Anti-Markovnikov Hydrofunctionalization of Alkenes: Use of a Benzyl Group as a Traceless Redox-Active Hydrogen Donor

Article abstract of DOI:10.1002/anie.201705368

A protocol for the anti-Markovnikov hydrofunctionalization of alkenes has been developed by the use of a benzyl group as a traceless redox-active hydrogen donor. Under copper catalysis and in the presence of CF₃- or N₃-containing hyp

Full text of DOI:10.1002/anie.201705368

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Anti-Markovnikov Hydrofunctionalization of Alkenes - Use of a
Benzyl Group as a Traceless Redox-active Hydrogen Donor
Authors: Geoffroy Hervé Lonca, Derek Yiren Ong, Thi Mai Huong Tran,
Ciputra Tejo, Shunsuke Chiba, and Fabien Gagosz
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: Angew. Chem. Int. Ed. 10.1002/anie.201705368
Angew. Chem. 10.1002/ange.201705368
Link to VoR: http://dx.doi.org/10.1002/anie.201705368
http://dx.doi.org/10.1002/ange.201705368

10.1002/anie.201705368
Angewandte Chemie International Edition
COMMUNICATION
Anti-Markovnikov Hydrofunctionalization of Alkenes - Use of a
Benzyl Group as a Traceless Redox-active Hydrogen Donor
Geoffroy Hervé Lonca,a Derek Yiren Ong,b Thi Mai Huong Tran,b Ciputra Tejo,b Shunsuke Chiba,*b and
Fabien Gagosz*a,c
Abstract: A protocol for the anti-Markovnikov hydrofunctionalization
of alkenes, that utilizes a benzyl group as a traceless redox-active
hydrogen donor, has been developed. Under copper catalysis and in
the presence of CF3- or N3-containing hypervalent iodine reagents, a
series of homoallylic alcohol derivatives could be regioselectivity
hydrofunctionalized. A similar principle was also applied to the
hydrofunctionalization of alkenols.
(V→VI). Overall, the temporarily introduced benzyl moiety would
function both as a redox active traceless H-donor and as a
protecting group for the hydroxy moiety. Herein, we demonstrate
the feasibility of this concept with the Cu-catalyzed
hydrotrifluoromethylation[6] and hydroazidation[7,8] of readily
accessible homoallylic alcohols (Scheme 1C). The design,
optimization, and substrate scope of these processes are
described herein.
The ability in hydrofunctionalization of alkenes in
a
regioselective manner is of prime importance for the
development of chemical processes to produce high value fine
chemicals. Despite the recent remarkable progress in this
area,[1] a number of challenges still remain for the anti-
Markovnikov hydrofunctionalization of non-activated alkenes.[2]
One of the most reliable ways to achieve the anti-Markovnikov
hydrofunctionalization involves the use of carbon- or heteroatom
centered radicals which can indeed add on the less
hindered/substituted side of an unactivated alkene, thus
generating a new C-C or C-heteroatom bond in an anti-
Markovnikov manner (Scheme 1A). Subsequent delivery of a H
atom onto the resulting highly reactive C-centered radical is then
required to complete the transformation. This last step often
A. anti-Markovnikov Hydrofunctionalization of alkenes with radicals
H
"
"
X
H
X
X
R
R
R
X = carbon or heteroatom centered radical species
B. Use of Bn ether for the redox active hydrogen radical source
OH
hydrofunctionalization with HX
OH
H
X
I
VI
traceless redox-active H donor
Ph
Ph
Ph
Ph
1,5-H
shift
appears to be
a
key issue to realize an efficient
H
H
O
H
–e–
O
H
hydrofunctionalization.[3] In this context, we wondered if a simple
benzyl ether moiety, that would be introduced in an alkenyl
