Nickel-Catalyzed Alkynylation of a C(sp2)-H Bond Directed by an 8-Aminoquinoline Moiety

Article abstract of DOI:10.1021/acs.joc.5b00669

An efficient nickel catalyst system for the direct ortho C-H alkynylation of the amides has been successfully developed with the directing assistance of 8-aminoquinoline. It was found that the flexible bis(2-dimethylaminoethyl) ether (BDMAE) ligand was cr

Full text of DOI:10.1021/acs.joc.5b00669

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Article
Nickel-Catalyzed Alkynylation of C(sp2)-
H Bond Directed by an 8-Aminoquinoline Moiety
Jun Yi, Li Yang, Chungu Xia, and Fuwei Li
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 18 May 2015
Downloaded from http://pubs.acs.org on May 18, 2015
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Nickel-Catalyzed Alkynylation of C(sp2)-H Bond Directed by an
8-Aminoquinoline Moiety
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Jun Yi†, Li Yang†‡, Chungu Xia,† and Fuwei Li*, †
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† State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP,
Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, P. R.
China
‡ University of Chinese Academy of Sciences, Beijing 100049, P. R. China
E-mail: fuweili@licp.cas.cn
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
ABSTRACT: An efficient nickel catalyst system for the direct ortho C-H alkynylation of the
amides has been successfully developed with the directing assistance of 8-aminoquinoline. It has
been investigated that the flexible bis(2-dimethylaminoethyl) ether (BDMAE) ligand was critical
to achieve the optimized reactivity. This protocol showed good tolerance toward not only a wide
range of (hetero)aryl amides but also the rarely studied α, β-unsaturated alkenyl amide. The
directing amide group could be easily transformed to aldehyde or ester in high yields. Meanwhile,
the removable TIPS substituent on the resultant aryl/alkenyl alkynes could be further converted to
aryl moiety through Sila-Sonogashira coupling reaction. This Ni-catalyzed alkynylation procedure
provides an alternative approach to construct C(sp2)-C(sp) bond.
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INTRODUCTION
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Transition-metal catalyzed direct C-H functionalization is perhaps the ideal method to
construct organic molecules.1 In the past decade, significant advances to promote C-H
functionalization have been achieved with second- and third-row transition metals,2 and
recently the earth-abundant first-row transition metals have been intensively studied to
emulate the reactivity of a noble transition metal catalyst and broaden the C-H
functionalization reactions at a lower cost.3
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Scheme 1. Transition-Metal Catalyzed C-H Alkynylation.
Alkyne motifs are ubiquity in pharmaceuticals, materials and other functional compounds.4
As is known that Sonogashira coupling reaction is the classical choice to synthesize aryl
alkynes,5 but the direct C-H alkynylation has been developed as a more attractive route to
construct C(sp2)-C(sp) bonds, which was mainly realized by Pd,6 Rh,7 Ru.8 (Scheme 1, eq 1)
Recently, Shi and Yu respectively reported their elegant Cu-mediated ortho C-H alkynylation
of the directed arenes and heteroarenes, demonstrating the significant potential of first-row
metal in C-H alkynylation,9 unfortunately, these transformations required either
stoichiometric copper catalyst9a or metallic oxidants9b. In addition, it is worthy to note that the
direct alkynylation of another kind of C(sp2)-H bond, alkenyl C-H, has not yet been
investigated. In comparison with the booming advances of the first-row transition metal
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catalyzed C-H functionalization, their successful application in the alkynylation of inert
C(sp2)-H bonds still remains at an early stage.
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In recent years, nickel has emerged as a promising catalyst for C-H functionalization,
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pioneer works developed by Chatani, Ge, Ackermann, You, Shi, Zeng and Zhang greatly
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broadened the reaction type.10,
However, unfortunately, most of these methods have
limitations such as high reaction temperature (> 140 oC) and limited substrate scope. Thus, it
is highly desirable to develop a new synthetic strategy procedure based on non-precious metal
catalyst to facilely introduce alkyne motifs onto different carbon skeletons considering their
great importance in diverse transformations.12 Herein, we report a nickel-catalyzed C−H
alkynylation reaction between two kinds of inactivated C(sp2)-H and triisopropylsilyl
(TIPS)-substituted bromoalkyne (Scheme 1, eq 2). The present alkynylation has remarkably
broad substrate scope, which is enabled by a bidentate directing group along with the
assistance of the bis(2-dimethylaminoethyl) ether (BDMAE) as a ligand to enhance the
catalytic activity. To the best of our knowledge, this is the first report on Ni-catalyzed
13, 14
C(sp2)-C(sp) bond formation via 8-quinolinyl-chelation assistance.
Besides the C-H
bonds of arylamides and heteroarylamides, the alkynylation of alkenylamides also proceeded
smoothly (26 examples, up to 98% yield).
RESULTS AND DISSCUSION
We
began
our
investigation
by
exploring
the
reaction
between
2-methyl-N-(quinolin-8-yl)benzamide (1) and TIPS-protected bromoalkyne (2) (Table 1).
When we screened the previous reported protocols of Ni-catalyzed C-H functionalization,
fortunately, Ackermann’s method gave the desired product with 25% yield (entries 1-4).10d
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BDMAE was investigated to be a critical ligand in promoting present Ni-catalyzed C-H
alkynylation,10d base screening showed that Na2CO3 produced the optimal yield (entries 4-8),
and appropriate combination of Na2CO3 and BDMAE even gave better performance (entry 9).
At higher reaction temperature, the decomposition of the raw material into 8-aminoquinoline
was detected, and the side reaction could be successfully depressed by lowering the reaction
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o
temperature to 100 C (entry 10). Notably, this is the lowest reaction temperature in
Ni-catalyzed C-H functionalizations directed by 8-quinolinyl.10, 13 Gratifyingly, the simple salt
NiCl2 could be used to perfectly replace [(DME)NiCl2], giving nearly quantitative product
yield (entry 11). As expected, no product was detected in the absence of NiCl2 or BDMAE
(entries 12-13), indicating indispensability of both NiCl2 and ligand for the reaction.
Replacement of BDMAE by classical phase transfer catalyst, tetrabutylammonium iodide
(TBAI), only gave 30% yield of the desired product, demonstrating that the role of BDMAE
was more than a phase transfer reagent. To disclose the role of anion, a series of nickel salts
(NiBr2, NiI2, Ni(OTf)2, Ni(acac)2 and Ni(COD)2) were evaluated under the optimal reaction
condition (entries 15-19). NiBr2 and NiCl2 showed nearly identical activity (entry 15).
Surprisingly, iodine ion hampered the reaction (entry 16), OTf- and acac- also greatly reduced
the yield (entries 17-18). Not only Ni(II) complexes but also Ni(0) complex showed high
catalytic activity in such alkynylation (entry 19). To learn more coordination information in
the active metal species, other bidentate and tridentate ligands were tested (entry 20-25).
When PMTDA, like changing the oxygen atom on BDMAE into nitrogen, was used as the
N-N-N tridentate ligand, the yield was significantly reduced to 65% (entry 20). Moreover, the
bidentate nitrogen ligand with similar flexible skeleton (TMEDA) showed better performance
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than the corresponding tridentate-nitrogen ligand (PMTDA), possibly due to the suitable
coordination ability to the nickel catalysis (entry 21). However, the bidentate nitrogen ligand
with rigid skeleton gave poor reactivity (entries 22-23). When all the nitrogen ligands were
replaced by corresponding structurally similar pure oxygen ligands, the yields were obviously
reduced (entries 24-25). All these results indicated that the coordination atom and
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environment are equally important to achieve the optimized catalytic reactivity.
