Copper(II)/Silver(I)-Catalyzed Sequential Alkynylation and Annulation of Aliphatic Amides with Alkynyl Carboxylic Acids: Efficient Synthesis of Pyrrolidones

Article abstract of DOI:10.1002/adsc.201500727

A highly efficient protocol for the synthesis of pyrrolidones by the copper-catalyzed alkynylation/annulation of aliphatic amides with alkynyl carboxylic acids is discussed in this paper. A broad range of easily accessible alkynyl carboxylic acids were introduced at the β-methyl group of aliphatic amides with the assistance of an 8-aminoquinolyl auxiliary group via decarboxylation to achieve the subsequent cyclic C-N bond formation within one hour. High selectivity of β-methyl groups over methylene groups was observed, and the extension of this catalytic system to the activation of methylene C-H bonds failed. The substrates with two different groups at the α-position of the aliphatic amides lead to the formation of diastereoisomers which is determined by ¹H NMR spectroscopy. The initially produced products with Z-configurations can be easily transformed to the corresponding products with E-configurations by the treatment with dilute p-toluenesulfonic acid after the reaction. This catalytic tandem decarboxylative cyclization provides a new opportunity for the direct functionalization of sp³ C-H bonds.

Full text of DOI:10.1002/adsc.201500727

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DOI: 10.1002/adsc.201500727
Very Important Publication
Copper(II)/Silver(I)-Catalyzed Sequential Alkynylation and An-
nulation of Aliphatic Amides with Alkynyl Carboxylic Acids: Ef-
ficient Synthesis of Pyrrolidones
Jitan Zhang,a Danyang Li,a Hui Chen,a Binjie Wang,a Zhanxiang Liu,a
and Yuhong Zhanga,b,*
a
Department of Chemistry, ZJU-NHU United R&D Center, Zhejiang University, Hangzhou 310027, Peopleꢀs Republic of
China
Fax: (+86)-571-8795-3244; e-mail: yhzhang@zju.edu.cn
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, Peopleꢀs Republic of China
b
Received: August 3, 2015; Revised: November 6, 2015; Published online: December 16, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500727.
Abstract: A highly efficient protocol for the synthe- groups at the a-position of the aliphatic amides lead
sis of pyrrolidones by the copper-catalyzed alkynyla- to the formation of diastereoisomers which is deter-
1
tion/annulation of aliphatic amides with alkynyl car- mined by H NMR spectroscopy. The initially pro-
boxylic acids is discussed in this paper. A broad duced products with Z-configurations can be easily
range of easily accessible alkynyl carboxylic acids transformed to the corresponding products with E-
were introduced at the b-methyl group of aliphatic configurations by the treatment with dilute p-tolue-
amides with the assistance of an 8-aminoquinolyl nesulfonic acid after the reaction. This catalytic
auxiliary group via decarboxylation to achieve the tandem decarboxylative cyclization provides a new
3
À
À
subsequent cyclic C N bond formation within one opportunity for the direct functionalization of sp C
hour. High selectivity of b-methyl groups over meth- H bonds.
ylene groups was observed, and the extension of this
À
catalytic system to the activation of methylene C H Keywords: alkynylation/annulations; C–H activation;
bonds failed. The substrates with two different copper; decarboxylation; pyrrolidones
3
À
Introduction
a number of new approaches for C(sp ) H bond func-
tionalization including arylation, alkynylation, alkoxy-
The transition metal-catalyzed direct functionalization lation, alkylation, cyclization, and amination.[6] De-
À
of C H bonds has proven to be an economical and spite these significant achievements, the direct func-
straightforward alternative to traditional synthetic tionalization of sp3 C H bonds is still in its early
À
methods which rely on the use of reactive functional stage. The coupling partners are very limited, and the
groups. The advantages of C H activation have en- exploration of new active coupling partners for the
smooth functionalization of C(sp ) H bonds is highly
heteroatom bonds with great efficiency and selectivi- desired.
ty. However, transition metal-catalyzed direct func- Catalytic decarboxylative coupling is considered to
tionalization of unactivated C(sp ) H bonds is espe- be one of the most promising atom-economical organ-
cially challenging due to its inertness and competing ic processes for C C bond formation, because the use
À
3
À
À
À
abled the construction of carbon carbon and carbon
3
[1]
À
À
b-hydride elimination. In recent years, the strategy of of a stoichiometric amount of organometallic or or-
chelation-assisted C H activation has significantly im- ganic halide reagents can be avoided.[7] Since Meyersꢀ
À
3
À
proved the selective C(sp ) H functionalization, and original reports of the palladium-mediated decarboxy-
important transformations of sp3 C H bonds have lative coupling of olefins and benzoic acids,[8] exten-
À
been achieved.[2,3] In particular, the bidentate strategy, sive studies on catalytic decarboxylation have been
which was first introduced by the Daugulis group,[4] carried out throughout the past few decades.[9] For ex-
presents a powerful capability to increase the reactivi- ample, biaryls were successfully prepared by palladi-
3
À
ty of sp C H bonds through the formation of stable um-catalyzed decarboxylative coupling of aryl carbox-
metallacycle
intermediates,[5,6a]
which
allowed ylic acid salts with aryl halides/tosylates by Gooßen
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Cu(II)/Ag(I)-Catalyzed Sequential Alkynylation and Annulation
Table 1. Optimization of reaction conditions.[a]
and coworkers.[10] The key point of this chemistry is
the formation of organometallic species from the low
cost, diverse, and ready availability carboxylate salts
via metal-mediated extrusion of CO2 to undergo the
subsequent coupling reactions. Depending on the cat-
alytic system and the reaction conditions employed,
diverse organometallic species, such as acyl and aryl
metallic intermediates, can be generated in situ, lead-
ing to the establishment of a range of useful cross-
coupling reactions.[11] In recent years, the develop-
Entry
[Cu]
Additive
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
Cu(OAc)2·H2O
Cu(OAc)2
Cu(OAc)2·H2O
Cu(OTFA)2
Cu(OTf)2
CuI
CuBr
CuCl
Cu(OAc)2·H2O
Cu(OAc)2·H2O
trace
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAB
NaI
92 (<1:99)
92 (<1:99)
70 (<1:99)
66 (<1:99)
72 (<1:99)
69 (<1:99)
51 (<1:99)
78 (<1:99)
16 (<1:99)
ment of new decarboxylation reactions capable of cat-
2
À
alytically transforming the inert C(sp ) H bonds of
organic molecules into useful functional groups has
opened up attractive new strategies for C C bond for-
mation, which has rapidly emerged as a very active
area of research.[12] However, the catalytic decarboxy-
lative coupling reaction with the use of an unactivated
À
À
alkyl C H bond as the reaction partner has not yet
been achieved.
[a]
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), [Cu]
(0.02 mmol), Ag2CO3 (0.4 mmol), additive (0.3 mmol),
DMF (1.5 mL), 1 h at 1408C. The reaction solution was
treated with p-toluenesulfonic acid for half an hour after
the reaction. The ratio of 3a to 3aꢀ before the treatment
with p-toluenesulfonic acid is presented in the parenthe-
ses.
