Copper-Catalyzed Alkynylation of C(sp3)?H Bonds in N-Fluoro-sulfonamides

Article abstract of DOI:10.1002/adsc.201900992

Herein, we developed a copper-catalyzed approach for the remote C(sp³)?H alkynylation of N-fluoro-sulfonamides. With Cu(OTf)₂ as the catalyst, the carbon radical which generated from nitrogen radical-mediated 1,5-hydrogen atom transf

Full text of DOI:10.1002/adsc.201900992

UPDATES
DOI: 10.1002/adsc.201900992
Copper-Catalyzed Alkynylation of C(sp3)À H Bonds in N-Fluoro-
sulfonamides
Zhiping Yin,+a Youcan Zhang,+b Shuo Zhang,c and Xiao-Feng Wua, b,*
a
Department of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou 310018, People’s Republic of China
E-mail: xiao-feng.wu@catalysis.de
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Straße 29a, 18059 Rostock, Germany
Department of Gastroenterology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Youdian Road No. 54,
b
c
Hangzhou 310006, People’s Republic of China
+
These authors contributed equally to this work
Manuscript received: August 8, 2019; Revised manuscript received: September 19, 2019;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201900992
(sp3)À H bonds in N-fluoro derivatives via homolysis of
Abstract: Herein, we developed a copper-catalyzed
approach for the remote C(sp3)À H alkynylation of
N-fluoro-sulfonamides. With Cu(OTf)2 as the cata-
lyst, the carbon radical which generated from nitro-
gen radical-mediated 1,5-hydrogen atom transfer, go
through an addition/fragmentation reaction with
various acetylene sulfones. A variety of internal
alkynes were synthesized in high yield and regiose-
lectivity. Notably, celecoxib-derived substrate can
also gave the corresponding functionalized product
in good yield under the standard conditions.
NÀ F bond proven to be a useful method. Different
radical coupling reagents were developed to capture
the carbon-centered radical. For example, independ-
ently, the groups of Nagib[5] and Zhu[6] reported a
radical mediated coupling reaction with arylboronic
acids. Trifluoromethylation and cyanation reactions
were also developed by Li's group[7a] and Zhang's
group,[7b] respectively. In 2019, a catalytic system for
the synthesis of pyrrolidines and piperidines has been
established as well.[8] A step by step control experiment
was performed to support the proposed reaction
mechanism together with computational studies. More
recently, our group also reported an interesting 1.5-
HAT/carbonylative process to produce the correspond-
ing six-membered lactams.[9]
Keywords: Copper catalyst; Alkynylation; N-
Fluoro-sulfonamides; C(sp3)À H functionalization;
1,5-Hydrogen atom transfer
On the other hand, alkyne is an important functional
group in organic chemistry, material science, and
The selective functionalization of inert CÀ H bond has chemical biology due to their electronic properties and
received great attention over the past years, as it abundant available methods for their further
simplifies organic synthesis and allows for late-stage transformations.[10] Recently, the using of electrophilic
modification of complexed compounds.[1] More specif- alkynes such as halogenoalkynes, hypervalent alkyny-
ically, the direct functionalization of alkyl C(sp3)À H liodoniums, and acetylene sulfones to construct inter-
bond is attractive but challenging due to its ubiquitous nal alkynes have become an efficient complement
presence in organic structures but high bond cleavage compared with nucleophilic terminal alkynes. Among
energy.[2] Concerning its selective activation, intra- them, acetylene sulfone derivatives are regularly
molecular modification via radical intermediate is applied in radical chemistry for internal alkynes syn-
more readily achievable. In particular, the Hofmann- thesis. Recently the research groups of Leonori[11] and
Löffler-Freytag (HLF) reaction gives an ideal choice Studer[12] reported their achievements on nitrogen
for the selective functionalization of C(sp3)À H bonds at radical mediated alkynylation reactions through homol-
δ-position.[3] In the HLF reaction and related trans- ysis of NÀ O and NÀ S bonds, respectively. The group
formations, the generated carbon radical via 1,5-HAT of Liu developed an interesting iron-catalyzed oxygen
process can be captured by different radical acceptors radical mediated alkynylation of remote carbon radical
to form the desired new CÀ C, C-halogen and C- recently.[13] Based on these backgrounds and our
heteroatom bonds.[4] Recently, the functionalization C continual interest in nitrogen radical mediated
Adv. Synth. Catal. 2019, 361, 1–6
1
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
reactions,[14] we became interested in exploring the yield by using EtOAc as the solvent (Table1, entry 7).
possibility of reacting N-fluoro-sulfonamides with All the other solvents, such as, DMAc, EtOH, CH3CN,
acetylene sulfones through 1,5-HAT-alkynylation.