Table 1. Optimization of the Reaction Conditionsa
yieldb
(%)
Catalyst
(10 mol %)
Ni(OTf)2
Ni(OTf)2
Ni(acac)2
(DME)NiCl2
(DME)NiCl2
(DME)NiCl2
(DME)NiCl2
(DME)NiCl2
(DME)NiCl2
(DME)NiCl2
NiCl2
Ligand
(20 mol %)
PPh3
Base
entry
(2 equiv)
Na2CO3
Na2CO3
Cs2CO3
LiOtBu
Cs2CO3
K3PO4
1
2
Trace
MesCOOH
dppbz
Trace
Trace
25
3
4
BDMAE
BDMAE
BDMAE
BDMAE
BDMAE
BDMAE
BDMAE
BDMAE
-
5
52
6
67
7
K2CO3
70
8
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
75
9c
89
10c, d
11c, d
12c, d
13c, d
14c, d
15 c, d
16 c, d
17 c, d
18 c, d
19 c, d
95
98
NiCl2
Trace
Trace
30
-
BDMAE
TBAI
NiCl2
NiBr2
BDMAE
BDMAE
BDMAE
BDMAE
BDMAE
94
NiI2
65
Ni(OTf)2
Ni(acac)2
Ni(COD)2
50
30
83
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20 c, d
21 c, d
22 c, d
23 c, d
24 c, d
25 c, d
NiCl2
PMDTA
TMEDA
2,2-dipyridyl
dtbpy
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
65
77
8
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
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DME
Diglyme
aUnless otherwise stated, all reactions were carried out with 1 (0.2 mmol), 2 (1.2 equiv), 10 mol% catalyst, 20 mol% ligand,
base (2 equiv.) and toluene (2 mL) at 160 oC for 24h under an argon atmosphere. Yield was calculated based on 1. 40 mol%
b
c
ligand, 5.0 equiv Na2CO3. At 100 oC. OTf = trifluoromethane sulfonate, acac = acetylacetonate, DME = 1,2-dimethoxyethane,
d
dppbz
= 1,2-bis(diphenylphosphino)benzene, Q = 8-quinolinyl, BDMAE = bis(2-dimethylaminoethyl)ether, TBAI =
tetrabutylammonium iodide, TMEDA = N,N,N',N'-Tetramethylethylenediamine, dtbpy = 4,4'-di-tert-butyl bipyridine, PMDTA =
Pentamethyldiethylenetriamine.
With the optimal conditions in hand, we then explored the substrate scope of the protocol
with various decorated benzamides (Table 2). To our delight, present Ni-catalyzed
alkynylation reaction is compatible with various benzamides containing an electron-rich or
electron-deficient substituent at the meta-position, affording the expected alkynes (3b-3j) in
excellent yields (75-92%) and with good mono-selectivity at the less hindered C-H bond.10
Among them, many synthetically valuable groups such as halide (Cl, Br, I) could be reserved
under mild reactions, which gave the chances for further modification of the products (3f, 3g,
3h). Surprisingly, nitro group which was scarcely tolerated in the nickel-catalyzed reactions
was also compatible with present transformation (3i).15 Acetyl group which was sensitive to
strong base also retained with good yield (3j). Ortho-fluoride substituted benzamide gave a
moderate yield of the expected (3k). Additionally, alkynylation of the corresponding
2-naphthamide smoothly solely occurred at the less hinder position, affording (3l) in a 88%
yield. When the para-substituted substrates were used, small amount of dialkynylation
products were found irrespective of the electronic nature of the substituent (3m, 3n, 3o).
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Disubstituted benzamides also gave the desired alkynylation products in excellent yields (3p,
3q).
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Scheme 2. Scope of Aromatic Amidesa, b
aCondition A: 1 (0.20 mmol), 2 (1.2 equiv), NiCl2 (10 mol%), BDMAE (40 mol%), Na2CO3 (5 equiv), toluene (2
mL), 100 oC, 24 h. bYield was calculated based on 1. c36h.
Encouraged by these results, we turned our interest to heterocyclic substrates which
were common motifs in medicinal chemistry (Table 3).16 To our delight, alkynylation of
heteroaromatic amides with pyridine, quinoxaline, benzothiophene, pyrazole and thiazole
moiety all gave the corresponding products with synthetically useful yields (5a-5e,
33-72%). Interestingly, strongly coordinating heteroatoms like sulfur and nitrogen have no
interference to the reaction. Because of the good compatibility of heterocyclic substrates,
this method has potential application in the pharmaceutical chemistry.
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Scheme 3. Scope of Heteroaromatic Amidesa, b
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aCondition B: 4 (0.2 mmol), 2 (1.2 equiv), NiCl2 (10 mol%), BDMAE (40 mol%), Na2CO3 (5.0 equiv), o-xylene (2
mL), 120 oC, 36 h. bYield was calculated based on 4. ctoluene (2 mL), 100 oC, 24 h.
Compared with above mentioned arylamide, the alkynylation of α, β-unsaturated amides
is far more challenging due to the higher flexibility of alkenylamides, and so far has been
rarely investigated. Interestingly, as shown in Table 4, present Ni/BDMAE catalyst system
showed good tolerance toward, both cyclic- and open-chain α, β-unsaturated alkenylamides,
giving corresponding alkenyl alkynes in good yield (7a-7d). But the substituent at
α-carbon was essential for the reactivity of the substrate. Otherwise, no alkynylation
reaction occured.
Scheme 4. Scope of Alkenylamidesa, b
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aCondition C: 6 (0.2 mmol), 2 (1.2 equiv), NiCl2 (10 mol%), BDMAE (40 mol%), Na2CO3 (5.0 equiv), toluene (2
mL), 100 oC, 24 h. bYield was calculated based on 6. c36h.
To further probe the practical utility of this nickel-catalyzed C-H alkynylation, a
gram-scale reaction was conducted. As depicted in Scheme 5, 1.130 g (4.0 mmol) scale of
1f could be converted to 3f in 75% yield under the optimized reaction condition. Next,
conversion of the directing amide group was also illustrated by treating 3f with Schwartz's
reagent, providing the corresponding aldehyde 8a in 82% yield. On the other hand, the
amide moiety of 3g could also transfer to ester 8b by reaction with BF3·Et2O and MeOH in
72% yield. Subsequently, the TIPS could be easily converted to phenyl group to yield 8c in
95% yield through the Sila-Sonogashira coupling reaction, which means other aryl
substituents could be similarly introduced. Notably, 8c is the key intermediate in the synthesis
of 17β-hydroxysteroid dehydrogenase type-3 (17β-HSD3) inhibitor which was considered to
be clinical candidate for the treatment of prostate cancer.17
Scheme 5. Gram-Scale Reaction and Further Conversion
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To probe the mechanism of the reaction, some deuterium-labeling experiments were carried out
as shown in Scheme 6. A significant intermolecular kinetic isotope effect (KIE = 3.2) was
observed (Scheme 6a),18 indicating the cleavage of the ortho-C-H bond of the substrate may be the
rate-determining step in the catalytic cycle. Moreover, intramolecular H/D exchange between N-H
bond of the amide and its ortho-C-H bonds with the chelation assistance was observed in the
absence of TIPS-substituted bromoalkyne (Scheme 6b). These two control experiments suggest
that rapid and reversible cleavages of C-H bonds are involved in the process. Additionally, the
competition experiment with different electronic substituent shows that the reaction favors with
electron-withdrawing group (Scheme 6c). The electronic effect of substituents and high KIE value
both indicate that the cleavage of ortho-C-H bond may be experienced
a
concerted-metalation-deprotonation (CMD) mechanism.10c, f, 19 Furthermore, no obvious yield
changing was observed although 3.0 equiv TEMPO was added (Scheme 6c), indicating the
single-electron transfer (SET) in this reaction could be ruled out. Based on our investigations and
the reported results, it is believed that BDMAE ligand may take multiple roles in this protocol,
first, it could stabilize the active organometallic species with a suitable geometry to prevent it
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against decomposition and enhance the catalytic activity,15, 21 which could be seen from the
obvious catalytic difference of catalytic system with (98%, entry 11 of Table 1) and without
BDMAE (trace, entry 12 of Table 1). In addition, BDMAE could help the C-H cleavage step
because no H/D exchanged was occurred without BDMAE (Scheme 6b).