Isolated yield of 3a based on 1a by flash column chroma-
tography. Q=Quinolin-8-yl, TBAI=Tetrabutylammoni-
um Iodide.
Results and Discussion
Recently, we developed nickel-catalyzed thioetherifi-
cation[13] and copper-mediated aryloxylation[14] of un-
[b]
3
À
activated C(sp ) H bonds by employing a bidentate
directing group. We envisioned that the difficult but
highly desirable decarboxylative cross-coupling of al-
kynyl carboxylic acids with unactivated aliphatic
3
À
C(sp ) H bonds might be achieved by applying biden-
tate strategy to form the alkynylated products. Al- Information). To understand the role of the TBAI,
2
À
though great efforts have been made towards C(sp )
various additives were tested. The replacement of
H bond alkynylation,[15,16] only few catalytic systems TBAI with tetrabutylammonium bromide (TBAB)
3
À
for the alkynylation of C(sp ) H bonds have been re- gave a yield of 78% (Table 1, entry 9). Other ammo-
ported.[17] We began by screening reaction conditions nium salts, such as tetrabutylammonium chloride
for the decarboxylative coupling of propionamide (TBACl), tetraethylammonium bromide (TEAB), and
(1a) with phenylpropiolic acid (2a) under copper cat- tetraethylammonium iodide (TEAI) proved less effec-
alysis with the assistance of an 8-aminoquinoline aux- tive for the reaction (see Supporting Information). It
iliary, which was first introduced by the Daugulis re- was observed that the addition of TBAI resulted in
search group[4] (Table 1).
the better solubility of the catalyst and metal oxidant
To our delight, a trace of new compound 3aꢀ was (see Supporting Information). These results indicate
observed using 20 mol% Cu(OAc)2 in the presence of that the main role of TBAI in this reaction might be
Ag2CO3 in DMF at 1408C for 1 h (Table 1, entry 1). as a phase transfer catalyst to promote the reaction.[18]
After extensive screening of a large array of reaction The use of Cu(OAc)2·H2O as the catalyst gave a com-
parameters, we found that the addition of tetrabutyl- parable result (Table 1, entry 3). After careful charac-
ammonium iodide (TBAI) significantly improved the terization, it was concluded that 3a was not the ex-
reaction and 3aꢀ was observed as the main product. pected simple alkynylated product but a five-mem-
However, after flash column chromatography separa- bered ring lactam, which is a derivative of pyrroli-
tion, a mixture of 3a and 3aꢀ was obtained. This done. Pyrrolidones are important structural motifs of
result illustrates that the transformation of compound natural products and pharmaceutical agents,[19] and
3aꢀ to 3a was easily achieved. To obtain a pure com- much effort is focused on their synthesis.[20] The single
pound, the reaction solution was treated with dilute crystal X-ray analysis further confirmed the structure
p-toluenesulfonic acid for half an hour after the reac- of the product[21] (see Supporting Information). Thus,
tion at room temperature (see Experimental Section a new set of reaction conditions for the synthesis of
for details). Fortunately, a thorough transformation of pyrrolidones by copper-catalyzed tandem decarboxy-
compound 3aꢀ to 3a took place, and pure 3a was iso- lative cross-coupling/cyclization of aliphatic amides
lated in 92% yield (Table 1, entry 2; see Supporting and alkynyl carboxylic acids was developed.
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Jitan Zhang et al.
Table 2. Substrate scope of alkynyl carboxylic acids.[a,b]
Other copper salts, including Cu(OTFA)2,
Cu(OTf)2, CuI, CuBr, and CuCl, also showed reactivi-
ty (Table 1, entries 4–8). The reaction can be per-
formed in many common solvents, such as DMSO,
toluene, and N,N-dimethylacetamide (DMA), albeit
DMF afforded the best result ( see Supporting Infor-
mation).
With this efficient catalytic system in hand, we stud-
ied the generality of this new tandem decarboxylative
cross-coupling/cyclization reaction with diverse alkyn-
yl carboxylic acids as summarized in Table 2. Notably,
most of the products presented excellent stereoselec-
tivity to give the products with an E-configuration.
Both electron-rich and electron-deficient alkynyl car-
boxylic acids displayed excellent reactivity to give the
corresponding five-membered ring lactams in high
yields (Table 2, 3a–3k), but 3-(4-methoxyphenyl)pro-
piolic acid presented a slightly lower reactivity
(Table 2, 3g). Various functionalities, such as -CH3,
-OCH3, -F, -Cl, -Br, and -CN (Table 2, 3h–3k), were
tolerated, showing the good generality of this catalytic
process. 3-(Naphthalen-1-yl)propiolic acid participat-
ed smoothly in the reaction, which resulted in 63%
yield (Table 2, 3l). The employment of heterocyclic
alkynyl carboxylic acids, such as 3-(thiophen-3-yl)pro-
piolic acid and 3-(thiophen-2-yl)propiolic acid, result-
ed in the successful generation of the desired lactam
products (Table 2, 3m and 3n). It should be noted
that the relatively less reactive alkylpropiolic acids,
such as 3-cyclohexylpropiolic acid and 3-cyclopropyl-
propiolic acid, showed comparable reactivity to afford
the corresponding lactams in good yields (Table 1, 3o
and 3p). However, the transformation and isolation
of the stereoisomer was quite difficult and a mixture
of Z- and E-isomers was obtained.
Under similar reaction conditions, various aliphatic
amides reacted smoothly with 2a to produce the cor-
responding substituted pyrrolidones (Table 3). When
the two substituent groups at the a-position of the ali-
phatic amides were different, a mixture of two iso-
mers was obtained, and the control experiments im-
plied that the mixture consisted of two diastereoiso-
1
mers whose ratio was determined by H NMR (see
Supporting Information for details). For instance, sub-
strate amides 1b–1m, which bear two different sub-
stituent groups at their a-position, generated the cor-
responding products as a mixture of two isomers
while substrate amides 1n–1r with two of the same
substituent groups at the a-position afforded the de-
sired products as a single isomer. Excellent site selec-
tivity of the b-methyl groups over the methylene and
benzyl groups was presented, and the coupling of g-
À
or d-methyl group C H bonds was not observed
(Table 3, 4a–4j). In the case of 2-phenyl-substituted
substrates, the reaction showed an excellent selectivity
3
À
for the sp C H bonds of the b-methyl group over the
À
aromatic C H bonds of the phenyl group (Table 3,
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Cu(II)/Ag(I)-Catalyzed Sequential Alkynylation and Annulation
Table 3. Substrate scope of aliphatic amides.
Table 2. (Continued)
[a]
Reaction conditions: 1a (0.1 mmol),
2 (0.2 mmol),
Cu(OAc)2·H2O (0.02 mmol), Ag2CO3 (0.4 mmol), TBAI
(0.3 mmol), DMF (1.5 mL), 1 h at 1408C. The reaction
solution was treated with dilute p-toluenesulfonic acid
for half an hour after the reaction at room temperature.