substrate I possessing a hydroxyl group at a suitable position
(Scheme 1B, I→II), could be used after the radical
functionalizing event (II→III) for the precise intramolecular H-
delivery via a remote H radical shift (III→IV).[4,5] We reasoned
that this H-radical shift could be driven by the formation of a
more stable α-oxy benzyl radical IV, which could be, if the
suitable redox reaction conditions are set, readily converted into
an oxonium cation V in a subsequent single-electron-oxidation
step (IV→V). The cationic intermediate V could finally be
degraded by hydrolysis/solvolysis to release the original
hydroxyl group with formation of benzaldehyde as a co-product
O
O
X
X
X
X
II
III
IV
V
C. Cu-catalyzed hydrotrifluoromethylation and -azidation of homo-
allylic alcohols (this work)
Ph
CuI CuII
X
I
O
OH
H
O
H
+
X
O
R
conditions
R
X= CF3 or N3
Scheme 1. Anti-Markovnikov hydrofunctionalization of alkenes
We initiated our investigations by studying the possibility to
perform the hydrotrifluoromethylation of the readily accessible
homoallylic alcohol benzyl ether 1a (Scheme 2A). The use of
Togni’s reagent 2[9] as a source of trifluoromethyl radical along
with a copper salt as a redox catalyst was considered as a
potentially suitable set of reagents to achieve the desired
transformation.[10] An extensive screening of the reaction
conditions (see SI for details) revealed that the anti-Markovnikov
hydrotrifluoromethylation of 1a could be efficiently performed in
the presence of CuI (10 mol%) and Togni’s reagent 2 (1.2 equiv)
in dioxane-MeOH (9:1) solvent system at 60 °C. Under these
conditions, 1a was completely consumed after 12 h of reaction,
[a]
[b]
G. H. Lonca, Prof. F. Gagosz
Département de Chimie, UMR 7652 and 7653 CNRS, Ecole
Polytechnique, 91128 Palaiseau, France.
D. Y. Ong, T. M. H. Tran, Dr. C. Tejo, Prof. S. Chiba
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, Singapore 637371 (Singapore)
E-mail: shunsuke@ntu.edu.sg
[c]
Prof. F. Gagosz
Department of Chemistry and Biomolecular Sciences, University of
Ottawa, K1N 6N5, Ottawa, Canada.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201705368
Angewandte Chemie International Edition
COMMUNICATION
and subsequent treatment of the reaction mixture with TsOH (20
the present method was found applicable to the synthesis of
primary alcohol such as 3l. It could also be employed for the
hydrotrifluoromethylation of N-benzylamine derivatives 1m and
1n to deliver amines 3m and 3n in 59% and 49% yields,
respectively.
mol%) in MeOH for
1
h
led to isolation of the
hydrotrifluoromethylated alcohol 3a in 92% yield (Scheme
2A).[11]
As shown in Scheme 2B, the catalytic process is initiated by
a single-electron reduction of Togni’s reagent 2 by the Cu(I)
species. This allows for the generation of a CF3-radical along
with a higher-valent Cu(II) species and a 2-iodobenzoate ion.
The CF3-radical then undergoes an anti-Markovnikov addition
onto the alkene moiety of 1a to produce a secondary carbon
centered radical VII. A subsequent 1,5-H radical shift leads to
the formation of an α-oxy benzyl radical VIII,[12,13] which is then
oxidized by the Cu(II) species, thus producing the oxonium
carbocation IX while maintaining the redox catalytic turnover
with regeneration of the active Cu(I) species. Trapping of
oxonium IX with MeOH produces acetal X,[14] which is finally
degraded in the presence of TsOH in MeOH to provide 3a.