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Scheme 6. Mechanistic Experiments
Based on the above investigations and previous reports,13 we propose a plausible mechanism
shown in Scheme 7. Initially, the coordination of amide to nickel catalyst followed by ligand
exchange to form complex 9, which could go through cyclometalation to give intermediate 10, the
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oxidative addition of the bromoalkyne afforded the high valent Ni(IV) complex 11, which
underwent reductive elimination and protonation to yield the alkynylation product with
regeneration of the Ni(II) catalyst.
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Scheme 7. Proposed Reaction Mechanism
CONCLUSIONS
In conclusion, we have developed a Ni-catalyzed direct C-H alkynylation via bidentate-chelation
strategy using BDMAE as an additional ligand, which significantly promoted the C-H bond
cleavage. The protocol was characterized by good compatibility with biologically important
heterocyclic amides and more challenging α, β-unsaturated alkenyl amides. Mechanistic studies
reveal that the C-H cleavage may be the rate-determining step and single-electron transfer route is
less possible. This method provided a new approach to synthesize aryl- and alkenyl-alkynes, and
may also inspire useful ideas for the development of Ni-catalyzed C-H functionalization.
EXPERIMENT SECTION
General Information
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Solvents and chemicals were used as received. H NMR, 13C NMR spectra were recorded on a
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400 MHz spectrometer at the ambient temperature, using TMS as an internal standard (chemical
shifts in δ). Data are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, dt = doublet of triplet, etc.),
coupling constant (Hz), and integration. Gas chromatographic (GC) analyses were performed on a
GC equipped with a flame-ionization detector. High resolution mass spectra were obtained on a
HRMS-TOF spectrometer. Analytical thin layer chromatography (TLC) was performed on
pre-coated silica gel plates. After elution, plate was visualized under UV illumination at 254 nm
for UV active materials. Organic solutions were concentrated under reduced pressure on a rotary
evaporator. Column chromatography was performed on silica gel (200−300 mesh) by standard
techniques eluting with solvents as indicated. Melting points were obtained on IA9000 SERIES
Digital Melting Point Apparatus.
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Preparation of 8-Aminoquinoline-bearing carboxamides.
8-Aminoquinoline-bearing carboxamides were prepared according to the conditions reported in
literatures. The acid chlorides were prepared from the corresponding acid by reaction with oxalic
dichloride. Purification of the crude product by silica gel column chromatography gave the final
product.
General Procedure for Examples Described in Table 2, 3, 4
In a glove box, NiCl2 (10 %, 2.6 mg), Na2CO3 (5.0 equiv., 106 mg) and 0.2 mmol
corresponding amide (if solid) were added to a 15 mL Schlenk tube equipped with a stir bar. The
vessel was evacuated and filled with nitrogen (three cycles). 0.2 mmol amide (if liqid), 2.0 mL
solvent, 15 µL BDMAE and 0.24 mmol TIPS-substituted bromoalkyne was added in turn under
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nitrogen atmosphere. The reaction mixture was stirred for particular time and temperature. Then
the reaction was diluted with EtOAc and filtered through silica gel with copious washings.
Purification of the crude product by flash chromatography on silica gel using the indicated solvent
system afforded the desired product.
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6-methyl-N-(quinolin-8-yl)-2-((triisopropylsilyl)ethynyl)benzamide (3a): According to the general
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procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by flash
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chromatography (PE : EA = 5 : 1, Rf = 0.2) as a colorless oil. Yield: 86.7 mg, 98%. H NMR (400
MHz, CDCl3) δ 10.13 (brs, 1H), 9.02 (dd, J = 7.4, 1.5 Hz, 1H), 8.74 (dd, J = 4.3, 1.6 Hz, 1H), 8.18 (dd,
J = 8.3, 1.6 Hz, 1H), 7.64 – 7.51 (m, 2H), 7.47 – 7.38 (m, 2H), 7.32 – 7.19 (m, 2H), 2.46 (s, 3H), 0.85 –
0.67 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ 167.3, 147.9, 140.1, 138.2, 136.5, 135.6, 134.6,
130.5, 130.4, 128.9, 127.9, 127.4, 121.8, 121.5, 120.9, 117.2, 103.9, 94.9, 19.5, 18.3, 11.0; HRMS
(ESI-TOF) m/z Calcd for C28H35N2OSi+ [M+H]+ 443.2513, found 443.2510.
5-methyl-N-(quinolin-8-yl)-2-((triisopropylsilyl)ethynyl)benzamide (3b): According to the general
o
procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by flash
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chromatography (PE : EA = 10 : 1, Rf = 0.3) as a colorless oil. Yield: 81.4 mg, 92%. H NMR (400
MHz, CDCl3) δ 10.50 (brs, 1H), 8.92 (dd, J = 7.5, 1.1 Hz, 1H), 8.76 (dd, J = 4.2, 1.6 Hz, 1H), 8.16 (dd,
J = 8.3, 1.6 Hz, 1H), 7.63 – 7.49 (m, 4H), 7.43 (dd, J = 8.2, 4.2 Hz, 1H), 7.28 – 7.21 (m, 1H), 2.42 (s,
3H), 0.90 – 0.73 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ 166.8, 148.3, 139.2, 139.2, 139.0,
136.4, 134.8, 134.0, 131.1, 129.4, 128.1, 127.5, 122.0, 121.6, 117.9, 117.3, 104.2, 96.2, 21.6, 18.5, 11.2;
HRMS (ESI-TOF) m/z Calcd for C28H35N2OSi+ [M+H]+ 443.2513, found 443.2511.
N-(quinolin-8-yl)-4-((triisopropylsilyl)ethynyl)-[1,1'-biphenyl]-3-carboxamide (3c): According to the
o
general procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by
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flash chromatography (PE : EA = 10 : 1, Rf = 0.35) as a colorless oil. Yield: 89.8 mg, 89%. H NMR
(400 MHz, CDCl3) δ 10.57 (brs, 1H), 8.95 (d, J = 7.4 Hz, 1H), 8.77 (dd, J = 4.2, 1.4 Hz, 1H), 8.17 (dd,
J = 8.3, 1.4 Hz, 1H), 8.05 (d, J = 0.9 Hz, 1H), 7.72 – 7.53 (m, 6H), 7.50 – 7.34 (m, 4H), 0.97 – 0.72 (m,
21H); 13C{1H}NMR (100 MHz, CDCl3) δ 166.5, 148.2, 141.5, 139.7, 139.5, 138.8, 136.4, 134.6, 134.4,
129.0, 128.6, 128.0, 128.0, 127.4, 127.3, 127.1, 122.0, 121.5, 119.5, 117.3, 103.8, 97.8, 18.4, 11.1;
HRMS (ESI-TOF) m/z Calcd for C33H37N2OSi+ [M+H]+ 505.2670, found 505.2673.
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N-(quinolin-8-yl)-5-(trifluoromethyl)-2-((triisopropylsilyl)ethynyl)benzamide (3d): According to the
o
general procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by
flash chromatography (PE : EA = 10 : 1, Rf = 0.35) as a white solid. Mp = 116 oC; Yield: 82.4 mg,
83%. 1H NMR (400 MHz, CDCl3) δ 10.55 (brs, 1H), 8.91 (dd, J = 7.1, 1.6 Hz, 1H), 8.77 (dd, J = 4.2,
1.5 Hz, 1H), 8.19 (dd, J = 8.3, 1.5 Hz, 1H), 8.07 (s, 1H), 7.71 (dd, J = 20.5, 8.2 Hz, 2H), 7.65 – 7.54 (m,
2H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H), 0.89 – 0.79 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ 165.0,
148.3, 139.8, 138.7, 136.4, 134.3, 134.3, 130.6 (q, J = 33.2 Hz), 127.9, 127.4, 126.7 (q, J = 3.5 Hz),
125.9 (q, J = 3.7 Hz), 124.3, 123.5 (q, J = 272.2 Hz), 122.3, 121.6, 117.4, 102.5, 100.6, 18.3, 11.0;
HRMS (ESI-TOF) m/z Calcd for C28H32F3N2OSi+ [M+H]+ 497.2231, found 497.2233.
