addition to HCHO is difficult due to reversibility.
(D) a-Aminoalkyl radicals enable XAT activation of alkyl iodides and bromides and the corresponding carbon radicals can be engaged in several
transformations. (E) This work shows the utilisation of XAT and phosphoranyl radical chemistry for the direct coupling of unactivated alkyl iodides
with HCHO.
harnesses the ability of PPh3 to trap the resulting O-radical. This transfer) with the amine D. Since O-radicals undergo related
approach effectively renders the radical addition to HCHO an HAT reactions at fast rates (ꢀ108 Mꢁ1 sꢁ1
)
and the amine
17
irreversible process. Crucially, the ensuing phosphoranyl would be used in excess, this step should provide 2 whilst
radical is able to sustain a radical chain propagation based on regenerating the chain-carrying a-aminoalkyl radical E.
XAT to give the hydroxymethylated product.
We started our investigations using 1 as the iodide, 4CzIPN
as the photocatalyst and paraformaldehyde in CH3CN–H2O
(10 : 1) solvent under blue light irradiation at room temperature
(Scheme 2B). Pleasingly, using Et3N as the amine, alcohol 2 was
formed in moderate yield which was improved by using i-Pr2NEt
(entries 1 and 2). In accordance with our mechanistic picture,
evaluation of amines that can act as efficient electron donors for
*4CzIPN but cannot lead to the formation of an a-aminoalkyl
radical (by either oxidation and deprotonation or HAT) led to no
product formation [compare entries 3 (TMP ¼ tetramethylpi-
peridine) and 4 (Ph3N) with 2 (i-Pr2NEt)]. Unfortunately, evalu-
ation of the other reaction parameters11 did not further improve
the efficiency of the process which likely underscores the chal-
lenges in overcoming the reversibility of the radical addition
process (F + HCHO $ H).
Results and discussion
Mechanistic considerations and reaction optimization
In approaching the development of
a radical hydrox-
ymethylation reaction using HCHO as a C1 synthon, we initially
considered the utilisation of a reductive quenching photoredox
cycle (Scheme 2A). In principle, this manifold would enable the
generation of the key a-aminoalkyl radical (D / E) for XAT with
the alkyl iodide (e.g. 4-iodo-N-Boc-piperidine 1). According to
our previous work, this step should be facile and provide radical
F along with the iminium iodide G. Addition of F to HCHO is
reversible making a potential SET reduction (followed by
protonation) of the O-radical H with the reduced photocatalyst
challenging. However, our interest was drawn by the fact that
this mechanism could potentially benet from radical-chain
reactivity where H undergoes polarity matched HAT (H-atom
We therefore proposed to overcome the unwanted b-frag-
mentation by trapping the transient O-radical H with an
immediate reaction. Specically, we were interested by the well-
© 2021 The Author(s). Published by the Royal Society of Chemistry
Chem. Sci., 2021, 12, 10448–10454 | 10449

View Article Online
Chemical Science
Edge Article
Scheme 2 (A) Mechanistic proposal for the coupling of alkyl iodides with HCHO using XAT and phosphoranyl radical chemistry. (B) Optimisation
of the radical coupling between iodide 1 and HCHO. (C) Literature rate constants for the reaction of O-radical with P(III) compounds to give
phosphoranyl radicals. (D) Experimental and calculated properties of phosphoranyl radicals suggest XAT as the alkyl iodide activation mechanism.
(E) “Reductant-free” reaction for hydroxymethylation of alkyl iodides via phosphoranyl radicals.
known ability of phosphines to trap O-radicals at diffusion- halides has not been reported before,21 we speculated that their
controlled rates leading to the corresponding phosphoranyl high nucleophilic character22 should lead to polar effects related
radicals (Scheme 2C).18 These open-shell intermediates can still to those demonstrated in abstraction reactions with tin, silicon
undergo b-scission across the sp3 C–O bond but the feasibility and a-aminoalkyl radicals.13a
of this process depends on the nature of the ensuing C-radical,
This mechanistic proposal was validated by the addition of
and it is only efficient when tertiary or stabilised (e.g. benzylic) PPh3 to the reaction mixture, which immediately led to
species are generated.19 In our case this fragmentation would a dramatic increase in the process yield (Scheme 2B, entry 6).