DCE, and t-BuOH gave lower reaction efficiency
Initially, N-fluoro-N-heptyl-4-methylbenzenesulfon- (Table 1, entries 2–6). In the testing of different copper
amide (1a) and (((trifluoromethyl)sulfonyl)ethynyl) salts, no better results could be obtained (Table 1,
benzene (2a) were synthesized and selected as the entries 8–9). Subsequently, various nitrogen ligands
model substrates to test our hypothesis. Inspired by our and bases were tested, we were very happy to find that
previous reports,[15] the reaction was firstly performed the yield can be further improved to 85% by using 2,9-
by using Cu(OTf)2 as the catalyst with bypridine as the dimethyl-4,7-diphenyl-1,10-phenanthroline (L5) as the
ligand and Li2CO3 as the base in toluene as the solvent. ligand and t-BuOLi as the base (Table 1, entry 16).
To our delight, we can detect our target coupling Furthermore, the reaction efficiency is influenced
product 3a in GC-MS with 4% GC yield (Table 1, significantly by changing the equivalent of 2a or the
entry 1). Encouraged by this positive result, we next reaction temperature (Table 1, entries 17 and 18). In
evaluated various solvents. The starting material 1a the absence of base, ligand, or copper salt, the yield
can be transformed into the desired product in 40% considerably decreased to 34–0% (Table 1, entries 19–
21). The final optimized reaction conditions were
found to be: 5 mol% Cu(OTf)2/5 mol% L5 and 1.0
Table 1. Optimization of reaction conditions.[a]
°
equivalent of t-BuOLi in EtOAc at 80 C which gave
3a in 79% isolated yield.
With the best reaction conditions in hand, we then
examined the substrate scope with a range of N-fluoro-
sulfonamides. As shown in Table 2, we firstly studied
the influence of the alkyl chain part. We found that this
reaction exhibited robust δ-position regioselectivity,
and a series of internal alkynes were synthesized in
good yields (Table 2, entries 1–5). Besides the secon-
Entry Catalyst
Solvent Ligand+Base Yield (%)[b]
Toluene L1+Li2CO3
DMAc L1+Li2CO3 34
EtOH L1+Li2CO3 36
CH3CN L1+Li2CO3 37
DCE L1+Li2CO3 30
tBuOH L1+Li2CO3 35
EtOAc L1+Li2CO3 40
EtOAc L1+Li2CO3 28
dary carbon radical, tertiary carbon radical can partic-
ipate in this reaction very well too (Table 2, entry 6).
In addition, cyclic carbon radical can also react
smoothly under the standard conditions; provide the
corresponding product in moderate yield (Table 2,
entry 7). However, in the cases of N-fluoro-4-methyl-
N-(4-phenylbutyl)benzenesulfonamide and N-fluoro-N-
1
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuBr·Me2S
4
2
3
4
5
6
7
8
(hex-5-en-1-yl)-4-methylbenzenesulfonamide,
only
trace amount of the desired products could be detected
under our standard conditions. Then, we investigated
the scope of sulfonamide groups. Different substrates
bearing electron-donating groups or electron-with-
drawing groups on the aromatic ring all worked well
and gave the corresponding products in high yields
(Table 2, entries 8–10).
The substrate scope with respect to acetylene
sulfone was studied systematically as well. As shown
in Table 3, different aromatic sulfonyl substituted
acetylenes worked well under the standard conditions
and gave the desired alkynylation products 3a in high
yields (Table 3, entry 1). According to literature,
halogenoalkynes are one of the frequently used
reagents for electrophilic alkynylation. However, in
our system, the reaction efficiency dropped signifi-
cantly by using (iodoethynyl)benzene as the reaction
partner (Table 3, entry 2). Subsequently, we tested
various other acetylene sulfones. Substrate with elec-
tron-donating group shows slightly better result com-
pared with substrate substituted with electron-with-
drawing group (Table 3, entries 6 and 7). The steric
effect exerted by the aryl moiety is week due to the
9
Cu(OTf)·toluene EtOAc L1+Li2CO3 34
10
11
12
13
14
15
16
17
18
19
20
21
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
-
EtOAc L2+Li2CO3 52
EtOAc L3+Li2CO3 74
EtOAc L4+Li2CO3 51
EtOAc L5+Li2CO3 77
EtOAc L5+Na2CO3 76
EtOAc L5+LiOH
79
EtOAc L5+tBuOLi 85(79)[c]
EtOAc L5+tBuOLi 48[d]
EtOAc L5+tBuOLi 58[e]
EtOAc L5
EtOAc tBuOLi
EtOAc L5+tBuOLi
34[f]
<5[g]
0
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst
(5 mol%), ligand (5 mol%), base (1.0 equiv.), solvents
°
(1 mL), 80 C, 20 h.