5-methoxy-N-(quinolin-8-yl)-2-((triisopropylsilyl)ethynyl)benzamide (3e): According to the general
o
procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by flash
chromatography (PE : EA = 10 : 1, Rf = 0.15) as a yellow solid. Mp = 62-63 oC; Yield: 83.4 mg, 91%.
1H NMR (400 MHz, CDCl3) δ 10.54 (brs, 1H), 8.93 – 8.88 (m, 1H), 8.75 (dd, J = 4.2, 1.7 Hz, 1H), 8.13
(dd, J = 8.3, 1.6 Hz, 1H), 7.60 – 7.49 (m, 3H), 7.40 (dd, J = 8.2, 4.2 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H),
6.95 (dd, J = 8.6, 2.8 Hz, 1H), 3.84 (s, 3H), 0.88 – 0.70 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ
166.1, 159.7, 148.2, 140.6, 138.9, 136.1, 135.4, 134.6, 127.9, 127.2, 121.9, 121.4, 117.1, 117.0, 113.1,
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112.9, 103.9, 95.1, 55.5, 18.3, 11.1; HRMS (ESI-TOF) m/z Calcd for C28H35N2O2Si+ [M+H]+ 459.2462,
found 459.2461.
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5-chloro-N-(quinolin-8-yl)-2-((triisopropylsilyl)ethynyl)benzamide (3f): According to the general
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procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by flash
chromatography (PE : EA = 10 : 1, Rf = 0.3) as a white solid, Mp = 67-68 oC; Yield: 80.4 mg, 87%. 1H
NMR (400 MHz, CDCl3) δ 10.50 (brs, 1H), 8.89 (dd, J = 7.1, 1.7 Hz, 1H), 8.77 (dd, J = 4.2, 1.5 Hz,
1H), 8.17 (dd, J = 8.3, 1.3 Hz, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.64 – 7.50 (m, 3H), 7.47 – 7.37 (m, 2H),
0.94 – 0.66 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ 164.9, 148.3, 140.6, 138.8, 136.3, 135.1,
134.8, 134.4, 130.3, 128.9, 127.9, 127.3, 122.2, 121.6, 119.2, 117.3, 102.8, 98.4, 18.3, 11.0; HRMS
(ESI-TOF) m/z Calcd for C27H32ClN2OSi+ [M+H]+ 463.1967, found 463.1971.
5-bromo-N-(quinolin-8-yl)-2-((triisopropylsilyl)ethynyl)benzamide (3g): According to the general
o
procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by flash
chromatography (PE : EA = 10 : 1, Rf = 0.3) as a white solid, Mp = 81-82 oC; Yield: 85.0 mg, 84%. H
1
NMR (400 MHz, CDCl3) δ 10.50 (brs, 1H), 8.89 (d, J = 7.1 Hz, 1H), 8.77 (dd, J = 4.2, 1.4 Hz, 1H),
8.17 (dd, J = 8.3, 1.4 Hz, 1H), 7.78 (d, J = 2.1 Hz, 1H), 7.62 – 7.52 (m, 3H), 7.42 (ddd, J = 10.5, 8.3,
3.2 Hz, 2H), 0.92 – 0.72 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ 165.0, 148.3, 140.6, 138.8,
136.3, 135.1, 134.8, 134.4, 130.3, 128.9, 127.9, 127.4, 122.2, 121.6, 119.2, 117.3, 102.8, 98.4, 18.3,
11.0; HRMS (ESI-TOF) m/z Calcd for C27H32BrN2OSi+ [M+H]+ 507.1462, found 507.1462.
5-iodo-N-(quinolin-8-yl)-2-((triisopropylsilyl)ethynyl)benzamide (3h): According to the general
o
procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by flash
chromatography (PE : EA = 10 : 1, Rf = 0.3) as a pink solid, Mp = 86-87 oC; Yield: 100.9 mg, 91%. 1H
NMR (400 MHz, CDCl3) δ 10.49 (brs, 1H), 8.91 (dd, J = 7.2, 1.8 Hz, 1H), 8.79 (dd, J = 4.2, 1.7 Hz,
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1H), 8.19 (dd, J = 8.3, 1.7 Hz, 1H), 8.15 (d, J = 1.8 Hz, 1H), 7.79 (dd, J = 8.2, 1.9 Hz, 1H), 7.64 – 7.55
(td, J = 8.7, 4.5 Hz, 2H), 7.46 (dd, J = 8.3, 4.2 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 0.92 – 0.74 (m, 21H);
13C{1H}NMR (100 MHz, CDCl3) δ 164.7, 148.3, 140.6, 139.0, 138.7, 137.5, 136.3, 135.0, 134.4, 127.9,
127.4, 122.1, 121.6, 120.2, 117.3, 103.0, 98.9, 94.3, 18.3, 11.0; HRMS (ESI-TOF) m/z Calcd for
C27H32IN2OSi+ [M+H]+ 555.1323, found 555.1319.
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5-nitro-N-(quinolin-8-yl)-2-((triisopropylsilyl)ethynyl)benzamide (3i): According to the general
o
procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by flash
chromatography (PE : EA = 20 : 1, Rf = 0.45) as a white solid, Mp = 98-99 oC; Yield: 71.0 mg, 75%.
1H NMR (400 MHz, CDCl3) δ 10.52 (brs, 1H), 8.89 (dd, J = 6.4, 2.6 Hz, 1H), 8.76 (dd, J = 4.2, 1.6 Hz,
1H), 8.64 (d, J = 2.4 Hz, 1H), 8.26 (dd, J = 8.5, 2.4 Hz, 1H), 8.18 (dd, J = 8.3, 1.7 Hz, 1H), 7.75 (d, J =
8.5 Hz, 1H), 7.62 – 7.55 (m, 2H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H), 0.94 – 0.71 (m, 21H); 13C{1H}NMR
(100 MHz, CDCl3) δ 163.9, 148.4, 147.0, 140.4, 138.7, 136.3, 134.8, 134.1, 127.9, 127.3, 127.0, 124.5,
124.0, 122.4, 121.6, 117.3, 104.0, 102.0, 18.2, 11.0; HRMS (ESI-TOF) m/z Calcd for C27H32N3O3Si+
[M+H]+ 474.2207, found 474.2210.
5-acetyl-N-(quinolin-8-yl)-2-((triisopropylsilyl)ethynyl)benzamide (3j): According to the general
o
procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by flash
chromatography (PE : EA = 10 : 1, Rf = 0.2) as a yellow solid, Mp = 70-71 oC; Yield: 76.2 mg, 81%.
1H NMR (400 MHz, CDCl3) δ 10.52 (brs, 1H), 8.89 (dd, J = 7.2, 1.7 Hz, 1H), 8.74 (dd, J = 4.2, 1.7 Hz,
1H), 8.33 (d, J = 1.8 Hz, 1H), 8.15 (dd, J = 8.3, 1.7 Hz, 1H), 7.99 (dd, J = 8.1, 1.8 Hz, 1H), 7.66 (d, J =
8.1 Hz, 1H), 7.60 – 7.52 (m, 2H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 2.62 (s, 3H), 0.88 – 0.72 (m, 21H);
13C{1H}NMR (100 MHz, CDCl3) δ 196.6, 165.5, 148.3, 139.5, 138.8, 136.5, 136.2, 134.4, 134.1, 129.1,
128.9, 127.9, 127.3, 125.0, 122.1, 121.5, 117.2, 103.1, 101.3, 26.7, 18.3, 11.0; HRMS (ESI-TOF) m/z
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Calcd for C29H35N2O2Si+ [M+H]+ 471.2462, found 471.2466.