Isolated yield of 3 based on 1a by flash column chroma-
tography. Q=Quinolin-8-yl, TBAI=Tetrabutylammoni-
um Iodide.
[b]
4k–4m), indicating the preferential formation of
a five-membered ring aliphatic copper intermediate
as opposed to a six membered ring aromatic copper
intermediate in the metalation step.[6p] It was worth-
while to note that the cyclic substrates, including cy-
clopropanecarboxamide, cyclobutanecarboxamide, cy-
clopentanecarboxamide, and cyclohexanecarbox-
amide, could participate in the reaction to produce
valuable spiro-g-lactams (4n–4q), which are impor-
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Table 4. Reactions of aromatic amides with alkynyl carbox-
ylic acids.
Table 3. (Continued)
2
À
activity (Table 4, 6a–6h). The cleavage of C(sp ) H
bonds in meta-methyl substituted benzamide occurred
predominantly at the sterically less congested site and
the yield of ortho-substituted benzamides was obvi-
ously decreased due to the steric factor (Table 4, 6b
and 6c). The generality of alkynyl carboxylic acids is
superior. A range of functionalities, such as methyl,
methoxyl, fluorine, and chlorine, could be tolerated
under the reaction conditions, which allowed for the
highly diverse synthesis of functionalized isoindolin-1-
ones (Table 4, 6i-6l). 3-(Thiophen-2-yl)propiolic acid
tant drug intermediates that are difficult to synthesize gave the thiophene containing isoindolinone in 94%
by the known methods.[22] Interestingly, along with the yield (Table 4<xtabr4, 6m). Cyclopropylpropiolic
enlargement of the ring at the a-position of the acid was compatible with the standard reaction condi-
amides, the enhanced reactivity was obtained by pro- tions to deliver 6n in 78% yield. Importantly, acryl-
ducing diverse spiro-g-lactam products in higher amide substrate showed comparable reactivity to
yields, which is due in part to the more suitable angle afford the fused pyrrolidone in good yield (Table 4,
for the formation of metallacycle intermediate.[6h] Un- 6o).
fortunately, the substrate amide bearing hydrogen at
The exact mechanism of this tandem decarboxyla-
the a-position could not be tolerated in this reaction tive cross-coupling/cyclization is not clear at the
À
and the C H bonds of methylene were not reactive moment. The decarboxylation may be promoted by
as well (4r and 4s).
either copper or silver salts to form phenylacetylide
The presented copper-catalyzed decarboxylative species.[7a] Alternatively, a protodecarboxylation pro-
cyclic-coupling reaction can be successfully extended cess might be involved to generate ethynylbenzene
to various substituted aromatic amides as shown in which transforms to phenylacetylide species in the
Table 4. A variety of aromatic amides bearing either presence of silver and copper salts. This possibility is
electron-withdrawing groups or electron-donating proven by the reaction of 1a and ethynylbenzene
groups were applicable to the transformation to pro- under the standard reaction conditions, which pro-
duce diverse isoindolin-1-ones.[16j] However, electron- duced pyrrolidone 3a in a low yield (Scheme 1, eq. 1).
deficient benzamides showed the relatively lower re- Furthermore, we optimized the reaction conditions
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Cu(II)/Ag(I)-Catalyzed Sequential Alkynylation and Annulation
Table 5. Reactions of 1a with terminal alkynes[a]
Scheme 1. The control experiments.
for terminal alkynes in this transformation and the
scope of substrates is summarized in Table 5. These
results indicate that terminal alkynes were less effec-
tive than alkynyl carboxylic acids in this copper cata-
lytic system. Further investigation proved that the al-
[a]
Reaction conditions: 1a (0.1 mmol),
2 (0.2 mmol),
Cu(OAc)2·H2O (0.02 mmol), Ag2CO3 (0.4 mmol), TBAI
(0.4 mmol), DMF (1.5 mL), 1 h at 1508C. The reaction
solution was treated with p-toluenesulfonic acid for half
an hour after the reaction. Isolated yield of 3 based on
1a by flash column chromatography. Q =Quinolin-8-yl,
TBAI=tetrabutylammonium iodide.
kynylated product
7
existed in the reaction
(Scheme 1, eq. 2; see Supporting Information). The
intramolecular cyclization process occurred with the
combination of catalytic Ag2CO3 and TBAI in the ab-
sence of copper catalysis but a trace of 3a was ob-
served in the absence of TBAI (Scheme 1, eq. 3–5).
Because the silver(I) catalyzed intramolecular hydro- nism. The subsequent reductive elimination of inter-
amination of alkynes has been reported by Looper mediate C generates the alkynylated product 7, which
and Bi,[23] we proposed that the TBAI might promote undergoes the intramolecular cyclization to give the
the dissolution of Ag2CO3 in the organic solvent so pyrrolidone derivative.
that the silver(I)-catalyzed cyclization of 7 could pro-
ceed smoothly. Based on the previous study[6p,24] and
our experiment results, a tentative reaction pathway Conclusions
is hypothesized as shown in Scheme 2. First, inter-
mediate A forms through a C–H cyclocupration pro- In summary, we have developed a highly efficient
cess and the oxidation of A by another copper(II) method for the synthesis of pyrrolidones via the
species gives rise to the alkyl/CuIII complex B, which copper-catalyzed tandem decarboxylative cross-cou-
undergoes the ligand exchange with metal phenylace- pling/cyclization of aliphatic amides and alkynyl car-
tylide to give alkynyl copper intermediate C. boxylic acids. For the first time, the catalytic decar-
MALDI-TOF mass analysis of the reaction mixture boxylative process is extended to the direct function-
3
À
of benzamide 5a and alkynyl carboxylic acid 2a alization of unactivated sp C H bonds. The reaction
indeed presented the signal of the exact mass of al- features short reaction time (1 h), a broad substrate
kynyl copper intermediate D (Scheme 3; see Support- scope, and readily available reagents. The detailed
ing Information), which partially supports the mecha- mechanistic study of the reaction and exploration of
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Jitan Zhang et al.
Scheme 2. The plausible mechanism.
Copper(II)/Silver(I)-Catalyzed Sequential
Alkynylation and Annulation of Aliphatic Amides
with Alkynyl Carboxylic Acids
A mixture of N-(quinolin-8-yl)pivalamide (1a, 22.8 mg,
0.1 mmol), Cu(OAc)2·H2O (3.9 mg, 0.02 mmol), Ag2CO3
(110.3 mg, 0.4 mmol), TBAI (110.8 mg, 0.3 mmol), phenyl-
propiolic acid (2a, 29.2 mg, 0.2 mmol) and DMF (1.5 mL)
was added to a 25 mL sealed tube. The tube was stirred at
1408C for 1 h. Then, the reaction mixture was cooled to
room temperature, and dilute p-toluenesulfonic acid
(1.0 mL, 0.2m in CH2Cl2) was added in the reaction system,
by stirring for half an hour at room temperature. A saturat-
ed solution of potassium carbonate (10.0 mL) was added to
the reaction tube. The mixture was extracted with ethyl ace-
tate (3”15 mL), and the organic phase was dried over
Na2SO4 and was concentrated in vacuo. Then the mixture
was subjected to column chromatography on silica gel
(hexane/ethyl acetate=2:1) to give the desired product (3a,
30.2 mg, 92%).
