Remote Site-Specific Radical Alkynylation of Unactivated C-H Bonds

Article abstract of DOI:10.1021/acs.orglett.8b02514

A method for remote radical C-H alkynylation at unactivated sites is reported. C-H functionalization proceeds via 1,5-hydrogen atom transfer (HAT) to amidyl radicals that are generated via an addition/fragmentation reaction. The readily installed N-allylsulfonyl moiety is used as a precursor of the N-centered radical. Unactivated secondary and tertiary as well as selected primary C-H bonds can be functionalized by this method.

Full text of DOI:10.1021/acs.orglett.8b02514

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Remote Site Specific Radical Alkynylation of Unactivated C-
H Bonds
Journal: Organic Letters
Manuscript ID ol-2018-025147.R1
Manuscript Type: Communication
Date Submitted by the Author: 27-Aug-2018
Complete List of Authors: Wang, Lin; University of Münster, Chemistry
Xia, Yong; University of Münster, Chemistry
Bergander, Klaus; University of Münster, Chemistry
Studer, Armido; University of Münster, Chemistry
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Submitted to Organic Letters
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Remote Site Specific Radical Alkynylation of Unactivated C−H
Bonds
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Lin Wang, Yong Xia, Klaus Bergander and Armido Studer*
Institute of Organic Chemistry, University of Münster, Corrensstrasse 40, 48149 Münster, Germany
Supporting Information Placeholder
ABSTRACT: A method for remote radical C−H alkynylation at unactivated sites is reported. C−H functionalization proceeds via 1,5-
hydrogen atom transfer (HAT) to amidyl radicals that are generated via an addition/fragmentation reaction. The readily installed N-
allylsulfonyl moiety is used as a precursor of the N-centered radical. Unactivated secondary and tertiary as well as selected primary C−H
bonds can be functionalized by this method.
Functionalization of inert C−H bonds has received great atten-
tion over the past years, as it allows for late stage modification of
complex compounds opening up novel retrosynthetic routes.1
Along with transition-metal-mediated processes, radical chemistry
has turned out to be highly valuable for alkane C−H functionaliza-
tion.2 Radical C−H modification generally relies on the H-
abstraction (hydrogen atom transfer, HAT) from a C−H bond by a
reactive (mostly) heteroatom centered radical.3 By using an inter-
molecular HAT, the regioselectivity problem has to be addressed.
Along these lines, site-selectivity is more readily achieved upon
switching to intramolecular variants. In particular, the 1,5-HAT to
reactive N-centered radicals has a long history with the Hoff-
mann-Löffler-Freytag (HLF) reaction to be named as the basis for
many recent developments.1b,3c,4,5c In HLF-type reactions, the N-
atom of the substrate amine/amide is first charged with a radical
leaving group X allowing for N-radical generation (Scheme 1,
A).3c,5 Remote 1,5-HAT and subsequent C-radical functionaliza-
tion afford the remotely functionalized amine/amide in a chain
reaction by X-atom or X-group transfer. Hence, the installed
functionality Y is often equal to X and at the same time is also a
good ionic leaving group. Ionic cyclization eventually leads to
pyrrolidines. In contrast, remote C−H functionalization via amidyl
radicals comprising intermolecular C−C bond formation (formal
C−H alkylation) is rare and has been developed only very recently
(Scheme 1, B).6,7 Herein, we introduce a method for remote site-
selective C−H alkynylation.8-10 To our knowledge, remote C−H
alkynylation at unactivated C−H bonds proceeding via intramo-
lecular HAT has been explored only very recently.11
Scheme 1. Remote radical C−H functionalization via HAT
to amidyl radicals
In 2004, Zard showed that N-allylsulfonamides can be used as
precursors for N-radical generation to construct lactams via radi-
cal cyclization reactions.12 The readily installed allylsulfonyl
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moiety serving as a stable amidyl radical precursor has surprising-
ly not found any application along these lines since.