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2-fluoro-N-(quinolin-8-yl)-6-((triisopropylsilyl)ethynyl)benzamide (3k): According to the general
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procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by flash
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chromatography (PE : EA = 10 : 1, Rf = 0.35) as a white solid, Mp = 105-106 oC; Yield: 37.5 mg, 42%.
1H NMR (400 MHz, CDCl3) δ 10.20 (brs, 1H), 8.97 (dd, J = 7.1, 1.8 Hz, 1H), 8.75 (dd, J = 4.2, 1.6 Hz,
1H), 8.17 (dd, J = 8.3, 1.6 Hz, 1H), 7.61 – 7.54 (m, 2H), 7.43 (dd, J = 8.2, 4.2 Hz, 1H), 7.38 (dd, J =
5.8, 4.3 Hz, 2H), 7.18 – 7.13 (m, 1H), 0.88 – 0.72 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ 162.1,
159.2 (d, J = 250.3 Hz), 148.1, 138.4, 136.2, 134.4, 130.7 (d, J = 9.0 Hz), 128.9 (d, J = 3.3 Hz), 128.3
(d, J = 18.6 Hz), 127.8, 127.3, 123.2 (d, J = 4.8 Hz), 122.0, 121.5, 117.0, 116.3 (d, J = 21.8 Hz), 102.3
(d, J = 3.8 Hz), 97.1, 18.3, 11.0; HRMS (ESI-TOF) m/z Calcd for C27H32FN2OSi+ [M+H]+ 447.2262,
found 447.2265.
N-(quinolin-8-yl)-3-((triisopropylsilyl)ethynyl)-2-naphthamide (3l): According to the general procedure,
o
the reaction mixture was stirred at 100 C for 24 h. The product was isolated by flash chromatography
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(PE : EA = 10 : 1, Rf = 0.2) as a pale yellow solid, Mp = 107-108 oC; Yield: 84.2 mg, 88%. H NMR
(400 MHz, CDCl3) δ 10.54 (brs, 1H), 8.98 (d, J = 7.6 Hz, 1H), 8.75 (dd, J = 4.2, 1.6 Hz, 1H), 8.30 (s,
1H), 8.16 (dd, J = 8.8, 2.1 Hz, 2H), 7.93 – 7.81 (m, 2H), 7.64 – 7.51 (m, 4H), 7.42 (dd, J = 8.2, 4.2 Hz,
1H), 0.95 – 0.74 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ 166.4, 148.2, 138.8, 136.2, 136.0, 134.8,
134.2, 133.4, 132.2, 128.8, 128.6, 127.9, 127.9, 127.5, 127.4, 127.3, 121.8, 121.4, 117.7, 117.1, 104.3,
96.3, 18.4, 11.2; HRMS (ESI-TOF) m/z Calcd for C31H35N2OSi+ [M+H]+ 479.2513, found 479.2510.
N-(quinolin-8-yl)-2-((triisopropylsilyl)ethynyl)benzamide (3m-mono): According to the general
o
procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by flash
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chromatography (PE : EA = 20 : 1, Rf = 0.35) as a colorless oil. Yield: 50.5 mg, 58%. H NMR (400
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MHz, CDCl3) δ 10.49 (brs, 1H), 8.93 (d, J = 7.4 Hz, 1H), 8.75 (dd, J = 4.1, 1.5 Hz, 1H), 8.14 (dd, J =
8.3, 1.7 Hz, 1H), 7.83 – 7.75 (m, 1H), 7.63 – 7.50 (m, 3H), 7.45 – 7.39 (m, 3H), 0.81 (dt, J = 7.1, 4.0
Hz, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ 166.4, 148.2, 139.2, 138.9, 136.2, 134.7, 133.9, 130.1,
128.6, 128.6, 127.9, 127.3, 121.8, 121.4, 120.7, 117.1, 103.9, 97.1, 18.3, 11.1; HRMS (ESI-TOF) m/z
Calcd for C27H33N2OSi+ [M+H]+ 429.2357, found 429.2353.
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N-(quinolin-8-yl)-2,6-bis((triisopropylsilyl)ethynyl)benzamide (3m-di): According to the general
o
procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by flash
chromatography (PE : EA = 50 : 1, Rf = 0.5) as a white oil. Yield: 14.7 mg, 13%. 1H NMR (400 MHz,
CDCl3) δ 10.07 (brs, 1H), 9.00 (dd, J = 7.4, 1.4 Hz, 1H), 8.74 (dd, J = 4.1, 1.5 Hz, 1H), 8.17 (d, J = 8.2
Hz, 1H), 7.60 – 7.50 (m, 4H), 7.43 (dd, J = 8.2, 4.2 Hz, 1H), 7.36 – 7.32 (m, 1H), 0.88 (s, 42H);
13C{1H}NMR (100 MHz, CDCl3) δ 165.5, 147.9, 143.5, 138.4, 136.1, 134.8, 132.3, 128.7, 127.7, 127.2,
+
121.4, 121.4, 121.3, 117.1, 103.0, 95.8, 18.3, 11.1; HRMS (ESI-TOF) m/z Calcd for C38H53N2OSi2
[M+H]+ 609.3691, found 609.3688.
4-methoxy-N-(quinolin-8-yl)-2-((triisopropylsilyl)ethynyl)benzamide (3n-mono): According to the
o
general procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by
flash chromatography (PE : EA = 20 : 1, Rf = 0.25) as a white solid, Mp = 63 oC; Yield: 46.6 mg, 51%.
1H NMR (400 MHz, CDCl3) δ 10.51 (brs, 1H), 8.88 (d, J = 7.2 Hz, 1H), 8.75 (dd, J = 4.2, 1.6 Hz, 1H),
8.13 (dd, J = 8.3, 1.7 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.54 (dt, J = 8.2, 7.6 Hz, 2H), 7.40 (dd, J = 8.2,
4.1 Hz, 1H), 7.09 (d, J = 2.6 Hz, 1H), 6.96 (dd, J = 8.7, 2.6 Hz, 1H), 3.86 (s, 3H), 0.91 – 0.71 (m, 21H);
13C{1H}NMR (100 MHz, CDCl3) δ 166.0, 160.7, 148.2, 139.0, 136.1, 134.8, 131.7, 130.8, 127.9, 127.3,
122.1, 121.6, 121.4, 118.5, 117.1, 114.9, 103.9, 97.2, 55.5, 18.3, 11.1; HRMS (ESI-TOF) m/z Calcd for
C28H35N2O2Si+ [M+H]+ 459.2462, found 459.2465.
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general procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by
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flash chromatography (PE : EA = 40 : 1, Rf = 0.5) as a white solid, Mp = 108-109 oC; Yield: 23.3 mg,
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18%. H NMR (400 MHz, CDCl3) δ 10.05 (brs, 1H), 8.99 (dd, J = 7.4, 1.5 Hz, 1H), 8.74 (dd, J = 4.1,
1.8 Hz, 1H), 8.16 (dd, J = 8.3, 1.6 Hz, 1H), 7.58 – 7.50 (m, 2H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 7.04 (s,
2H), 3.87 (s, 3H), 0.88 (s, 42H); 13C{1H}NMR (100 MHz, CDCl3) δ 165.5, 159.2, 147.9, 138.5, 136.9,
136.0, 135.0, 127.7, 127.2, 122.6, 121.3, 121.2, 118.0, 116.9, 103.1, 95.6, 55.6, 18.3, 11.1; HRMS
(ESI-TOF) m/z Calcd for C39H55N2O2Si2+ [M+H]+ 639.3797, found 639.3801.