Scheme 3. Matrix-assisted Laser Desorption Ionization
Time-of-flight Mass Spectroscopy (MALDI-TOF-MS) of D
obtained from the reaction of 5a and 2a under standard
conditions for 15 min.
decarboxylative coupling of other carboxylic acids
3
À
with sp C H bonds are currently underway in our
laboratory.
(Z)-5-Benzylidene-3,3-dimethyl-1-(quinolin-8-yl)pyrroli-
din-2-one (3a’): Rf 0.53 (hexane/EtOAc=2:1). Yellow oil.
Isolated yield: 28.9 mg, 89%. 1H NMR ([D6]DMSO,
400 MHz) d 8.86 (dd, J1 =1.6 Hz, J2 =4.0 Hz, 1H), 8.17 (dd,
J1 =1.6 Hz, J2 =8.0 Hz, 1H), 7.92 (dd, J1 =1.2 Hz, J2 =
8.0 Hz, 1H), 7.44–7.47 (m, 1H), 7.37–7.39 (m, 1H), 7.27–
7.31 (m, 1H), 6.56–6.60 (m, 1H), 6.44 (t, J=7.6 Hz, 2H),
6.35 (d, J=7.6 Hz, 2H), 5.69 (s, 1H), 2.88–2.96 (m, 2H),
1.39 (s, 3H), 1.33 (s, 3H). 13C NMR ([D6]DMSO, 100 MHz)
d 181.1, 150.1, 143.2, 138.5, 135.9, 134.6, 134.2, 129.2, 128.3,
128.0, 127.7, 125.9, 125.5, 124.7, 121.4, 102.7, 42.7, 39.9, 25.0,
24.5. HRMS (EI-TOF) calcd for C22H20N2O (M+): 328.1576,
found: 328.1578.
Experimental Section
General Information
All commercial materials were used as received unless oth-
1
erwise noted. H NMR spectra were recorded at 400 MHz
and 500 MHz using TMS as internal standard. 13C NMR
spectra were recorded at 100 MHz and 125 MHz using TMS
as internal standard. The multiplicities are reported as fol-
lows: singlet (s), doublet (d), doublet of doublets (dd), mul-
tiplet (m), and triplet (t). Mass spectroscopy data of the
products were collected on an HRMS-TOF instrument.
(E)-5-Benzylidene-3,3-dimethyl-1-(quinolin-8-yl)pyrroli-
din-2-one (3a): Rf 0.51 (hexane/EtOAc=2:1). White solid.
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Cu(II)/Ag(I)-Catalyzed Sequential Alkynylation and Annulation
1
1
Isolated yield: 30.2 mg, 92%. H NMR (CDCl3, 400 MHz) d
8.87 (dd, J1 =1.6 Hz, J2 =4.4 Hz, 1H), 8.20 (dd, J1 =1.6 Hz,
J2 =8.0 Hz, 1H), 7.92 (dd, J1 =2.0 Hz, J2 =7.6 Hz, 1H), 7.63–
7.70 (m, 2H), 7.40–7.43 (m, 1H), 7.21–7.25 (m, 2H), 7.06
À7.10 (m, 3H), 5.28 (t, J=2.0 Hz, 1H), 3.10–3.28 (m, 2H),
1.53 (s, 3H), 1.43 (s, 3H). 13C NMR (CDCl3, 100 MHz) d
181.1, 151.1, 144.3, 143.0, 137.0, 136.2, 133.3, 130.4, 129.6,
129.3, 128.3, 127.6, 126.4, 125.2, 121.9, 104.4, 41.2, 40.9, 26.1,
25.7. HRMS (EI-TOF) calcd for C22H20N2O (M+): 328.1576,
found: 328.1578.
White solid. Isolated yield: 28.9 mg, 81%. H NMR (CDCl3,
400 MHz) d 8.86 (dd, J1 =2.0 Hz, J2 =4.0 Hz, 1H), 8.18 (dd,
J1 =1.6 Hz, J2 =8.4 Hz, 1H), 7.91 (dd, J1 =1.6 Hz, J2 =
8.0 Hz, 1H), 7.62–7.69 (m, 2H), 7.39–7.42 (m, 1H), 7.12–
7.17 (m, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.63–6.65 (m, 2H),
5.25 (t, J=1.6 Hz, 1H), 3.73 (s, 3H), 3.11–3.28 (m, 2H), 1.53
(s, 3H), 1.43 (s, 3H). 13C NMR (CDCl3, 100 MHz) d 181.2,
159.5, 151.2, 144.3, 143.3, 138.4, 136.2, 133.3, 130.4, 129.6,
129.3, 129.2, 126.4, 121.9, 120.2, 113.3, 110.6, 104.3, 55.2,
41.3, 40.9, 26.1, 25.7. HRMS (EI-TOF) calcd for C23H22N2O2
(M+): 358.1681, found: 358.1682.
(E)-3,3-Dimethyl-5-(2-methylbenzylidene)-1-(quinolin-8-
yl)pyrrolidin-2-one (3b): Rf 0.50 (hexane/EtOAc=2:1).
(E)-5-(4-Methoxybenzylidene)-3,3-dimethyl-1-(quinolin-8-
yl)pyrrolidin-2-one (3g): Rf 0.42 (hexane/EtOAc=2:1).
1
White solid. Isolated yield: 29.0 mg, 85%. H NMR (CDCl3,
1
400 MHz) d 8.88 (dd, J1 =1.6 Hz, J2 =4.4 Hz, 1H), 8.19 (dd,
J1 =1.6 Hz, J2 =8.4 Hz, 1H), 7.90 (dd, J1 =1.2 Hz, J2 =
8.0 Hz, 1H), 7.63–7.72 (m, 2H), 7.40–7.43 (m, 1H), 7.24–
7.26 (m, 1H), 7.11–7.15 (m, 1H), 7.04–7.07 (m, 2H), 5.26 (s,
1H), 2.95–3.10 (m, 2H), 1.90 (s, 3H), 1.50 (s, 3H), 1.40 (s,
3H). 13C NMR (CDCl3, 100 MHz) d 181.3, 151.0, 144.3,
142.6, 136.2, 136.1, 135.6, 133.5, 130.3, 129.9, 129.5, 129.2,
127.6, 126.4, 125.9, 125.5, 121.8, 102.7, 40.9, 40.5, 25.8, 25.4,
19.8. HRMS (EI-TOF) calcd for C23H22N2O (M+): 342.1732,
found: 342.1734.