lead to a primary alkyl radical, so we were hopeful that J would Further improvements were made by using formalin in place of
be long-lived enough to participate in a following reaction. In paraformaldehyde and increasing the equivalents of both i-
particular, we anticipated that J might be able to abstract an I- Pr2NEt and PPh3. Under the conditions reported in entry 7, 2
atom from 1 and therefore establish a phosphoranyl radical- was obtained in 86% yield. Other triaryl/trialkyl phosphines
based chain propagating system. This step would give the P(V) were evaluated and were also successful albeit in lower yield
intermediate K (ref. 20) that could provide the targeted 2 upon (entries 9–12). Phosphites and triaryl boranes are also known to
hydrolysis. While XAT between phosphoranyl radicals and alkyl efficiently trap O-radicals18 and were evaluated. While P(OEt)3
10450 | Chem. Sci., 2021, 12, 10448–10454
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Edge Article
Chemical Science
resulted in signicantly lower yield (entry 12) and BPh3 transformation. Nevertheless, we believe the strong nucleo-
completely suppressed the reactivity (entry 13), P(OPh)3 gave 2 philic character of phosphoranyl radical [determined by calcu-
in 74% yield (entry 14).23 Finally, control experiments demon- lating the ionization potential (IP) and electrophilicity index
strated the reaction required all components as well as (urc+) for L] should provide effective charge-transfer stabilisa-
continuous blue LEDs irradiation.11
tion in a XAT transition state, just like the chain initiating a-
A photoredox initiation based on a reductive quenching cycle aminoalkyl radicals. Furthermore, its intermediate reductive
is supported by our Stern–Volmer studies whereby the amine power (determined by measuring the reduction potential of the
quenches *4CzIPN uorescence with the largest rate constant.11 phosphonium salt Ph3(MeO)P(OTf) to give M) supports a reac-
Obtaining evidence on the XAT reactivity of the phosphoranyl tion with alkyl iodide 1 (Ered ¼ ꢁ2.09 V vs. SCE) based on XAT
radical J has been more difficult since, despite considerable over SET (Scheme 2D).11 In addition, we have been able to
efforts, we have not be able to locate a transition state for this translate this reactivity under “reductant-free” conditions. As
Scheme 3 (A) Alkyl iodide scope. (B) Application of the hydroxymethylation strategy in the 1C homologation of high-value alcohols via Appel
iodination followed by radical coupling with HCHO. (C) Difficulties in extending the hydroxymethylation reactivity to unactivated alkyl bromide
30. rsm is remaining starting material.
© 2021 The Author(s). Published by the Royal Society of Chemistry
Chem. Sci., 2021, 12, 10448–10454 | 10451

View Article Online
Chemical Science
Edge Article
shown in Scheme 2E we have used the photochemical O–O and identied by mass spectrometry analysis several by-
bond homolysis of (t-BuO)2 to generate a t-BuO-containing products resulting from the hydroxymethylation of the amine
phosphoranyl radical from which XAT from 1 and a subse- reagent. We believe that in these cases where XAT is slower, the
quent reaction with HCHO enables formation of 2 (30% yield).11 nucleophilic a-aminoalkyl radical E can be trapped by HCHO
Overall, we believe this reaction provides supporting evidence leading to O-radical N. This species can either react with PPh3,
for the ability of phosphoranyl radicals to abstract iodine atoms or, in the case of linear trialkyl amines (e.g. Et3N), undergo
from alkyl residues.
intramolecular and polarity matched HAT from the other a-N-
positions (O). This radical translocation process ultimately
leads to the accumulation of polar poly-hydroxymethylated
derivatives (P).11
Substrate scope
Having identied optimal conditions for the radical coupling
between alkyl iodides and formaldehyde, we evaluated the
scope of the process. A series of commercial iodides based on
valuable N-heterocyclic systems provided access to C3-
functionalised N-Boc-piperidine (3), -azepane (4), -pyrrolidine
(5) and -proline (6) in generally high yields. The chemistry was
also translated to I-containing N-Boc-azetidine and 4-iodo-
(thio)pyran to give alcohols 7–10. Alcohol 9 Represents an
example of a chemoselective XAT process as aryl bromides are
more difficult to activate using a-aminoalkyl radicals, allowing
selective targeting of the sp3 C–I bond. The successful forma-
tion of 11 in good yield demonstrates compatibility with
carbonyl functionalities that might be problematic when using
reactive organometallic intermediates. The chemistry was then
applied to the hydroxymethylation of unactivated 4-Ph-
cyclohexyl iodide (12) and also used on 2- and 1-iodo-
adamantane (13 and 14), thus demonstrating compatibility
with tertiary substrates.