CuI (10 mol%)
Ph
2 (1.2 equiv)
1,4-dioxane-MeOH (9:1)
60 °C[a]
YH
Y
R1
R2
CF3
R1
R2
R3 R3
3b-m
R3 R3
1b-m
then
TsOH (20 mol%)
MeOH, 23 °C, 1 h
(Y = O or NR)
OH
OH
OH
CF3
CF3
TBDPSO
CF3
Ph
3b 81%
3c 79%
3d 66% (78%)[b]
OH
OH
O
OH
CF3
A. Optimized reaction conditions: hydrotrifluoromethylation of 1a
CF3
(EtO)2P
CF3
Ph
Ph
S
OBn
CuI (10 mol%)
PhthN
3e 64%
3f 68%
OH
CO2Et
3i 82%[c]
3g 84%
OH
1,4-dioxane-MeOH (9:1)
60 °C, 12 h
OH
1a
+
I
OH
PhthN
CF3
PhthN
CF3
CF3
Ph
CF3
then
F3C
O
CF3
3a 92%
Me Me
TsOH (20 mol%)
MeOH, 23 °C
O
O
3h 87%
3j 78%[c]
N
PhthN =
(1.2 equiv)
2
PMP
Me
Me
NH
O
CF3
OH
n-C6H13
3m 59% (66%)[b]
B. Proposed catalytic cycle
2
OH
CF3
Ph
Me
Ph
3l 67%
CF3
CuI
PMP
O
NH
ArCO2
CF3
O
3k 40%
R
CF3
Ph
IX
CuII
MeOH
3n 49%
Ph
OMe
F3C
Scheme 3. Substrate scope for the Cu-catalyzed hydrotrifluoromethylation.
[a] The reactions were conducted using 0.2-0.3 mmol of 1 with 10 mol% of CuI
in 1,4-dioxane-MeOH (0.3 M) for 12-24 h followed by treatment with TsOH (20
mol%) in MeOH for solvolysis and isolated yields were noted above unless
otherwise stated. [b] 1H NMR yield based on the internal standard (3d was
volatile and 3m was not very stable). [c] 20 mol% of CuI was used. TBDPS =
tert-butyldiphenylsilyl; PhthN = phthalimido; PMP = para-methoxyphenyl.
1a
CF3
Ph
Ph
1,5-H
shift
R
X
O
H
O
H
TsOH
MeOH
R
R
CF3
CF3
VII
(Ar = 2-I-C6H4
VIII
R = PhthN-CH2)
3a
/
Scheme 2. Cu-catalyzed hydrotrifluoromethylation of 1a with Togni’s reagent
2.
The method was not limited to the introduction of a CF3
group onto alkenes. As proof of the synthetic potential of our
approach, hydroazidation of alkenes 1 with hypervalent iodine
reagent 4 as a source of the azido radical was developed by
slightly modifying the reaction conditions (Scheme 4).[15]
With optimized reaction conditions in hands, we next
investigated the scope and limitation of this anti-Markovnikov
hydrotrifluoromethylation. As shown in Scheme 3, the
transformation could be applied to a variety of homoallylic
alcohols 1b-k with good efficiency in general. Various functional
groups such as silyl ether (3c), cyclopropyl (3d), phosphonate
(3e), and thienyl (3g) moieties were tolerated. A quaternary
carbon center could be introduced at position α to the alcohol
with high efficiency (3h). In addition to secondary alcohols 3b-h,
tertiary alcohols 3i and 3j could be afforded in good yields, while
the yield of 3k, derived from camphor, was moderate. Moreover,
Treatment of alkene 1a with 4 (1.5 equiv) in the presence of
[16]
CuBr2
(20 mol%) as the catalyst in 1,2-dichloroethane at
60 °C delivered, after the acidic work-up, the hydroazidation
product 5a in 57% isolated yield. Notably, this product is a
precursor of 1,5-diamino-2-pentanol in which the two amino
functionalities are orthogonally protected. The hydroazidation
protocol could be applied to other homoallylic alcohol benzyl
ethers 1, which were converted into the corresponding
azidoalcohols 5 in moderate to good yields. Given the versatile
This article is protected by copyright. All rights reserved.

10.1002/anie.201705368
Angewandte Chemie International Edition
COMMUNICATION
reactivity of organic azides,[17] the products obtained using this
protocol would be of high value in various applications.