White solid. Isolated yield: 21.8 mg, 61%. H NMR (CDCl3,
400 MHz) d 8.87 (dd, J1 =2.0 Hz, J2 =4.0 Hz, 1H), 8.19 (dd,
J1 =1.6 Hz, J2 =8.4 Hz, 1H), 7.90 (dd, J1 =1.6 Hz, J2 =
8.0 Hz, 1H), 7.64–7.67 (m, 2H), 7.39–7.42 (m, 1H), 7.02–
7.04 (m, 2H), 6.77–6.79 (m, 2H), 5.23 (s, 1H), 3.75 (s, 3H),
3.10–3.20 (m, 2H), 1.53 (s, 3H), 1.42 (s, 3H). 13C NMR
(CDCl3, 100 MHz) d 181.0, 157.3, 151.1, 144.3, 141.3, 136.2,
133.4, 130.4, 129.6, 129.6, 129.2, 128.7, 126.4, 121.9, 113.8,
103.9, 55.3, 41.1, 40.9, 26.1, 25.7. HRMS (EI-TOF) calcd for
C23H22N2O2 (M+): 358.1681, found: 358.168.
(E)-3,3-Dimethyl-5-(3-methylbenzylidene)-1-(quinolin-8-
yl)pyrrolidin-2-one (3c): Rf 0.52 (hexane/EtOAc=2:1).
White solid. Isolated yield: 31.1 mg, 91%. H NMR (CDCl3,
(E)-5-(4-Fluorobenzylidene)-3,3-dimethyl-1-(quinolin-8-
yl)pyrrolidin-2-one (3h): Rf 0.50 (hexane/EtOAc=2:1).
White solid. Isolated yield: 30.4 mg, 88%. H NMR (CDCl3,
1
1
400 MHz) d 8.87 (dd, J1 =1.6 Hz, J2 =4.4 Hz, 1H), 8.19 (dd,
J1 =1.6 Hz, J2 =8.4 Hz, 1H), 7.91 (dd, J1 =2.0 Hz, J2 =
7.6 Hz, 1H), 7.63–7.69 (m, 2H), 7.39–7.42 (m, 1H), 7.13 (t,
J=7.6 Hz, 1H), 6.89–6.94 (m, 3H), 5.24 (d, J=1.6 Hz, 1H),
3.10–3.28 (m, 2H), 2.26 (s, 3H), 1.53 (s, 3H), 1.43 (s, 3H).
13C NMR (CDCl3, 100 MHz) d 181.1, 151.1, 144.3, 142.8,
137.8, 136.9, 136.1, 133.4, 130.4, 129.6, 129.2, 128.5, 128.2,
126.4, 126.0, 124.5, 121.8, 104.5, 41.2, 40.9, 26.1, 25.7, 21.5.
HRMS (EI-TOF) calcd for C23H22N2O (M+): 342.1732,
found: 342.1735.
400 MHz) d 8.88 (dd, J1 =2.0 Hz, J2 =4.4 Hz, 1H), 8.20 (dd,
J1 =1.6 Hz, J2 =8.4 Hz, 1H), 7.92 (dd, J1 =2.4 Hz, J2 =
7.6 Hz, 1H), 7.63–7.68 (m, 2H), 7.40–7.43 (m, 1H), 7.03–
7.06 (m, 2H), 6.90–6.94 (m, 2H), 5.23 (s, 1H), 3.05–3.23 (m,
2H), 1.53 (s, 3H), 1.43 (s, 3H). 13C NMR (CDCl3, 100 MHz)
d 181.1, 160.6 (JCÀF =243.1 Hz), 151.2, 144.3, 142.6 (JCÀF
2.1 Hz), 136.2, 133.2, 130.0 (JCÀF =3.6 Hz), 130.4, 129.6,
129.3, 128.9 (JCÀF =7.5 Hz), 126.4, 121.9, 115.1 (JCÀF
=
=
21.4 Hz), 103.3, 41.0, 40.8, 26.1, 25.7. HRMS (EI-TOF) calcd
for C22H19FN2O (M+): 346.1481, found: 346.1481.
(E)-3,3-Dimethyl-5-(4-methylbenzylidene)-1-(quinolin-8-
yl)pyrrolidin-2-one (3d): Rf 0.51 (hexane/EtOAc=2:1).
White solid. Isolated yield: 30.7 mg, 90%. H NMR (CDCl3,
(E)-5-(4-Chlorobenzylidene)-3,3-dimethyl-1-(quinolin-8-
yl)pyrrolidin-2-one (3i): Rf 0.49 (hexane/EtOAc=2:1).
White solid. Isolated yield: 32.2 mg, 89%. H NMR (CDCl3,
1
1
400 MHz) d 8.85 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.92 (d,
J=7.6 Hz, 1H), 7.60–7.67 (m, 2H), 7.40–7.43 (d, J=3.6 Hz,
1H), 7.00–7.02 (m, 4H), 5.25 (s, 12H), 3.08–3.25 (m, 2H),
3.26 (3, 1H), 1.52 (s, 3H), 1.42 (s, 3H). 13C NMR (CDCl3,
100 MHz) d 181.1, 151.1, 144.4, 144.2, 136.2, 134.9, 134.1,
133.5, 130.4, 129.6, 129.2, 129.0, 127.5, 126.4, 121.9, 104.3,
41.2, 40.9, 26.1, 25.7, 21.1. HRMS (EI-TOF) calcd for
C23H22N2O (M+): 342.1732, found: 342.1736.
400 MHz) d 8.88 (dd, J1 =1.6 Hz, J2 =4.0 Hz, 1H), 8.21 (dd,
J1 =1.6 Hz, J2 =8.4 Hz, 1H), 7.93 (dd, J1 =2.4 Hz, J2 =
7.2 Hz, 1H), 7.65–7.68 (m, 2H), 7.41–7.44 (m, 1H), 7.17–
7.19 (m, 2H), 7.00 À7.12 (m, 2H), 5.22 (s, 1H), 3.05–3.24
(m, 2H), 1.53 (s, 3H), 1.43 (s, 3H). 13C NMR (CDCl3,
100 MHz) d 181.1, 151.1, 144.1, 143.5, 136.3, 135.5, 133.1,
130.6, 130.5, 129.6, 129.4, 128.7, 128.4, 126.4, 121.9, 103.3,
41.1, 40.8, 26.1, 25.7. HRMS (EI-TOF) calcd for
C22H19ClN2O (M+): 362.1186, found: 362.1187.
(E)-5-(4-Bromobenzylidene)-3,3-dimethyl-1-(quinolin-8-
yl)pyrrolidin-2-one (3j): Rf 0.47 (hexane/EtOAc=2:1).