electronically distinct para-substituted phenylalkynyl triflones 2b-
h reacted to the corresponding C−H alkynylation products 3ab-
3ah in 70-85% yields. Since the aryl moiety in these alkynes is
distal from the site of radical addition, steric effects do not play an
important role and similar yields were obtained for reagents bear-
ing ortho and meta-substituted aryl groups (3ai-3ak). Slightly
worse results were achieved for the naphthyl, biphenyl, phenan-
thryl and phenyl carbazole systems (see 3al-3ao). As expected,
the activating aryl moiety in the alkynylation reagent is beneficial
for the transformation and with the alkylalkynyl sulfone 2p, the
targeted product 3ap was isolated in moderate 36% yield. An
improved yield was noted for the silylalkynylation (3aq, 45%).
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Our reaction design is depicted in Scheme 1, C. As radical al-
kynylation reagents we chose acetylenic triflones, which were
first introduced by Fuchs for this purpose.8a In our approach, they
serve both as trifluoromethyl and alkynyl sources. By alkynyla-
tion of the initiating radical, a CF3 radical will be generated.13 For
electronic and steric reasons, this electrophilic radical should
chemoselectively react at the terminal double bond of the allyl
sulfone. The thus formed secondary adduct radical will fragment
allylCF3 and SO2 to give the corresponding amidyl radical
(Scheme 1). Importantly, both side products are highly volatile
and allylCF3 as undesirable radical acceptor should be removed
from the reaction mixture. 1,5-HAT to the amidyl radical will lead
to the translocated C-radical which in turn gets alkynylated by the
triflone reagent to provide via addition/elimination the targeted
product along with SO2 and the chain carrying CF3 radical.
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Scheme 3. Remote alkynylation of allylsulfonamide 1a –
variation of reagent 2
O
O
S
F3C
R
Bz
O
R
N
S
Bz
2a q
-
(2 equiv)
The starting allylic sulfones 1a-c were prepared from the corre-
sponding amines by converting them first to allylsulfonamides
(allylSO2Cl) followed by N-protection (see the Supporting Infor-
mation (SI)). Careful reaction optimization on sulfonamide 1a
revealed that remote alkynylation with reagent 2a (2 equiv) is best
conducted in EtOAc as a solvent and α,α’-azobisisobutyronitrile
(AIBN, 0.3 equiv) as an initiator in a sealed tube at 85 °C to
provide benzamide 3aa in 78% isolated yield (Scheme 2, see SI
for reaction optimization). Note than in acetonitrile a similar
result was obtained. Lowering the amount of reagent 2a led to a
decreased yield and increasing reagent stoichiometry to 3 equiv
did not further improve reaction outcome. Dibenzoyl peroxide can
also be used as an initiator to obtain a similar yield (see SI). With
sulfonamide 1b, leading to a less electrophilic amidyl radical,
reaction was lower yielding under otherwise identical conditions
(3ba, 50%). The fluorobenzoylated amide 1c reacted with similar
efficiency than 1a (3ca, 79%) and benzyloxycarbonyl-protected
1d gave target 3da in 58% yield. A good result was achieved with
pivaloylated amide 1e (3ea, 69%).
H
N
O
H
AIBN (0.3 equiv)
EtOAc, 85 °C, 24 h
allyl
3
1a
R
Bz
Bz
N
N
H
R
H
3ai
3aj
3aa
, 80% (R = F)
, 75% (R = Me)
, 78% (R = H)
3ab
3ac
3ad
3ae
, 72% (R = OMe)
, 70% (R = Bu)
, 74% (R = Hex)
, 85% (R = CF3)
, 85% (R = F)
t-
n-
F
Bz
N
H
3af
3ag
3ah
, 81% (R = Cl)
, 80% (R = Br)
3ak
, 79%
n-Pr
OMe
Bz
Bz
Based on these screenings, all further experiments were con-
ducted with the N-benzoylated derivatives since the para-
fluorobenzoyl congeners are more expensive. In agreement with
our reaction design, remote alkynylation of 1a with PhCCSO2Ph
was not a clean reaction and a significantly lower yield of 3aa
(27%) was obtained.