A. diastereoselective hydrofunctionalization of 1o-1q
1o
OH Me
(X= Me)
PhthN
CF3
Ph
2
CuBr2 (20 mol%)
Ph
3o 72% (dr = 60:40)[a]
(1.2 equiv)
O
X
N3
I
O
ClCH2CH2Cl
60 °C[a]
OH
PhthN
1p (X= Br)
1q (X = Cl)
1r (X = F)
conditions
as
Scheme 3
O
R1
R2
N3
OH
X
O
+
R1
R2
1o-r
PhthN
CF3
then
R3 R3
R3 R3
TsOH (20 mol%)
MeOH, 23 °C, 1 h
3p (X= Br) 73% (dr = 84:16)[b]
3q (X= Cl) 65% (dr = 85:15)[b]
3r (X= F) 55% (dr = 85:15)[b,c]
1
4 (1.5 equiv)
5
1p
(X= Br)
OH
OH
O
OH
OH Br
N3
4 (1.5 equiv)
PhthN
PhthN
N3
(EtO)2P
N3
Ph
Ph
PhthN
N3
conditions as Scheme 4
5a 57%
5e 43%
5f 42%
5p 47% (dr = 80:20)[a]
OH
OH
OH
B. Origin of the diastereoselectivity
N3
Ph
N3
N3
CO2Et
CF3
Me Me
R
O
R
O
5h 48% (55%)[b]
5i 47%
5j 56%
3p-r
X
Ph
Ph
H
F3C
H
or
1p-r
Scheme 4. Cu-catalyzed hydroazidation. [a] The reactions were conducted
using 0.2 mmol of 1 with 20 mol% of CuBr2 in ClCH2CH2Cl (0.3 M) for 10-20 h
followed by treatment with TsOH (20 mol%) in MeOH for solvolysis and
isolated yields were noted above unless otherwise stated. [b] 1H NMR yield
based on the internal standard.
N
or
H
3
H
X
5p
CF3
3
X = Br, Cl, or F
R = PhthN-CH2
N
or
XII favoured
XI unfavoured
C. Derivatization of 3p and 5p to pyrrolidines 6p and 7p
TBSO
OH Br
i) TBS protection
We also sought for the possibility to apply the current
protocol to 1,1-disubstituted alkenes. As shown in Scheme 5A,
the Cu(I)-catalyzed hydrotrifluoromethylation of methyl
substituted alkene 1o delivered the desired adduct 3o in 72%
yield but with poor diastereoselectivity (60:40). The replacement
of the methyl group by a bromine (for 1p), a chlorine (for 1q) or a
fluorine (for 1r) atom did not alter the reactivity, affording 3p, 3q,
and 3r in 73%, 65%, and 55% (65% brsm) yields, respectively,
and more fascinatingly, we observed an enhancement of the
diastereoselectivity (84:16 for 3p, 85:15 for 3q, and 85:15 for 3r).
A similar level of selectivity was obtained in the hydroazidation
of bromoalkene 1p, that afforded 5p in decent 47% yield with a
good diastereoisomeric ratio (80:20). The origin of the
diastereoselectivity likely stems from the transition states in the
1,5-H shift process.[18] In the possible chair-like transition states
XI and XII (Scheme 5B), both the phenyl group of the benzyl
moiety and the phthalimidomethyl group would preferentially
PhthN
X
X
N
ii) aq. NH2NH2
EtOH, 60 °C
H
3p (X = CF3)
5p (X= N3)
6p (X = CF3)[d]
7p (X = N3)[e]
Scheme 5. Hydrofunctionalization of 1,1-disubstituted alkenes.
[a]
[b]
Diastereomeric ratio was determined by 1H NMR spectroscopy.