4-chloro-N-(quinolin-8-yl)-2-((triisopropylsilyl)ethynyl)benzamide (3o-mono): According to the
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general procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by
flash chromatography (PE : EA = 20 : 1, Rf = 0.3) as a white solid. Mp = 79-80 oC; Yield: 39.6 mg,
43%. 1H NMR (400 MHz, CDCl3) δ 10.48 (brs, 1H), 8.87 (dd, J = 7.3, 1.6 Hz, 1H), 8.74 (dd, J = 4.2,
1.7 Hz, 1H), 8.14 (dd, J = 8.3, 1.7 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.62 – 7.50 (m, 3H), 7.44 – 7.37
(m, 2H), 0.92 – 0.65 (m, 21H). 13C{1H}NMR (100 MHz, CDCl3) δ 165.3, 148.3, 138.8, 137.5, 136.2,
136.1, 134.4, 133.4, 130.1, 129.0, 127.9, 127.3, 122.3, 122.0, 121.5, 117.2, 102.5, 99.0, 18.3, 11.0;
HRMS (ESI-TOF) m/z Calcd for C27H32ClN2OSi+ [M+H]+ 463.1967, found 463.1962.
4-chloro-N-(quinolin-8-yl)-2,6-bis((triisopropylsilyl)ethynyl)benzamide (3o-di): According to the
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general procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by
flash chromatography (PE : EA = 30 : 1, Rf = 0.5) as a white solid. Mp = 97-98 oC; Yield: 33.7 mg,
26%. 1H NMR (400 MHz, CDCl3) δ 10.07 (brs, 1H), 8.96 (dd, J = 7.0, 2.0 Hz, 1H), 8.75 (dd, J = 4.2,
1.7 Hz, 1H), 8.17 (dd, J = 8.3, 1.6 Hz, 1H), 7.61 – 7.48 (m, 4H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H), 0.87 (s,
42H); 13C{1H}NMR (100 MHz, CDCl3) δ 164.7, 148.0, 141.8, 138.4, 136.1, 134.7, 134.5, 132.0, 127.7,
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127.2, 123.0, 121.6, 121.4, 117.0, 101.7, 97.6, 18.3, 11.0; HRMS (ESI-TOF) m/z Calcd for
C38H52ClN2OSi2+ [M+H]+ 643.3301, found 643.3299.
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4-fluoro-2-methyl-N-(quinolin-8-yl)-6-((triisopropylsilyl)ethynyl)benzamide (3p): According to the
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general procedure, the reaction mixture was stirred at 100 C for 36 h. The product was isolated by
flash chromatography (PE : EA = 20 : 1, Rf = 0.25) as a colorless oil. Yield: 95.05mg, 95%. 1H NMR
(400 MHz, CDCl3) δ 10.09 (brs, 1H), 8.97 (dd, J = 7.2, 1.6 Hz, 1H), 8.73 (dd, J = 4.2, 1.6 Hz, 1H),
8.14 (dd, J = 8.3, 1.6 Hz, 1H), 7.59 – 7.51 (m, 2H), 7.41 (dd, J = 8.2, 4.2 Hz, 1H), 7.06 (dd, J = 8.9, 2.5
Hz, 1H), 6.93 – 6.87 (m, 1H), 2.44 (s, 3H), 0.86 – 0.62 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ
166.4, 162.0 (d, J = 248.8 Hz), 148.1, 138.7 (d, J = 8.9 Hz), 138.5, 136.6 (d, J = 3.1 Hz), 136.2, 134.6,
127.9, 127.2, 122.8 (d, J = 10.3 Hz), 121.9, 121.5, 117.6 (d, J = 21.4 Hz), 116.8, 116.8 (d, J = 22.9 Hz),
102.7 (d, J = 3.2 Hz), 96.4, 19.6, 18.2, 11.0; HRMS (ESI-TOF) m/z Calcd for C28H34FN2OSi+ [M+H]+
461.2419, found 461.2422.
2-methyl-3-(quinolin-8-ylcarbamoyl)-4-((triisopropylsilyl)ethynyl)phenyl acetate (3q): According to
the general procedure, the reaction mixture was stirred at 100 oC for 36 h. The product was isolated by
flash chromatography (PE : EA = 10 : 1, Rf = 0.15) as a white solid. Mp = 141-142 oC; Yield: 81.0 mg,
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88%. H NMR (400 MHz, CDCl3) δ 10.13 (brs, 1H), 8.98 (dd, J = 7.1, 1.9 Hz, 1H), 8.75 (dd, J = 4.2,
1.7 Hz, 1H), 8.16 (dd, J = 8.3, 1.7 Hz, 1H), 7.62 – 7.51 (m, 2H), 7.48 – 7.39 (m, 2H), 7.08 (d, J = 8.4
Hz, 1H), 2.34 (s, 3H), 2.28 (s, 3H), 0.97 – 0.54 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ 168.9,
166.1, 149.4, 148.2, 142.0, 138.5, 136.1, 134.6, 131.4, 128.3, 127.8, 127.2, 123.0, 121.9, 121.5, 118.9,
116.9, 103.2, 95.2, 20.8, 18.2, 13.2, 11.0; HRMS (ESI-TOF) m/z Calcd for C30H37N2O3Si+ [M+H]+
501.2568, found 501.2571.
2-methyl-N-(quinolin-8-yl)-4-((triisopropylsilyl)ethynyl)nicotinamide (5a): According to the general
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procedure, the reaction mixture was stirred at 120 C for 36 h. The product was isolated by flash
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chromatography (PE : EA = 5 : 1, Rf = 0.15) as a yellow oil. Yield: 48.8 mg, 55%. 1H NMR (400 MHz,
CDCl3) δ 10.11 (brs, 1H), 8.95 (dd, J = 6.7, 2.3 Hz, 1H), 8.73 (dd, J = 4.2, 1.7 Hz, 1H), 8.51 (d, J = 5.2
Hz, 1H), 8.16 (dd, J = 8.3, 1.7 Hz, 1H), 7.62 – 7.51 (m, 2H), 7.43 (dd, J = 8.3, 4.2 Hz, 1H), 7.30 – 7.21
(m, 1H), 2.68 (s, 3H), 0.90 – 0.51 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ 165.6, 156.0, 149.3,
148.2, 138.4, 136.2, 134.4, 134.1, 129.0, 127.8, 127.3, 123.7, 122.1, 121.6, 117.0, 101.3, 101.1, 22.7,
18.2, 10.9; HRMS (ESI-TOF) m/z Calcd for C27H34N3OSi+ [M+H]+ 444.2466, found 444.2466.
N-(quinolin-8-yl)-7-((triisopropylsilyl)ethynyl)quinoxaline-6-carboxamide (5b): According to the
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general procedure, the reaction mixture was stirred at 120 C for 36 h. The product was isolated by
flash chromatography (PE : EA = 5 : 1, Rf = 0.15) as a yellow solid. Mp = 175-176 oC; Yield: 65.3 mg,
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68%. H NMR (400 MHz, CDCl3) δ 10.52 (brs, 1H), 8.97 (dd, J = 7.3, 1.6 Hz, 1H), 8.90 (dd, J = 9.4,
1.8 Hz, 2H), 8.75 (dd, J = 4.2, 1.7 Hz, 1H), 8.51 (d, J = 4.8 Hz, 1H), 8.39 (d, J = 3.0 Hz, 1H), 8.18 (dd,
J = 8.3, 1.7 Hz, 1H), 7.63 – 7.56 (m, 2H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H), 0.97 – 0.79 (m, 21H);
13C{1H}NMR (100 MHz, CDCl3) δ 165.0, 148.3, 146.7, 146.1, 143.0, 142.2, 140.3, 138.7, 136.3, 135.2,
134.4, 129.7, 127.9, 127.3, 122.5, 122.2, 121.6, 117.2, 102.8, 99.9, 18.3, 11.1; HRMS (ESI-TOF) m/z
Calcd for C29H33N4OSi+ [M+H]+ 481.2418, found 481.2414.