N
H
N
H
3al
, 53%
3am
, 69%
N
Bz
Bz
Bz
Scheme 2. Variation of the N-protecting group (PG)
N
H
N
H
3an
3ao, 47%
, 65%
Si
Bz
N
H
N
H
3ap
3aq
, 45%
, 36%
The substrate scope with respect to the sulfonamide component
1 was evaluated next, first focusing on the alkynylation of tertiary
C−H bonds (Scheme 4). The reaction worked well on 4-, 5- and 6-
membered cyclic systems (3fa, 3ga, 3ha). The backbone of the
amide can also be substituted, as documented by the successful
preparation of 3ka-3oa (60-86% yields). Importantly, regioselec-
tivity was excellent also for these more complex derivatives. Of
particular note are products 3ja, 3ma and 3oa which carry addi-
tional activated C−H bonds that were not functionalized but
would be tackled in an intermolecular HAT-approach. These
examples convincingly document the benefit of the regioselective
Under the optimized conditions substrate scope was evaluated
with respect to reagent 2 keeping sulfonamide 1a as the substrate
(Scheme 3). In the first series of experiments the R substituent in
2 was systematically varied. For aryl-substituted alkynes, elec-
tronic effects exerted by the aryl moiety are weak and various
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intramolecular 1,5-HAT-step. As expected, remote alkynylation
next to an O-atom can also be achieved (see 3pa, 69%).
1,2-stereoinduction was good (5q, 60%, trans:cis = 7:1) and even
complete stereocontrol was achieved for alkynylation of a rigid
bicyclic compound (see 5r). In case of 5p, regioselectivity was
not perfect and alkynylation at the tertiary C−H bond occurred to
a small extent. Note that only for 5p and 5f (see above), regiose-
lectivity was not complete and in all other cases studied other
regioisomers could not be identified.
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Scheme 4. Variation of substrate 1 – alkynylation of ter-
tiary C−H bonds
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Scheme 5. Variation of substrate – alkynylation of second-
ary and primary C−H bonds
O
O
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S
F3C
2a (2 equiv)
R1
Ph
Bz
O
X
R2
Ph
R1
N
S
Bz
Ph
X
N
H
O
H
R2
AIBN (0.4 equiv)
EtOAc, 85 °C, 24 h
allyl
5a-t
4a-t
Ph
Ph
Bz
N
Bz
X
Bz
N
H
N
H
H
R2
R'
5a, 59% (R2 = Me)
5b, 61% (R2 = Et)
5e, 63% (R' = Cl)
5f, 70% (R' = OTBS, rr = 1:1.2)
5c, 70% (R2 = n-hexyl) 5g, 56% (R' = CO2Me)
5d, 49% (R2 = Ph)
5h, 66% (X = O)
5i, 62% (X = S)
Ph
Ph
Ph
Bz
Bz
O
Bz
O
N
N
H
N
H
H
Cl
5k, 19%
5l, 54%
5j, 57%
O
O
Bz
HN
Ph
Bz
N
O
O
H
O
Ph
The more challenging C−H-functionalization at secondary C−H
bonds was studied next. Pleasingly, radical alkynylation of N-
protected pentyl-, hexyl- and decylamine occurred with complete
regiocontrol in good yields (5a-5c, 59-70%). Compound 5b was
successfully also prepared at larger scale (2 mmol, 53%). Func-
tionalization of the secondary benzylic position was achieved with
slightly lower yield (5d) and methylene-alkynylation also worked
with complete 1,5-regioselectivity next to a chloromethyl group
(5e, 63%). However, for the congener bearing a silyloxymethyl
substituent, the 1,5-alkynylation product 5f was formed as minor
regioisomer along with the corresponding 1,6-product (70% com-
bined yield, regioselectivity = 1:1.2). Although the ester function-
ality also activates the α-CH2 group, complete 1,5-regioselectivity
was noted for the formation of product 5g. This can be understood
considering polar effects, since the amidyl radical is an electro-
philic radical and 1,6-H abstraction would lead to an electrophilic
α-ester radical.