Diastereomeric ratio was determined by 19F NMR spectroscopy. [c] 65% yield
based on recovery of 1r (brsm). [d] i) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 95%
yield; ii) aq. NH2NH2, EtOH, 60 °C, 97% yield of 6p as an inseparable mixture
of two diastereomers. [e] i) TBSCl, imidazole, DMF, 23 °C, 68% yield of the
single diastereomer derived from the major isomer of 5p; ii) aq. NH2NH2, EtOH,
60 °C, 96% yield of 7p as the single diastereomer.
We also envisaged using the present concept to perform the
hydrotrifluoromethylation of a simple alkenol XIII (Scheme 6). In
this case, a suitably located alcohol moiety in XIII would play the
role of a redox-active hydrogen donor. We considered that the
1,n-H shift step (XIV→XV) would proceed favourably from the α-
H of the hydroxyl group to the reactive C-centered radical, while
the resulting hydroxy-substituted C-centered radical intermediate
XV could be subsequently oxidized into ketone XVI. Overall, this
transformation would be a combination of anti-Markovnikov
hydrotrifluoromethylation and alcohol oxidation.
adopt
a
pseudo-equatorial position. Considering that
a
trifluoroethyl group or an azidomethyl group would be more
sterically demanding than a halogen atom,[19] the reaction would
more favourably proceed via transition state XII, in which the
halogen atom stands in a pseudo-axial position. As a result, the
major isomer from 1p-r would be the one having the resulting
hydroxyl group and the halogen atom in a relative 1,3-anti-
configuration (see Scheme 5A). We took advantage of the high
density of functional groups present in 3p and 5p to derivatize
them. They could be readily converted into the valuable
pyrrolidines 6p and 7p through a sequence of hydroxyl group
protection as a TBS ether, removal of the phthalimide moiety
with hydrazine followed by spontaneous intramolecular
substitution of the secondary bromide by the resulting primary
amine (Scheme 5C).
This article is protected by copyright. All rights reserved.

10.1002/anie.201705368
Angewandte Chemie International Edition
COMMUNICATION
CF3
redox-active H donor
Cu(OAc)2 (10 mol%)
F3C
I
O
2,2'-bipyridine (10 mol%)
1,4-dioxane, 60 °C[a]
(n = 1 or 2)
OH
n
1,n-H
shift
O
O
+
n
OH
CuI
/ 2
OH
O
R
R
R
OH
R1
H
H
H
R2
R
R2
CF3
CF3
8
2 (2 equiv)
9
CuII
ArCO2
XV
XIII
XIV
CuII
ArCO2
CF3
CF3
CF3
ArCO2H
CuI
O
O
F3C
I
O
N
Ar = 2-I-C6H4
O
R
2 :
O
H
R
S
CF3
XVI
9a (R = H): 79%
9g 43%
9h 61%
9b (R = 4-Me): 83%
9c (R = 2-Me): 65%
9d (R = 4-MeO): 78%
9e (R = 4-Br): 83%
9f (R = 4-F): 79%
CF3
CF3
CF3
Scheme 6. Cu-catalyzed hydrotrifluoromethylation of alkenes using alcohols
as redox active hydrogen donor groups
O
O
O
Ph
Ph
Ph
Gratifyingly, we found that the treatment of 1-aryl-5-
hexenols 8a-k with 2 (2 equiv) in the presence of Cu(OAc)2 (10
mol%)[16] and 2,2’-bipyridine (10 mol%) in 1,4-dioxane at 60 °C
resulted in the formation of the hydrotrifluoromethylated ketones
9a-k in generally good yields (Scheme 7). Notably, the
cyclopropyl moiety in 9k could be kept intact during the redox
radical process probably due to a higher oxidation rate of the α-
hydroxy radical XV to ketone 9k than the radical ring-opening.