Hydroxymethylation of other alkyl radical precursors
Since phosphoranyl radicals are relatively good reductants
(Eox ¼ ꢁ1.63 V vs. SCE, see Scheme 2D), we wondered if this
strategy could be extended to the hydroxymethylation of other
alkyl radical precursors based on electrophores easier to reduce
than alkyl iodides. We were particularly interested by the use of
Katritzky's pyridinium salts24 and imidazole thiocarbonyls25 as
these species would enable the overall hydroxymethylation of
amines and alcohols. As shown in Scheme 4, we succeeded in
engaging pyridinium 31 (Ered ¼ ꢁ0.94 V vs. SCE) in this reac-
tivity using either photoredox or EDA (electron donor–
acceptor)26 conditions. In the rst case an oxidative quenching
photoredox cycle using Ir(ppy)3 photocatalyst was used as the
initiation mechanism for alkyl radical F generation. In the latter
We also succeeded in employing this chemistry on iodinated
N-Boc-protected cyclohexylamine (15) and cyclobutylamine (16)
as well as two commercial spirocyclic building blocks (17 and
18) and a bicyclic derivative (19) in high yield.
To showcase the applicability of this methodology we
sought to use it to achieve the one-carbon homologation of
high-value alcohols using Appel iodination followed by XAT–
phosphoranyl radical-mediated hydroxymethylation. As
shown in Scheme 3B, the commercial N-heterocycle 20 gave 21
which can lead to the preparation of analogues of the kidney
cancer treatment drug tesevatinib. Piperidine 22 provided 23,
which is a synthetic intermediate in the manufacture of the
orexin antagonist lorexant. The blockbuster cardiac stimu-
lant proxyphylline 24 could also be engaged thus broadening
the functional group compatibility and providing access to the
1C-homologated drug analogue 25 in useful yield. Further-
more, subjecting the N-Boc protected alkaloid nortropine 26
and cholesterol 28 to this two-step sequence gave the 1C-
homologation products 27 and 29.
While a-aminoalkyl radicals can be successfully used for the
homolytic activation of both alkyl iodides and bromides,13a this
hydroxymethylation strategy is at the moment synthetically
useful only for the iodides. In the case of the bromides, as XAT
is slower (kXAT < 105 Mꢁ1 sꢁ1 for Cy–Br and the Et3N a-amino-
alkyl radical),13a other unwanted reactivities become competi-
tive which may hamper product formation. Indeed, when we
attempted the reaction with 4-bromo-N-Boc-piperidine 30 using
various combinations of photocatalysts, amines and oxidants,
Scheme
4 Mechanistic analysis and reaction conditions for the
we obtained 2 in up to 30% yield, recovered 30 in >60% yield hydroxymethylation of Katritzky's pyridinium 31 and xanthate 33.
10452 | Chem. Sci., 2021, 12, 10448–10454
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Edge Article
Chemical Science
case, the supramolecular association of 31 and 4-Me-Hantzsch
ester (4-Me-HE) generated an EDA complex26 32 that under-
went photoinduced SET upon irradiation of its charge-transfer
band with blue light.
Extension of this chemistry to thiocarbamate 33 proved more
challenging due to the tendency of these species to undergo
radical O / S rearrangement.27 Nevertheless, optimisation of
the reaction parameters led to conditions for its implementa-
tion in useful yield using oxidative quenching of the photo-
catalyst Ir(ppy)3 as the initiation step.
Notes and references
1 (a) R. Richa and R. P. Sinha, EXCLI J., 2014, 13, 592–610; (b)
M. C. White and J. Zhao, J. Am. Chem. Soc., 2018, 140, 13988–
14009; (c) S. D. Roughley and A. M. Jordan, J. Med. Chem.,
2011, 54, 3451–3479; (d) D. G. Brown and J. Bostrom, J.
Med. Chem., 2016, 59, 4443–4458.
2 D. C. Blakemore, L. Castro, I. Churcher, D. C. Rees,
A. W. Thomas, D. M. Wilson and A. Wood, Nat. Chem.,
2018, 10, 383–394.
¨
In all three cases, we believe that upon alkyl radical F
generation, reversible reaction with HCHO and fast trapping of
H with PPh3, leads to phosphoranyl radical J that could sustain
a chain propagation based on SET (instead of XAT) as the alkyl
radical re-generation step. The feasibility of this step is sup-
ported by the matching redox potentials for SET between M (see
Scheme 2D) and those of 31 and 33.