5n, 39% (dr = 1.3:1)
5m, 66% (dr = 1:1)
Ph
Ph
Ph
Bz
Bz
N
H
N
Bz
N
H
H
5o, 57% (dr = 1:1)
5p, 71% (dr = 1:1, rr = 4.7:1)
5q, 60% (dr = 7:1)
H
Ph
Bz
HN
N
H
Bz
NH
Ph
Bz
Ph
5r, 51% (dr > 98:2)
5s, 67% (dr = 1:1)
5t, 53% (dr = 1:1)
Finally, we can show that the product δ-alkynylated ben-
zamides can be readily transformed to isoquinolinones using
known Rh-catalysis,14 as documented by the successful transfor-
mation of 5b to the heterocycle 6 (Scheme 6).
C−H alkynylation next to O and S-atoms in ethers and thi-
oethers worked well (5h, 5i) and an activating O-atom even al-
lows for remote alkynylation of a primary C−H bond (5j). How-
ever, for non-activated primary C−H bonds, the yields significant-
ly decreased (5k). Methylene groups next to a chloride could be
functionalized (5l) and reaction worked well for remote function-
alization of an α-amino acid ester (see 5m) and other complex
amino esters (5n). No stereoselectivity was observed (1,3- and
1,4-stereoinduction) for the intermolecular radical C−H alkynyla-
tion in open chain systems (5m, 5o, 5p). The same is true for 7-
and 12-membered ring-systems that show conformational flexibil-
ity (see 5s, 67%; 5t, 53%). However, for a rigid cyclic system, the
Scheme 6. Further transformation to an isoquinolinone
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Tang, P. Angew. Chem., Int. Ed., 2015, 54, 4065. (g) Xia, J.-B.; Zhu, C.;
In summary, a method for remote radical C−H-alkynylation of
unactivated C−H bonds was introduced. The process uses readily
prepared allylsulfonamides as N-radical precursors and excellent
regioselectivity is achieved via reliable intramolecular 1,5-H atom
transfer. The allylsulfonyl moiety, which is clearly underdevel-
oped in our eyes, shows great potential as a stable readily ac-
cessed N-radical precursor moiety.15 Using this approach, func-
tionalization of secondary and tertiary unactivated C−H bonds can
be achieved. In the case of methyl group activation, reasonable
yields are obtained for activated systems, where the methyl group
sits next to a heteroatom. Thanks to the great functional group
tolerance of radical chemistry, substrate scope is broad for these
transformations.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
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H.; Studer, A. Angew. Chem., Int. Ed. 2018, 57, 1692.
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4486. (b) Hoshikawa, T.; Kamijo, S.; Inoue, M. Org. Biomol. Chem.,
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Nagatomo, M.; Yoshioka, S.; Inoue, M. Chem. Asian J. 2015, 10, 120.
(9) Radical alkynylation with I(III) reagents: (a) Wang, X.; Studer, A.
Acc. Chem. Res. 2017, 50, 1712. (b) Yoshimura, A.; Zhdankin, V. V.
Chem. Rev. 2016, 116, 3328. (c) Brand, J. P.; Gonzalez, D. F.; Nicolai, S.;
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Zhang, T.; Mehrkens, N.; Rudolph, M.; Hashmi, A. S. K. Angew. Chem.
Int. Ed. 2015, 54, 6046. (b) Schaffner, A.-P.; Darmency, V.; Renaud, P.
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(12) Moutrille, C.; Zard, S. Z. Chem. Commun. 2004, 1848.
(13) Depending on the initiating radical, initiation can also proceed by
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(14) Quinones, N.; Seoane, A.; Garcia-Fandino, R.; Mascarenas, J. L.;
Gulias, M. Chem. Sci. 2013, 4, 2874.
(15) For application of this approach for remote radical C−N3, C−Cl,
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Experimental procedures and analytical data for all compounds.
(PDF)
AUTHOR INFORMATION
Corresponding Author
studer@uni-muenster.de
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was financially supported by the China Scholarship
Council (stipend to L.W.) and the Deutsche Forschungsgemein-
schaft (DFG).
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