The method could be extended to the synthesis of benzene-
tethered carbonyl compounds 9l and 9m as well as aliphatic
ketones such as 9n. Interestingly, the reaction of 1-phenyl-6-
heptenol 8o, which has a linker with an additional carbon unit
(as compared to 8a-n), proceeded smoothly via a probable 1,6-
hydrogen shift to furnish 9o in 66% yield. The method also
allowed for the use of substituted alkenes. The reaction of 1,1-
disubstituted alkene 8p was shown to be highly efficient
affording the desired hydrotrifluoromethylated ketone 9p in 89%
yield. The reaction of 8q possessing a styryl moiety (as an
example of internal alkene substrate) provided the γ-
trifluoromethyl ketone 9q in 57% yield via benzylic radical XVII
intermediately formed by a regioselective addition of the CF3
radical onto the styryl moiety.
9i 74%
9j 78%
9k 82%
CF3
CF3
CF3
CF3
O
R
O
O
O
O
Ph
Ph
O
Ph
9l (R = Me): 80%
9n 53%
9o 66%
9p 89%
9m (R = H): 77%
Ph
OH
Ph
2 (2 equiv)
conditions[b]
1,5-H
shift
F3C
O
OH
Ph
Ph
Ph
Ph
then [O]
CF3
XVII
8q
9q
57% (70% brsm[c]
)
Scheme 7. Cu-catalyzed sequence of hydrotrifluoromethylation/oxidation of
alkenols. [a] The reactions were conducted using 0.5 mmol of 8 in 1,4-dioxane
(0.1 M) at 60 °C for 2-61 h and isolated yields were noted above. [b] The
reaction was run at 80 °C. [c] brsm = based on recovery of the starting
material.
Acknowledgements
In summary, this work demonstrated that a simple benzyl
protecting group can be employed as a traceless redox-active
hydrogen radical donor for the anti-Markovnikov alkene hydro-
functionalization of homoallylic alcohols and their derivatives.
The hydrotrifuoromethylation and azidation developed herein are
easy to set up, relatively efficient and exhibit a high functional
group tolerance. This concept has been successfully extended
to the hydrotrifluoromethylation of 5-hexenol and 6-heptenol
derivatives. Application of this general concept to develop other
types of catalytic redox molecular transformations is the subject
of our ongoing investigations.
This work was supported by funding from Ecole Polytechnique
(for F.G.), Nanyang Technological University (for S.C.) and the
Singapore Ministry of Education (Academic Research Fund Tier
1: RG2/15 for S.C.). F.G. and S.C. are grateful to PHC Merlion
grant (Project 5.02.15) for the support of this collaboration
project.
Keywords: anti-Markovnikov alkene functionalization •
trifluoromethylation • azidation • radicals • copper catalysis
[1]
For reviews, see: a) M. Beller, J. Seayad, A. Tillack, H. Jiao, Angew.
Chem. Int. Ed. 2004, 43, 3368; Angew. Chem. 2004, 116, 3448; b) L.-B.
Han, M. Tanaka, Chem. Commun. 1999, 395.
[2]
[3]
K. A. Margrey, D. A. Nicewicz, Acc. Chem. Res. 2016, 49, 1997.
For
a
seminal work on radical mediated anti-Markovnikov
hydroamination by Studer et al., see: a) J. Guin, C. Mück-Lichtenfeld, S.
Grimme, A. Studer, J. Am. Chem. Soc. 2007, 129, 4498; b) J. Kemper,
A. Studer, Angew. Chem. Int. Ed. 2005, 44, 4914; Angew. Chem. 2005,
117, 4993.
This article is protected by copyright. All rights reserved.

10.1002/anie.201705368
Angewandte Chemie International Edition
COMMUNICATION
Ph
(>95%)
D
[4]
For selected reviews, see: a) S. Chiba, H. Chen, Org. Biomol. Chem.
2014, 12, 4051. b) F. Dénès, F. Beaufils, P. Renaud, Synlett, 2008,
2389; c) J. Robertson, J. Pillai, R. K. Lush, Chem. Soc. Rev. 2001, 30,
94; d) G. Majetich, K. Wheless, Tetrahedron 1995, 51, 7095.