3 (a) I. Ryu, N. Sonoda and D. P. Curran, Chem. Rev., 1996, 96,
177–194; (b) G. Yuan, C. Qi, W. Wu and H. Jiang, Current
Opinion in Green and Sustainable Chemistry, 2017, 3, 22–27;
(c) Y. Shi, B.-W. Pan, Y. Zhou, J. Zhou, Y.-L. Liu and
F. Zhou, Org. Biomol. Chem., 2020, 18, 8597–8619; (d)
T. E. Hurst, J. A. Deichert, L. Kapeniak, R. Lee, J. Harris,
P. G. Jessop and V. Snieckus, Org. Lett., 2019, 21, 3882–3885.
4 B. Fraser-Reid, N. L. Holder and M. B. Yunker, J. Chem. Soc.,
Chem. Commun., 1972, 1286–1287.
5 (a) A. Citterio, A. Gentile, F. Minisci, M. Serravalle and
S. Ventura, Tetrahedron, 1985, 41, 617–620; (b) C. A. Huff,
R. D. Cohen, K. D. Dykstra, E. Streckfuss, D. A. DiRocco
and S. W. Krska, J. Org. Chem., 2016, 81, 6980–6987; (c)
Conclusions
We have demonstrated that the unfavorable addition of carbon
radicals to HCHO can be overcome by trapping the resulting O-
radical with Ph3P in a fast and irreversible reaction. This leads
to the generation of a phosphoranyl radical that can sustain
chain propagations based on either XAT or SET. This provides
versatility to the hydroxymethylation protocol that can be
applied to alkyl iodides and Katritzky's salts in high yield and
also thiocarbamates.
´
F. Rammal, D. Gao, S. Boujnah, A. A. Hussein, J. Lalevee,
A.-C. Gaumont, F. Morlet-Savary and S. Lakhdar, ACS
Catal., 2020, 10, 13710–13717.
6 (a) S. Kim, I. Y. Lee, J.-Y. Yoon and D. H. Oh, J. Am. Chem.
Soc., 1996, 118, 5138–5139; (b) S. Kim and S. Y. Jon,
Tetrahedron Lett., 1998, 39, 7317–7320; (c) M. Shee,
S. S. Shah and N. D. P. Singh, Chem. Commun., 2020, 56,
4240–4243; (d) D. J. Hart and F. L. Seely, J. Am. Chem. Soc.,
1988, 110, 1631–1633; (e) H. Miyabe, R. Shibata, C. Ushiro
and T. Naito, Tetrahedron Lett., 1998, 39, 631–634.
7 Z. Fan, Z. Zhang and C. Xi, ChemSusChem, 2020, 13, 6201–
6218.
Data availability
The data that support the ndings of this study are available in
the ESI and from the corresponding author upon reasonable
request.
8 (a) I. Ryu, K. Kusano, A. Ogawa, N. Kambe and N. Sonoda, J.
Am. Chem. Soc., 1990, 112, 1295–1297; (b) I. Ryu, K. Kusano,
H. Yamazaki and N. Sonoda, J. Org. Chem., 1991, 56, 5003–
5005.
Author contributions
FJ and DL designed the project. LC, CS, TC and FJ performed all
the synthetic experiments. JJD performed some mechanistic
experiments. NSS performed the computational studies. All
authors analysed the results and wrote the manuscript.
9 (a) V. Gupta and D. Kahne, Tetrahedron Lett., 1993, 34, 591–
594; (b) H. Matsubara, S. Yasuda, H. Sugiyama, I. Ryu, Y. Fujii
and K. Kita, Tetrahedron, 2002, 58, 4071–4076; (c)
S. Kobayashi, T. Kawamoto, S. Uehara, T. Fukuyama and
I. Ryu, Org. Lett., 2010, 12, 1548–1551; (d) S. Kobayashi,
T. Kinoshita, T. Kawamoto, M. Wada, H. Kuroda,
A. Masuyama and I. Ryu, J. Org. Chem., 2011, 76, 7096–
7103; (e) T. Kawamoto, T. Fukuyama and I. Ryu, J. Am.