[b] GC yields were determined by using hexadecane as the
internal standard.
[c] Isolated yield is in the parenthesis.
[d]
°
60 C.
[e] 1.2 equivalent of 2a.
[f] no base.
[g] no ligand.
Adv. Synth. Catal. 2019, 361, 1–6
2
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
Table 2. Scope of N-fluoro-sulfonamides.[a]
Table 3. Scope of substituted alkynes.[a]
[a] Reaction conditions: 1a (0.20 mmol), 2b–2o (0.40 mmol),
Cu(OTf)2 (5 mol%), ligand 5 (5 mol%), t-BuOLi (1.0
[a] Reaction conditions: 1a–1n (0.20 mmol), 2a (0.40 mmol),
Cu(OTf)2 (5 mol%), ligand (5 mol%), t-BuOLi (1.0 equiv.),
°
equivalent), EtOAc (2 mL), 80 C, 20 h, isolated yield.
°
EtOAc (2 mL), 80 C, 20 h, isolated yield.
[b] the diastereomeric ratio was determined by 1H NMR analysis
of the crude reaction mixture
Based on previous literatures,[7–9,12] a possible
reaction mechanism is proposed in Scheme 2. The
reaction begins with a CuI induced single electron
distance of radical addition site (Table 3, entry 4). reduction of N-fluoro-sulfonamides to form the copper
Various halogen functional groups were well tolerated (II)-coordinated amidyl radical A. Then the amidyl
in this reaction, which potentially providing a synthetic radical complex undergo an intramolecular 1,5-HAT to
handle for further synthetic modifications (Table 3, afford the new carbon-centered radical B, which go
entries 7–9). Moderate yield can be achieved with 3- through a radical addition process to form the
thiophene system as well (Table 3, entry 10).
intermediate C. Subsequently, an intramolecular elec-
To further demonstrate the functional group com- tron transfer between Cu(II) and vinyl radical in
patibility of this methodology, late-stage functionaliza- intermediate C gives the corresponding cation inter-
tion of medicine celecoxib-derived substrate was mediate D and regenerate the CuI species for the next
studied in this reaction system. Delightfully, the catalytic cycle. Under the assistant of base, the final
reaction of celecoxib-derived substrate worked well product is formed from D.
under the standard conditions and gave the correspond-
ing product in 49% yield (Scheme 1).
In summary, we have develop a cooper-catalyzed
alkynylation of remote C(sp3)À H bonds in N-fluoro-
sulfonamides. This reaction involves amidyl radical
Adv. Synth. Catal. 2019, 361, 1–6
3
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline (Ligand 5)
(1.8 mg, 5 mol%), Cu(OTf)2 (1.8 mg, 5 mol%), and EtOAc
(2 mL). The vials then were changed with argon three times
°
before stirring at 80 C for 20 hours. Afterwards, the tube was
cooled to room temperature and diluted with H2O solution
(1 mL) and extracted with EtOAc (3×3 mL). The solvent was
then evaporated under vacuum. The crude products were
purified by using column chromatography on silica gel
(pentane/ethyl acetate=10: 1) to give the pure products.
References
[1] a) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110,
1147–1169; b) T. Newhouse, P. S. Baran, Angew. Chem.
Int. Ed. 2011, 50, 3362–3374; c) J. He, M. Wasa, K. S.
Chan, Q. Shao, J.-Q. Yu, Chem. Rev. 2016, 117, 8754–
8786; d) J. C. Chu, T. Rovis, Angew. Chem. Int. Ed.
2018, 57, 62–101; e) P. B. Arockiam, C. Bruneau, P. H.
Dixneuf, Chem. Rev. 2012, 112, 5879–5918.
[2] a) H. Matsubara, T. Kawamoto, T. Fukuyama, I. Ryu,
Acc. Chem. Res. 2018, 51, 2023–2035; b) S. Sumino, A.
Fusano, T. Fukuyama, I. Ryu, Acc. Chem. Res. 2014, 47,
1563–1574; c) M. Brubaker, D. Coffman, H. Hoehn, J.
Am. Chem. Soc. 1952, 74, 1509–1515.