Liu and Tan developed elegant strategies on remote aliphatic C-H
functionalization triggered by radical trifluoromethylation of alkenes,
see: a) P. Yu, S.-C. Zheng, N.-Y. Yang, B. Tan, X.-Y. Liu, Angew.
Chem. Int. Ed. 2015, 54, 4041; Angew. Chem. 2015, 127, 4113; b) P.
Yu, J.-S. Lin, L. Li, S.-C. Zheng, Y.-P. Xiong, L.-J. Zhao, B. Tan, X.-Y.
Liu, Angew. Chem. Int. Ed. 2014, 53, 11890; Angew. Chem. 2014, 126,
12084; c) L. Huang, S.-C. Zheng, B. Tan, X.-Y. Liu, Org. Lett. 2015, 17,
1589; d) L. Huang, S.-C. Zheng, B. Tan, X.-Y. Liu, Chem. Eur. J. 2015,
21, 6718; e) L. Huang, J.-S. Lin, B. Tan, X.-Y. Liu, ACS Catal. 2015, 5,
2826.
same conditions
as Scheme 2A
(>95%)
OH
D
O
D
PhthN
CF3
PhthN
D2-1a
88%
D-3a
[5]
[13] Beau reported regioselective de-O-benzylation on carbohydrate
templates using xanthate-mediated 1,7-H radical shift, see: A. Attouche,
D. Urban, J.-M. Beau, Angew. Chem. Int. Ed. 2013, 52, 9572; Angew.
Chem. 2013, 125, 9751.
[14] Formation of acetal X was confirmed prior to treatment with TsOH in
MeOH.
[15] To the best of our knowledge, this is the first example of hydroazidation
of non-activated alkenes with azido iodine(III) reagent 4. For reports on
the difunctionalization of alkenes with 4, see: a) Y.-A. Yuan, D.-F. Lu,
Y.-R. Chen, H. Xu, Angew. Chem. Int. Ed. 2016, 55, 534; Angew.
Chem. 2016, 128, 544; b) G. Fumagalli, P. T. G. Rabet, S. Boyd, M. F.
Greaney, Angew. Chem. Int. Ed. 2015, 54, 11481; Angew. Chem. 2015,
127, 11643; c) M.-Z. Lu, C.-Q. Wang, T.-P. Loh, Org. Lett. 2015, 17,
6110; d) B. Zhang, A. Studer, Org. Lett. 2013, 15, 4548.
[6]
For recent reports on anti-Markovnikov hydrotrifluoromethylation of
alkenes, see: a) L. Zhu, L.-S. Wang, B. Li, B. Fu, C.-P. Zhang, W. Li,
Chem. Commun. 2016, 52, 6371; b) Y. Cheng, S. Yu, Org. Lett. 2016,
18, 2962; c) H. Egami, Y. Usui, S. Kawamura, S. Nagashima, M.
Sodeoka, Chem. Asian J. 2015, 10, 2190; d) S. Choi, Y. J. Kim, S. M.
Kim, J. W. Yang, S. W. Kim, E. J. Cho, Nature Commun. 2014, 5, 4881;
e) D. J. Wilger, N. J. Gesmundo, D. A. Nicewicz, Chem. Sci. 2013, 4,
3160; f) X. Wu, L. Chu, F.-L. Qing, Angew. Chem. Int. Ed. 2013, 52,
2198; Angew. Chem. 2013, 125, 2254; g) S. Mizuta, S. Verhoog, K. M.
Engle, T. Khotavivattana, M. O’Duill, K. Wheelhouse, G. Rassias, M.
Médebielle and V. Gouverneur, J. Am. Chem. Soc. 2013, 135, 2505.
For a report on anti-Markovnikov hydroazidation of alkenes, see: A.
Kapat, A. Konig, F. Montermini, P. Renaud, J. Am. Chem. Soc. 2011,
133, 13890.