N-(quinolin-8-yl)-2-((triisopropylsilyl)ethynyl)benzo[b]thiophene-3-carboxamide (5c): According to
the general procedure, the reaction mixture was stirred at 100 oC for 24 h. The product was isolated by
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flash chromatography (PE : EA = 10 : 1, Rf = 0.25) as a pink solid. Mp = 84-85 C; Yield: 69.7 mg,
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72%. H NMR (400 MHz, CDCl3) δ 10.66 (brs, 1H), 8.95 (dd, J = 7.5, 1.4 Hz, 1H), 8.77 (dd, J = 4.2,
1.6 Hz, 1H), 8.36 – 8.31 (dd, J = 8.3, 1.6 Hz, 1H), 8.16 (dd, J = 8.3, 1.6 Hz, 1H), 7.78 – 7.73 (m, 1H),
7.65 – 7.53 (m, 2H), 7.46 – 7.40 (m, 3H), 1.01 – 0.76 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ
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161.6, 148.3, 139.0, 138.9, 137.2, 136.2, 135.6, 134.5, 128.0, 127.3, 126.4, 125.5, 124.9, 124.4, 122.0,
121.6, 121.5, 117.4, 105.3, 97.4, 18.3, 11.0; HRMS (ESI-TOF) m/z Calcd for C29H33N2OSSi+ [M+H]+
485.2077, found 485.2082.
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1-methyl-N-(quinolin-8-yl)-4-((triisopropylsilyl)ethynyl)-1H-pyrazole-5-carboxamide (5d): According
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to the general procedure, the reaction mixture was stirred at 120 C for 36 h. The product was isolated
by flash chromatography (PE : EA = 5 : 1, Rf = 0.3) as a red oil. Yield: 52.7 mg, 61%. 1H NMR (400
MHz, CDCl3) δ 10.62 (brs, 1H), 8.77 (dd, J = 4.2, 1.7 Hz, 1H), 8.70 (t, J = 4.5 Hz, 1H), 8.15 (dd, J =
8.3, 1.7 Hz, 1H), 7.64 (s, 1H), 7.56 (d, J = 4.6 Hz, 2H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 4.15 (s, 3H),
0.99 – 0.75 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ 157.6, 148.7, 141.7, 139.3, 137.7, 136.3,
134.0, 128.0, 127.1, 122.8, 121.7, 118.3, 104.6, 97.6, 96.5, 39.7, 18.5, 11.2; HRMS (ESI-TOF) m/z
Calcd for C25H33N4OSi+ [M+H]+ 433.2418, found 433.2417.
2-methyl-N-(quinolin-8-yl)-5-((triisopropylsilyl)ethynyl)thiazole-4-carboxamide (5e): According to the
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general procedure, the reaction mixture was stirred at 120 C for 36 h. The product was isolated by
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flash chromatography (PE : EA = 10 : 1, Rf = 0.3) as a yellow solid. Mp = 82-83 C; Yield: 29.7 mg,
33%. 1H NMR (400 MHz, CDCl3) δ 10.77 (brs, 1H), 8.80 (dd, J = 4.2, 1.7 Hz, 1H), 8.65 (t, J = 4.5 Hz,
1H), 8.17 (dd, J = 8.3, 1.7 Hz, 1H), 7.60 – 7.55 (m, 2H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H), 2.73 (s, 3H),
1.02 – 0.87 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ 168.4, 158.7, 148.5, 139.2, 138.3, 136.3,
135.1, 133.9, 128.0, 127.1, 122.7, 121.5, 118.7, 99.5, 98.9, 19.6, 18.4, 11.1; HRMS (ESI-TOF) m/z
Calcd for C25H32N3OSSi+ [M+H]+ 450.2030, found 450.2028.
N-(quinolin-8-yl)-2-((triisopropylsilyl)ethynyl)cyclohex-1-ene-1-carboxamide (7a): According to the
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general procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated by
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flash chromatography (PE : EA = 10 : 1, Rf = 0.3) as a white solid. Mp = 81-82 C; Yield: 74.4 mg,
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86%. H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.84 (dd, J = 7.3, 1.4 Hz, 1H), 8.80 (dd, J = 4.2, 1.6
Hz, 1H), 8.16 (dd, J = 8.3, 1.6 Hz, 1H), 7.59 – 7.48 (m, 2H), 7.43 (dd, J = 8.2, 4.2 Hz, 1H), 2.53 (brs,
2H), 2.38 (brs, 2H), 1.79 – 1.67 (m, 4H), 0.82 – 0.66 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ
168.0, 148.1, 141.4, 138.8, 136.3, 134.6, 128.0, 127.4, 121.7, 121.6, 121.4, 117.2, 105.3, 97.0, 31.2,
26.5, 21.9, 21.6, 18.3, 11.0; HRMS (ESI-TOF) m/z Calcd for C27H37N2OSi+ [M+H]+ 433.2670, found
433.2673.
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N-(quinolin-8-yl)-6-((triisopropylsilyl)ethynyl)-3,4-dihydro-2H-pyran-5-carboxamide (7b): According
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to the general procedure, the reaction mixture was stirred at 100 C for 24 h. The product was isolated
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by flash chromatography (PE : EA = 20 : 1, Rf = 0.35) as a white solid. Mp = 60-61 C; Yield: 66.9
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mg, 77%. H NMR (400 MHz, CDCl3) δ 10.30 (brs, 1H), 8.79 – 8.72 (m, 2H), 8.13 (dd, J = 8.3, 1.6 Hz,
1H), 7.54 – 7.45 (m, 2H), 7.41 (dd, J = 8.2, 4.2 Hz, 1H), 4.13 – 4.08 (m, 2H), 2.55 (t, J = 6.5 Hz, 2H),
1.98 – 1.90 (m, 2H), 0.84 – 0.55 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ 166.6, 148.1, 139.1,
138.8, 136.2, 134.7, 127.9, 127.3, 121.4, 121.3, 118.1, 117.0, 99.1, 97.6, 66.7, 22.2, 21.1, 18.12, 10.9;
HRMS (ESI-TOF) m/z Calcd for C26H35N2O2Si+ [M+H]+ 435.2462, found 435.2461.
(Z)-2-methyl-N-(quinolin-8-yl)-5-(triisopropylsilyl)pent-2-en-4-ynamide (7c): According to the general
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procedure, the reaction mixture was stirred at 100 C for 36 h. The product was isolated by flash
chromatography (PE : EA = 20 : 1, Rf = 0.3) as a white solid, Mp = 109-110 oC; Yield: 61.2 mg, 78%.
1H NMR (400 MHz, CDCl3) δ 10.40 (brs, 1H), 8.84 – 8.74 (m, 2H), 8.13 (dd, J = 8.3, 1.7 Hz, 1H), 7.56
– 7.48 (m, 2H), 7.41 (dd, J = 8.2, 4.2 Hz, 1H), 5.93 (d, J = 1.6 Hz, 1H), 2.14 (d, J = 1.6 Hz, 3H), 0.83 –
0.66 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ 166.4, 148.2, 145.7, 138.9, 136.1, 134.3, 127.9,
127.3, 121.8, 121.4, 117.2, 111.2, 102.0, 98.7, 20.3, 18.2, 11.0; HRMS (ESI-TOF) m/z Calcd for
C24H33N2OSi+ [M+H]+ 393.2357, found 393.2354.
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(Z)-3-ethyl-2-methyl-N-(quinolin-8-yl)-5-(triisopropylsilyl)pent-2-en-4-ynamide (7d): According to the
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general procedure, the reaction mixture was stirred at 100 C for 36 h. The product was isolated by
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flash chromatography (PE : EA = 20 : 1, Rf = 0.25) as a pink solid, Mp = 45 oC; Yield: 46.2 mg, 55%.