[3] A. W. Hofmann, Ber. Dtsch. Chem. Ges. 1883, 16, 558–
560.
Scheme 1. Late-stage functionalization of celecoxib.
[4] a) L. M. Stateman, K. M. Nakafuku, D. A. Nagib, Syn-
thesis 2018, 50, 1569–1586; b) S. Chiba, H. Chen, Org.
Biomol. Chem. 2014, 12, 4051–4060; c) J. Robertson, J.
Pillai, R. K. Lush, Chem. Soc. Rev. 2001, 30, 94–103;
d) J. Hartung, T. Gottwald, K. Špehar, Synthesis 2002,
2002, 1469–1498.
[5] Z. Zhang, L. M. Stateman, D. A. Nagib, Chem. Sci.
2019, 10, 1207–1211.
[6] Z. Li, Q. Wang, J. Zhu, Angew. Chem. Int. Ed. 2018, 57,
13288–13292.
[7] a) Z. Liu, H. Xiao, B. Zhang, H. Shen, L. Zhu, C. Li,
Angew. Chem. Int. Ed. 2019, 58, 2510–2513; b) H.
Zhang, Y. Zhou, P. Tian, C. Jiang, Org. Lett. 2019. 21,
1921–1925.
[8] D. Bafaluy, J. M. Muñoz-Molina, I. Funes-Ardoiz, S.
Herold, A. J. de Aguirre, H. Zhang, F. Maseras, T. R.
Belderrain, P. J. Pérez, K. Muñiz, Angew. Chem. Int. Ed.
2019, 58, 8912–8916.
[9] a) Z. Yin, Z. Zhang, Y. Zhang, P. Dixneuf, X. F. Wu,
Chem. Commun. 2019. 55, 4655–4658; b) Z. Yin, Y.
Zhang, S. Zhang, X.-F. Wu, J. Catal. 2019, 377, 507–
510.
Scheme 2. Proposed mechanism.
[10] F. Diederich, P. J. Stang, R. R. Tykwinski, Acetylene
chemistry: chemistry, biology and material science, John
Wiley & Sons, 2006.
[11] S. P. Morcillo, E. M. Dauncey, J. H. Kim, J. J. Douglas,
N. S. Sheikh, D. Leonori, Angew. Chem. Int. Ed. 2018,
57, 12945–12949.
generation, 1,5-HAT, and alkynylation processes,
which provide an efficient method to construct various
internal alkynes in high yield and regioselectivity.
More importantly, this methodology can also be
applied in the late-stage functionalization of celecoxib.
[12] L. Wang, Y. Xia, K. Bergander, A. Studer, Org. Lett.
2018, 20, 5817–5820.
[13] H. Guan, S. Sun, Y. Mao, L. Chen, R. Lu, J. Huang, L.
Liu, Angew. Chem. 2018, 130, 11583–11587.
Experimental Section
To each sealed tube (4 mL),
alkylsulfonamide (0.30 mmol), t-BuOLi (16.0 mg, 0.2 mmol),
a mixture of N-fluoro-N-
Adv. Synth. Catal. 2019, 361, 1–6
4
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
[14] a) Z. P. Yin, Z. Zhang, J. F. Soule, P. H. Dixneuf, X. F. [15] a) Z. P. Yin, Z. C. Wang, W. F. Li, X. F. Wu, Eur. J. Org.
Wu, J. Catal. 2019, 372, 272–276; b) Z. P. Yin, Z. C.
Wang, X. F. Wu, Org. Biomol. Chem. 2018, 16, 2643–
2646; c) Z. P. Yin, J. Rabeah, A. Bruckner, X. F. Wu,
Org. Lett. 2019, 21, 1766–1769; d) Z. P. Yin, J. Rabeah,
A. Bruckner, X. F. Wu, ACS Catal. 2018, 8, 10926–
10930.
Chem. 2017, 1769–1772; b) Y. H. Li, F. X. Zhu, Z. C.
Wang, X. F. Wu, Chem. Commun. 2018, 54, 1984–1987;
c) Y. H. Li, F. X. Zhu, Z. C. Wang, X. F. Wu, ACS Catal.
2016, 6, 5561–5564.
Adv. Synth. Catal. 2019, 361, 1–6
5
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

UPDATES
Copper-Catalyzed Alkynylation of C(sp3)À H Bonds in N-
Fluoro-sulfonamides
Adv. Synth. Catal. 2019, 361, 1–6
Z. Yin, Y. Zhang, S. Zhang, X.-F. Wu*