Yellow solid. Isolated yield: 36.9 mg, 91%. 1H NMR
(CDCl3, 400 MHz) d 8.88 (dd, J1 =1.6 Hz, J2 =4.4 Hz, 1H),
8.20 (dd, J1 =1.6 Hz, J2 =8.4 Hz, 1H), 7.92 (dd, J1 =2.4 Hz,
J2 =7.2 Hz, 1H), 7.63–7.68 (m, 2H), 7.40–7.43 (m, 1H),
7.32–7.34 (m, 2H), 6.94–6.956 (m, 2H), 5.20 (s, 1H), 3.04–
3.23 (m, 2H), 1.53 (s, 3H), 1.43 (s, 3H). 13C NMR (CDCl3,
100 MHz) d 175.9, 146.0, 139.0, 138.4, 131.0, 130.8, 127.9,
126.1, 125.2, 124.4, 124.2, 123.9, 121.2, 116.7, 113.4, 98.1,
35.9, 35.6, 20.9, 20.5. HRMS (EI-TOF) calcd for
C22H19BrN2O (M+): 406.0681, found: 406.0684.
(E)-5-(2-Methoxybenzylidene)-3,3-dimethyl-1-(quinolin-8-
yl)pyrrolidin-2-one (3e): Rf 0.43 (hexane/EtOAc=2:1).
1
White solid. Isolated yield: 27.9 mg, 78%. H NMR (CDCl3,
400 MHz) d 8.85 (dd, J1 =1.6 Hz, J2 =4.4 Hz, 1H), 8.13 (dd,
J1 =1.2 Hz, J2 =8.4 Hz, 1H), 7.85–7.87 (m, 1H), 7.71 (dd,
J1 =1.2 Hz, J2 =7.2 Hz, 1H), 7.60–7.64 (m, 1H), 7.34–7.37
(m, 1H), 7.28–7.30 (m, 1H), 7.07–7.11 (m, 1H), 6.87–6.91
(m, 1H), 6.72–6,74 (m, 1H), 5.53 (s, 1H), 3.57 (s, 3H), 3.02–
3.24 (m, 2H), 1.51 (s, 3H), 1.40 (s, 3H). 13C NMR (CDCl3,
100 MHz) d 181.2, 156.4, 151.0, 144.3, 142.6, 136.1, 133.5,
130.4, 129.6, 129.1, 128.0, 126.8, 126.4, 125.9, 121.7, 120.3,
110.6, 99.3, 55.4, 41.1, 40.9, 25.8, 25.7. HRMS (EI-TOF)
calcd for C23H22N2O2 (M+): 358.1681, found: 358.1683.
(E)-5-(3-Methoxybenzylidene)-3,3-dimethyl-1-(quinolin-8-
yl)pyrrolidin-2-one (3 f): Rf 0.42 (hexane/EtOAc=2:1).
(E)-4-((4,4-Dimethyl-5-oxo-1-(quinolin-8-yl)pyrrolidin-2-
ylidene)methyl)benzonitrile (3k): Rf 0.44 (hexane/EtOAc=
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Jitan Zhang et al.
2:1). White solid. Isolated yield: 26.1 mg, 74%. 1H NMR
(CDCl3, 400 MHz) d 8.86 (dd, J1 =1.6 Hz, J2 =4.4 Hz, 1H),
8.21 (dd, J1 =1.6 Hz, J2 =8.4 Hz, 1H), 7.95 (dd, J1 =3.6 Hz,
J2 =5.6 Hz, 1H), 7.66–7.68 (m, 2H), 7.42–7.49 (m, 3H),
7.13–7.16 (m, 2H), 5.26 (s, 1H), 3.11–3.28 (m, 2H), 1.55 (s,
3H), 1.45 (s, 3H). 13C NMR (CDCl3, 100 MHz) d 181.1,
151.3, 146.5, 144.1, 142.1, 136.2, 132.8, 132.1, 130.3, 129.6,
127.7, 126.4, 122.0, 119.4, 107.8, 103.1, 41.5, 40.8, 26.2, 25.7.
HRMS (EI-TOF) calcd for C23H19N3O (M+): 353.1528,
found: 353.1530.
isomer), 1.63 (s, 3H, Z-isomer), 1.00–1,04 (m, 1H, E-
isomer), 0.85–0.92 (m, 3H, Z- and E-isomers), 0.65–0.70 (m,
2H, Z-isomer), 0.34–0.38 (m, 1H, E-isomer), 0.28–0.32 (m,
1H, E-isomer), 0.18–0.24 (m, 2H, Z-isomer). 13C NMR
(CDCl3, 100 MHz) d 181.9, 181.0, 151.0, 149.2, 144.3, 143.6,
139.4, 137.9, 136.1, 134.5, 133.5, 132.1, 130.2, 129.7, 129.5,
128.9, 127.6, 127.0, 126.3, 121.7, 121.4, 105.8, 91.4, 47.3, 45.3,
40.9, 40.6, 38.8, 26.9, 26.2, 25.8, 9.3, 6.7, 6.6, 6.2, 4.6, 4.5.
HRMS (EI-TOF) calcd for C19H20N2O (M+): 292.1576,
found: 292.1576.
(E)-3,3-Dimethyl-5-(naphthalen-1-ylmethylene)-1-(quino-
lin-8-yl)pyrrolidin-2-one (3l): Rf 0.52 (hexane/EtOAc=2:1).
White solid. Isolated yield: 23.8 mg, 63%. H NMR (CDCl3,
5-(Cyclohexylmethylene)-3,3-dimethyl-1-(quinolin-8-yl)
pyrrolidin-2-one (3p): Z-Rf 0.55, E-Rf 0.55, (hexane/
EtOAc=2:1). Yellow oil. Isolated yield: 12.7 mg, 39%. The
1
1
1
400 MHz) d 8.96 (dd, J1 =1.6 Hz, J2 =4.4 Hz, 1H), 8.22 (dd,
J1 =1.6 Hz, J2 =8.4 Hz, 1H), 7.93 (dd, J1 =1.6 Hz, J2 =
8.4 Hz, 1H), 7.77–7.82 (m, 2H), 7.63–7.71 (m, 3H), 7.44–
7.47 (m, 1H), 7.38–7.43 (m, 3H), 7.30–7.34 (m, 1H), 5.75 (d,
J=2.0 Hz, 1H), 2.92–3.08 (m, 2H), 1.48 (s, 3H), 1.39 (s,
3H). 13C NMR (CDCl3, 100 MHz) d 181.5, 151.1, 144.3,
143.9, 136.3, 133.8, 133.7, 133.5, 132.1, 130.4, 129.7, 129.3,
128.4, 126.5, 125.7, 125.6, 125.5, 125.4, 124.6, 121.9, 101.5,
40.9, 40.4, 25.7, 25.4. HRMS (EI-TOF) calcd for C26H22N2O
(M+): 378.1732, found: 378.1734.
(E)-3,3-Dimethyl-1-(quinolin-8-yl)-5-(thiophen-3-ylmethy-
lene)pyrrolidin-2-one (3m): Rf 0.48 (hexane/EtOAc=2:1).