1H NMR (400 MHz, CDCl3) δ 10.24 (brs, 1H), 8.84 (dd, J = 7.3, 1.6 Hz, 1H), 8.79 (dd, J = 4.2, 1.6 Hz,
1H), 8.14 (dd, J = 8.3, 1.7 Hz, 1H), 7.56 – 7.48 (m, 2H), 7.42 (dd, J = 8.2, 4.2 Hz, 1H), 2.35 (q, J = 7.5
Hz, 2H), 2.09 (d, J = 0.5 Hz, 3H), 1.22 (t, J = 7.5 Hz, 3H), 0.82 – 0.61 (m, 21H); 13C{1H}NMR (100
MHz, CDCl3) δ 168.8, 148.1, 138.9, 138.8, 136.1, 134.6, 127.9, 127.3, 125.4, 121.5, 121.3, 116.9,
104.8, 97.3, 26.5, 18.2, 15.7, 12.3, 11.0; HRMS (ESI-TOF) m/z Calcd for C26H37N2OSi+ [M+H]+
421.2670, found 421.2674.
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Gram Scale Reaction and Further Conversion
In a glove box, NiCl2 (10 %, 52 mg), Na2CO3 (5.0 equiv., 2.12 g) and 1f (4.0 mmol, 1.13 g) were
added to a 100 mL Schlenk tube equipped with a stir bar. The vessel was evacuated and filled with
nitrogen (three cycles). 40 mL toluene, 300 µL BDMAE and 4.8 mmol TIPS-substituted bromoalkyne
was added under nitrogen atmosphere. The reaction mixture was stirred at 100 oC for 24h. Then the
reaction was diluted with EtOAc and filtered through silica gel with copious washings. Purification of
the crude product by flash chromatography (PE : EA = 10 : 1, Rf = 0.3) on silica gel afforded 3f with
75% yield.
5-chloro-2-((triisopropylsilyl)ethynyl)benzaldehyde (8a): In a glove box, 3f (1 mmol), Cp2ZrHCl (2
mmol), and THF (10 mL) were added to a 25 mL Schlenk tube. The reaction mixture was stirred at
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room temperature for 6 h before carefully quenched by saturated ammonium chloride at 0 C. After
extracted with CH2Cl2 (3×25 mL), the combined organic extract was washed with brine, dried over
MgSO4 and concentrated in vacuum. Purification of the crude product by flash chromatography (PE :
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EA = 50 : 1, Rf = 0.5) on silica gel afforded 8a as colorless oil with 82% yield (52.5 mg). H NMR
(400 MHz, CDCl3) δ 10.53 (s, 1H), 7.99 – 7.68 (m, 1H), 7.63 – 7.42 (m, 2H), 1.20 – 1.12 (m, 21H);
13C{1H}NMR (100 MHz, CDCl3) δ 190.4, 137.2, 135.2, 135.1, 133.7, 126.9, 125.3, 100.8, 100.5, 18.6,
11.2; HRMS (ESI-TOF) m/z Calcd for C18H26ClOSi+ [M+H]+ 321.1436, found 321.1438.
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methyl 5-bromo-2-((triisopropylsilyl)ethynyl)benzoate (8b): To a 10 mL Kontes flask equipped with a
stir bar was added 3g (0.3 mmol, 1 equiv.). Inside the glove box, dry methanol (4 mL) was added to the
flask. Outside the glove box, BF3·Et2O (0.25 mL) was added dropwise to the stirred solution. The
resulting mixture was stirred at 100 °C for 24 h. After cooling to rt, Et3N (4 mL) was added dropwise
to the reaction mixture with stirring, then concentrated in vacuo. Purification of the crude product by
flash chromatography (PE : EA = 100 : 1, Rf = 0.6) on silica gel afforded 8a as colorless oil with 72%
yield (56.8 mg); 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 2.1 Hz, 1H), 7.60 (dd, J = 8.3, 2.1 Hz, 1H),
7.49 (d, J = 8.3 Hz, 1H), 3.96 (s, 3H), 1.22 – 1.13 (m, 21H); 13C{1H}NMR (100 MHz, CDCl3) δ 165.7,
136.2, 134.4, 133.9, 133.1, 122.3, 121.9, 104.0, 98.0, 52.5, 18.6, 11.3; HRMS (ESI-TOF) m/z Calcd for
C19H28BrO2Si+ [M+H]+ 395.1036, found 395.1032.
methyl 5-bromo-2-(phenylethynyl)benzoate (8c): In a glovebox, 8b (0.2 mmol), iodobenzene (0.3
mmol), PdCl2 (5%, 1.8 mg), CuI (2.5%, 1 mg), TBAF (0.6 mmol), THF (5 mL) were added to a 25 mL
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Schlenk tube. The reaction mixture was stirred at 50 C for 6 h. Purification of the crude product by
flash chromatography (PE : EA = 100 : 1, Rf = 0.5) on silica gel afforded 8a as colorless oil with 95%
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yield (59.7 mg); H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 2.1 Hz, 1H), 7.69 – 7.48 (m, 4H), 7.45 –
7.31 (m, 3H), 3.99 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 165.3, 135.2, 134.8, 133.5, 133.2, 131.7,
+
128.8, 128.4, 123.0, 122.7, 121.8, 95.5, 87.3, 52.5; HRMS (ESI-TOF) m/z Calcd for C16H12BrO2
[M+H]+ 315.0015, found 315.0017.
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In a glove box, NiCl2 (10 %, 2.6 mg), Na2CO3 (5.0 equiv., 106 mg), 0.1 mmol 1m and 0.1 mmol D-1m
were added to a Schlenk tube equipped with a stir bar. The vessel was evacuated and filled with
nitrogen (three cycles). 2.0 mL toluene, 15 µL BDMAE and 0.24 mmol TIPS-substituted bromoalkyne
was added in turn under nitrogen atmosphere. The reaction mixture was stirred 100 °C for 1 hour. Then
the reaction was diluted with EtOAc, and filtered through silica gel with copious washings (EtOAc).
The residue was concentrated, and purified by column chromatography. The product was analyzed by
1H NMR. The corresponding dialkynylation product was not detected. A KIE value of KH/KD = 3.2
was obtained.
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Intermolecular competition experiment
In a glove box, NiCl2 (10 %, 2.6 mg), Na2CO3 (5.0 equiv., 106 mg), 0.24 mmol 1d and 0.24 mmol 1e
were added to a Schlenk tube equipped with a stir bar. The vessel was evacuated and filled with
nitrogen (three cycles). 2.0 mL toluene, 15 µL BDMAE and 0.20 mmol TIPS-substituted bromoalkyne
was added in turn under nitrogen atmosphere. The reaction mixture was stirred 100 °C for 4 hours.
Then the reaction was diluted with EtOAc and filtered through silica gel with copious washings
(EtOAc). The residue was concentrated, and purified by column chromatography. 3d was yield 31.7
mg (32%). 3e was yield 8.2 mg (9%).
Radical trapping experiment
In a glove box, NiCl2 (10 %, 2.6 mg), Na2CO3 (5.0 equiv., 106 mg), 0.20 mmol of 1a , and 0.6 mmol of
TEMPO (3.0 equiv. 94 mg) were added to a Schlenk tube equipped with a stir bar. The vessel was
evacuated and filled with nitrogen (three cycles). 2.0 mL toluene, 15 µL BDMAE and 0.24 mmol
TIPS-substituted bromoalkyne was added in turn under nitrogen atmosphere. The reaction mixture was
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stirred 100 °C for 24 hours. Then the reaction was diluted with EtOAc, filtered through silica gel with
copious washings (EtOAc). The residue was concentrated, and purified by column chromatography. 3a
was yield 76 mg (86%).
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ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
*Email: cgxia@licp.cas.cn and fuweili@licp.cas.cn
Notes
We declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the National Natural Science Foundation of
China (21133011 and 21373246) and the Chinese Academy of Sciences
Supporting Information.
Characterization data of all new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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