[16] Cu(II) species could be readily reduced to Cu(I) by various factors to
initiate the catalytic cycle. For several relevant literature precedents,
see: (a) S. Chiba, Chem. Lett. 2012, 41, 1554; b) Y.-F. Wang, K. K. Toh,
J.-Y. Lee, S. Chiba, Angew. Chem. Int. Ed. 2011, 50, 5927; Angew.
Chem. 2011, 123, 6049; c) J. Kim, S. Chang, J. Am. Chem. Soc. 2010,
132, 10272; d) A. Y. S. Malkhasian, M. E. Finch, B. Nikolovski, A.
Menon, B. E. Kucera, F. A. Chavez, Inorg. Chem. 2007, 46, 2950; e) J.
J. Teo, Y. Chang, H. C. Zeng, Langmuir 2006, 22, 7369.
[7]
[8]
[17] a) S. Bräse, C. Gil, K. Knepper, V. Zimmermann, Angew. Chem. Int. Ed.
2005, 44, 5188; Angew. Chem. 2005, 117, 5320; b) Organic Azides:
Syntheses and Applications; S. Bräse, K. Banert, Eds.; Wiley:
Chichester, U.K., 2010.
For reports on Markovnikov hydroazidation of alkenes, see: a) J. Waser,
H. Nambu, E. M. Carreira, J. Am. Chem. Soc. 2005, 127, 8294; b) J.
Waser, B. Gaspar, H. Nambu, E. M. Carreira, J. Am. Chem. Soc. 2006,
128, 11693; c) B. Gaspar, J. Waser, E. M. Carreira, Synthesis, 2007,
3839.
[18] A. E. Dorigo, M. A. McCarrick, R. J. Loncharich, K. N. Houk, J. Am.
Chem. Soc. 1990. 112. 7508.
[9]
For a review, see: J. Charpentier, N. Früh, A. Togni, Chem. Rev. 2015,
115, 650.
[19] The relative steric demands are evaluated on the basis of the A-values
for a bromine atom (0.48-0.67 kcal/mol), a chlorine atom (0.53-0.64
kcal/mol), a fluorine atom (0.25-0.42 kcal/mol), and an ethyl group (1.79
kcal/mol) whose value should be close to that of a trifluoroethyl or
azidomethyl group. For A-values of various substituents, see: E. L. Eliel,
S. H. Wilen, M. P. Doyle, Basic Organic Stereochemistry, Wiley, 2001,
p. 443.
[10] For the mechanistic study on the reactions of Togni reagents with Cu(I)
complex, see: a) F. Wang, D. Wang, X. Wan, L. Wu, P. Chen, G. Liu, J.
Am. Chem. Soc. 2016, 138, 15547; b) S. Kawamura, H. Egami, M.
Sodeoka, J. Am. Chem. Soc. 2015, 137, 4865.
[11] Use of MOM, Et, and PMB ethers was not optimal for this
transformation (see the SI for more details).
[12] The selective hydrogen atom delivery from the benzylic position
(IIV→VIII) was supported by the reaction of deuterated substrate D2-1a
which, under identical reaction conditions, was converted into mono-
deuterated compound D-3a.
This article is protected by copyright. All rights reserved.

10.1002/anie.201705368
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Geoffroy Hervé Lonca, Derek Yiren Ong,
Thi Mai Huong Tran, Ciputra Tejo,
Shunsuke Chiba* and Fabien Gagosz*
Page No. – Page No.
Anti-Markovnikov
Hydrofunctionalization of Alkenes -
Use of a Benzyl Group as a Traceless
Redox-active Hydrogen Donor
A protocol for the anti-Markovnikov hydrofunctionalization of alkenes, that utilizes a
benzyl group as a traceless redox-active hydrogen donor, has been developed.
Under copper catalysis and in the presence of CF3- or N3-containing hypervalent
iodine reagents, a series of homoallylic alcohol derivatives could be regioselectivity
hydrofunctionalized.
A
similar
principle
was
also
applied
to
the
hydrofunctionalization of alkenols.
This article is protected by copyright. All rights reserved.