Yellow solid. Isolated yield: 21.0 mg, 63%. 1H NMR
(CDCl3, 400 MHz) d 8.88 (dd, J1 =1.6 Hz, J2 =4.0 Hz, 1H),
8.21 (dd, J1 =1.6 Hz, J2 =8.0 Hz, 1H), 7.93 (dd, J1 =2.8 Hz,
J2 =6.4 Hz, 1H), 7.65–7.67 (m, 2H), 7.41–7.44 (m, 1H), 7.20
(dd, J1 =2.8 Hz, J2 =3.2 Hz, 1H), 6.90 (dd, J1 =1.2 Hz, J2 =
5.2 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 5.31 (t, J=1.6 Hz,
1H), 3.09–3.20 (m, 2H), 1.55 (s, 3H), 1.44 (s, 3H). 13C NMR
(CDCl3, 100 MHz) d 181.2, 151.2, 144.3, 142.4, 137.7, 136.2,
133.2, 130.4, 129.6, 129.3, 127.8, 126.4, 125.0, 121.9, 119.3,
98.9, 41.1, 40.8, 26.3, 25.9. HRMS (EI-TOF) calcd for
C20H18N2OS (M+): 334.1140, found: 334.1140.
(E)-3,3-Dimethyl-1-(quinolin-8-yl)-5-(thiophen-2-ylmethy-
lene)pyrrolidin-2-one (3n): Rf 0.48 (hexane/EtOAc=2:1).
Yellow solid. Isolated yield: 23.7 mg, 71%. 1H NMR
(CDCl3, 400 MHz) d 8.86 (dd, J1 =1.6 Hz, J2 =4.0 Hz, 1H),
8.19 (dd, J1 =1.6 Hz, J2 =8.4 Hz, 1H), 7.92 (dd, J1 =2.8 Hz,
J2 =6.8 Hz, 1H), 7.62–7.67 (m, 2H), 7.39–7.42 (m, 1H), 7.09
(d, J=5.2 Hz, 1H), 6.88–6.90 (m, 1H), 6.62 (d, J=3.6 Hz,
1H), 5.50 (s, 1H), 3.05–3.25 (m, 2H), 1.56 (s, 3H), 1.46 (s,
3H). 13C NMR (CDCl3, 100 MHz) d 181.3, 151.3, 144.3,
142.1, 140.4, 136.2, 133.1, 130.4, 129.6, 129.4, 127.0, 126.4,
124.2, 122.7, 121.9, 98.2, 41.0, 40.9, 26.5, 26.0. HRMS (EI-
TOF) calcd for C20H18N2OS (M+): 334.1140, found:
334.1140.
ratio of Z/E was 1:2 as determined by H NMR. H NMR
(CDCl3, 400 MHz, a mixture of two isomers) d 8.86 (dd, J1 =
1.6 Hz, J2 =4.0 Hz, 1H, E-isomer), 8.81 (dd, J1 =1.6 Hz, J2 =
4.4 Hz, 1H, Z-isomer), 8.28 (d, J=8.4 Hz, 1H, Z-isomer),
8.16 (d, J=8.4 Hz, 1H, E-isomer), 7.84–7.87 (m, 1H, E-
isomer), 7.81–7.83 (m, H, Z-isomer), 7.58–7.66 (m, 3H, Z-
and E-isomers), 7.46–7.49 (m, 1H, Z-isomer), 7.37–7.40 (m,
1H, E-isomer), 4.03–4.06 (m, 2H, Z- and E-isomers), 2.71–
2.91 (m, 2H, E-isomer), 2.00–2.41 (m, 2H, Z- and E-iso-
mers), 1.80–1.84 (m, 1H, Z-isomer), 1.51–1.65 (m, 9H, Z-
and E-isomers), 1.48 (s, 3H, E-isomer), 1.38 (s, 3H, E-
isomer), 1.38 (s, 3H, Z-isomer), 1.14–1.27 (m, 3H, Z- and E-
isomers), 0.97–1.06 (m, 2H, Z- and E-isomers), 0.84–0.94
(m, 1H, Z-isomer), 0.71–0.82 (m, 2H, E-isomer). 13C NMR
(CDCl3, 100 MHz) d 181.5, 181.1, 150.8, 149.1, 144.3, 143.6,
138.5, 137.9, 136.0, 134.7, 133.8, 132.2, 130.2, 129.7, 129.5,
128.7, 127.5, 127.1, 126.2, 121.6, 121.4, 108.7, 91.3, 48.6, 48.3,
40.9, 40.6, 38.7, 36.3, 35.0, 34.8, 33.8, 33.7, 26.9, 26.9, 26.5,
26.3, 26.2, 26.2, 26.1, 26.0, 25.9, 25.6. HRMS (EI-TOF) calcd
for C22H26N2O (M+): 334.2045, found: 334.2050.
(E)-5-Benzylidene-3-ethyl-3-methyl-1-(quinolin-8-yl) pyr-
rolidin-2-one (4a): Rf1 0.55, Rf2 0.53 (hexane/EtOAc=2:1).
Yellow oil. Isolated yield: 24.9 mg, 73%. The ratio of two
isomers was 1:1.1 as determined by 1H NMR. 1H NMR
(CDCl3, 400 MHz, a mixture of two isomers) d 8.84–8.87 (m,
2H), 8.18 (s, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 7.88 (s, 1H),
7.61–7.69 (m, 4H), 7.37–7.40 (m, 2H), 7.21–7.24 (m, 4H),
7.05–7.12 (m, 6H), 5.27 (s, 1H), 5.25 (s, 1H), 2.97–3.35 (m,
4H), 1.69–2.00 (m, 4H), 1.51 (s, 3H), 1.39 (s, 3H), 1.15 (t,
J=7.2 Hz), 1.05 (t, J=7.6 Hz). 13C NMR (CDCl3, 100 MHz)
d 180.7, 180.6, 151.2, 151.1, 144.3, 144.3, 143.4, 143.3, 137.1,
136.2, 136.1, 133.5, 133.4, 130.5, 130.4, 129.6, 129.3, 129.2,
128.3, 127.6, 126.4, 126.4, 125.2, 121.89, 104.2, 104.0, 44.6,
39.2, 38.1, 31.7, 31.5, 24.6, 24.0, 9.1, 9.0. HRMS (EI-TOF)
calcd for C23H22N2O (M+): 342.1732, found: 342.1732.