Chem. Soc., 2012, 134, 875–877; (f) T. Kawamoto, T. Okada,
D. P. Curran and I. Ryu, Org. Lett., 2013, 15, 2144–2147.
10 M. Oyama, J. Org. Chem., 1965, 30, 2429–2432.
11 See ESI† for more information.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
DL thanks EPSRC for a Fellowship (EP/P004997/1), and the
European Research Council for a research grant (758427). LC
thanks the Integrated Catalysis (iCAT) CDT (EPSRC grant: EP/
S023755/1) for a PhD Studentship. CS thanks AstraZeneca for
a PhD Studentship. NSS acknowledges the Deanship of Scien-
tic Research at the King Faisal University for the nancial
support under the annual research grants.
12 C. Bernardon, J. Organomet. Chem., 1989, 367, 11–17.
´
13 (a) T. Constantin, M. Zanini, A. Regni, N. S. Sheikh, F. Julia
and D. Leonori, Science, 2020, 367, 1021–1026; (b)
´
T. Constantin, F. Julia, N. S. Sheikh and D. Leonori, Chem.
Sci., 2020, 11, 12822–12828, for a Cu/peroxide mediated
© 2021 The Author(s). Published by the Royal Society of Chemistry
Chem. Sci., 2021, 12, 10448–10454 | 10453

View Article Online
Chemical Science
Edge Article
approach for a-aminoalkyl radical generation and XAT on 20 Intermediate K has been depicted as an iodophosphorane
activated alkyl halides, see; (c) R. K. Neff, Y.-L. Su, S. Liu,
M. Rosado, X. Zhang and M. P. Doyle, J. Am. Chem. Soc.,
2019, 141, 16643–16650.
but it could also exist as the corresponding phosphonium
iodide.
21 For mechanistic studies on XAT with diethoxyphosphonyl
radicals, see:(a) M. Anpo, R. Sutcliffe and K. U. Ingold, J.
Am. Chem. Soc., 1983, 105, 3580–3583; (b) S. Kim,
C. H. Cho and C. J. Lim, J. Am. Chem. Soc., 2003, 125,
9574–9575.
14 P. J. DeLaive, T. K. Foreman, C. Giannotti and D. G. Whitten,
J. Am. Chem. Soc., 1980, 102, 5627–5631.
15 (a) S. F. Nelsen and J. T. Ippoliti, J. Am. Chem. Soc., 1986, 108,
4879–4881; (b) J. P. Dinnocenzo and T. E. Banach, J. Am.
Chem. Soc., 1989, 111, 8646–8653.
22 W. G. Bentrude, Acc. Chem. Res., 1982, 15, 117–125.
´
16 J. Lalevee, X. Allonas and J. P. Fouassier, Chem. Phys. Lett., 23 The lower yield observed in the case of P(OEt)3 with respect
2008, 454, 415–418.
to P(OPh)3 might be due a b-fragmentation of the
17 D. Griller, J. A. Howard, P. R. Marriott and J. C. Scaiano, J.
Am. Chem. Soc., 1981, 103, 619–623.
18 (a) D. Griller, K. U. Ingold, L. K. Patterson, J. C. Scaiano and
corresponding phosphoranyl radical.
24 A. R. Katritzky and S. S. Thind, J. Chem. Soc., Perkin Trans. 1,
1980, 1895–1900.
R. D. Small, J. Am. Chem. Soc., 1979, 101, 3780–3785; (b) 25 D. H. R. Barton and S. W. McCombie, J. Chem. Soc., Perkin
´
A. Inial, F. Morlet-Savary, J. Lalevee, A.-C. Gaumont and
Trans. 1, 1975, 1574–1585.
S. Lakhdar, Org. Lett., 2020, 22, 4404–4407.
26 C. G. S. Lima, T. de M. Lima, M. Duarte, I. D. Jurberg and
˜
M. W. Paixao, ACS Catal., 2016, 6, 1389–1407.
19 (a) W. G. Bentrude, E. R. Hansen, W. A. Khan and
P. E. Rogers, J. Am. Chem. Soc., 1972, 94, 2867–2868; (b) 27 L. Chenneberg, A. Baralle, M. Daniel, L. Fensterbank,
M. Bietti, A. Calcagni and M. Salamone, J. Org. Chem.,
2010, 75, 4514–4520.
J.-P. Goddard and C. Ollivier, Adv. Synth. Catal., 2014, 356,
2756–2762.
10454 | Chem. Sci., 2021, 12, 10448–10454
© 2021 The Author(s). Published by the Royal Society of Chemistry