(E)-5-Benzylidene-3-methyl-3-propyl-1-(quinolin-8-yl)
5-(Cyclopropylmethylene)-3,3-dimethyl-1-(quinolin-8-yl)-
pyrrolidin-2-one (3o): Z-Rf 0.41, E-Rf 0.41, (hexane/
EtOAc=2:1). Yellow oil. Isolated yield: 12.7 mg, 39%. The
pyrrolidin-2-one (4b): Rf1 0.55, Rf2 0.52 (hexane/EtOAc=
2:1). Yellow oil. Isolated yield: 27.1 mg, 76%. The ratio of
1
1
two isomers was 1:1.3 as determined by H NMR. H NMR
(CDCl3, 400 MHz, a mixture of two isomers) d 8.86–8.88 (m,
2H), 8.21 (t, J=1.6 Hz, 1H), 8.18 (t, J=1.6 Hz, 1H), 7.90–
7.93 (m, 2H), 7.63–7.69 (m, 4H), 7.39–7.42 (m, 2H), 7.21–
7.25 (m, 4H), 7.06–7.12 (m, 6H), 5.27 (s, 1H), 5.24 (s, 1H),
3.14–3.24 (m, 4H), 1.73–1.90 (m, 4H), 1.60–1.70 (m, 4H),
1.51 (s, 3H), 1.40 (s, 3H), 0.95–1.02 (m, 6H). 13C NMR
(CDCl3, 100 MHz) d 180.8, 180.7, 151.2, 151.2, 144.3, 143.4,
143.3, 137.1, 136.2, 136.1, 133.5, 133.3, 130.5, 130.4, 129.6,
129.6, 129.3, 129.2, 128.3, 127.6, 126.4, 126.4, 125.1, 121.9,
104.2, 104.0, 44.3, 44.3, 41.4, 41.0, 38.8, 38.6, 24.9, 24.3, 17.9,
1
1
ratio of Z/E was 1:1.5 as determined by H NMR. H NMR
(CDCl3, 400 MHz, a mixture of two isomers) d 9.16 (dd, J1 =
1.6 Hz, J2 =4.0 Hz, 1H, E-isomer), 9.09 (dd, J1 =1.6 Hz, J2 =
4.0 Hz, 1H, Z-isomer), 8.55 (dd, J1 =1.6 Hz, J2 =8.4 Hz, 1H,
Z-isomer), 8.43 (dd, J1 =1.6 Hz, J2 =8.4 Hz, 1H, E-isomer),
8.07–8.13 (m, 2H, Z- and E-isomers), 7.84–7.95 (m, 4H, Z-
and E-isomers), 7.73–7.76 (m, 1H, Z-isomer), 7.65–7.68 (m,
1H, E-isomer), 3.96–3.99 (m, 2H, Z- and E-isomers), 3.11–
3.31 (m, 2H, E-isomer), 2.54–2.68 (m, 2H, Z-isomer), 1.87
(s, 3H, Z-isomer), 1.79 (s, 3H, E-isomer), 1.68 (s, 3H, E-
800
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FULL PAPERS
Cu(II)/Ag(I)-Catalyzed Sequential Alkynylation and Annulation
17.8, 14.7, 14.6. HRMS (EI-TOF) calcd for C24H24N2O (M+):
356.1889, found: 356.1884.
136.5, 135.7, 135.6, 135.1, 135.0, 134.5, 134.4, 130.4, 130.4,
130.4, 129.4, 129.1, 128.8, 128.1, 128.0, 126.2, 126.1, 125.6,
125.0, 124.9, 123.7, 123.7, 121.2, 121.2, 120.9, 120.7, 112.1,
112.1, 103.5, 103.4, 43.9, 43.8, 41.4, 41.1, 35.2, 35.0, 24.9, 23.8,
23.6, 21.5, 16.0. HRMS (EI-TOF) calcd for C32H32N2O2
(M+): 476.2464, found: 476.247.
(E)-5-Benzylidene-3-butyl-3-methyl-1-(quinolin-8-yl) pyr-
rolidin-2-one (4c): Rf1 0.56, Rf2 0.54 (hexane/EtOAc=2:1).
Yellow oil. Isolated yield: 26.2 mg, 71%. The ratio of two
isomers was 1:1.1 as determined by 1H NMR. 1H NMR
(CDCl3, 400 MHz, a mixture of two isomers) d 8.85–8.88 (m,
2H), 8.21 (t, J=1.6 Hz, 1H), 8.18 (t, J=1.6 Hz, 1H), 7.90–
7.93 (m, 2H), 7.63–7.69 (m, 4H), 7.39–7.43 (m, 2H), 7.16–
7.25 (m, 4H), 7.06–7.12 (m, 6H), 5.27 (s, 1H), 5.24 (s, 1H),
2.99–3.36 (m, 4H), 1.75–1.86 (m, 4H), 1.54–1.71 (m, 4H),
1.52 (s, 3H), 1.36–1.42 (s, 7H), 0.92–0.98 (m, 6H). 13C NMR
(CDCl3, 100 MHz) d 180.8, 180.8, 151.2, 151.0, 144.3, 143.4,
143.3, 137.1, 136.2, 136.1, 133.5, 133.3, 130.5, 130.4, 129.6,
129.6, 129.3, 129.2, 128.3, 127.6, 127.5, 126.4, 126.4, 125.1,
121.9, 104.1, 104.0, 44.3, 44.2, 38.8, 38.7, 38.6, 38.5, 26.8, 26.7,
24.9, 24.4, 23.3, 23.2, 14.2, 14.1. HRMS (EI-TOF) calcd for
C25H26N2O (M+): 370.2045, found: 370.2048.
(E)-5-Benzylidene-3-ethyl-3-propyl-1-(quinolin-8-yl) pyr-
rolidin-2-one (4d): Rf1 0.49, Rf2 0.49 (hexane/EtOAc=5:1).
Yellow oil. Isolated yield: 27.4 mg, 74%. The ratio of two
isomers was 1:1 as determined by 1H NMR. 1H NMR
(CDCl3, 400 MHz, a mixture of two isomers) d 8.85–8.88 (m,
2H), 8.21 (t, J=1.6 Hz, 1H), 8.18 (t, J=1.6 Hz, 1H), 7.90–
7.94 (m, 2H), 7.65–7.66 (m, 4H), 7.39–7.43 (m, 2H), 7.22–
7.25 (m, 4H), 7.06–7.14 (m, 6H), 5.23 (d, 2H), 3.07–3.29 (m,
4H), 1.57–1.2.00 (m, 10H), 1.43–1.54 (m, 2H), 1.17 (t, J=
7.2 Hz, 3H), 1.05 (t, J=7.2 Hz, 3H), 0.95–1.02 (m, 6H).
13C NMR (CDCl3, 100 MHz) d 179.9, 179.9, 151.1, 151.1,
144.3, 144.3, 143.8 137.2, 136.1, 133.6, 130.4, 129.5, 129.2,
128.3, 127.5, 126.4, 126.3, 125.0, 121.8, 103.6, 48.3, 40.2, 39.9,
35.5, 30.7, 17.7, 17.6, 14.8, 14.6, 8.8, 8.8. HRMS (EI-TOF)
calcd for C25H26N2O (M+): 370.2045, found: 370.2043.
(E)-3-Benzyl-5-benzylidene-3-methyl-1-(quinolin-8-yl)pyr-
rolidin-2-one (4g): Rf1 0.52, Rf2 0.50 (hexane/EtOAc=2:1).
Yellow oil. Isolated yield: 32.3 mg, 80%. The ratio of two
isomers was 1:2 as determined by 1H NMR. 1H NMR
(CDCl3, 400 MHz, a mixture of two isomers) d 8.84–8.87 (m,
2H), 8.15–8.20 (m, 2H), 7.92 (dd, J1 =1.6 Hz, J2 =8.0 Hz),
7.87 (dd, J1 =1.2 Hz, J2 =8.0 Hz), 7.65–7.70 (m, 1H), 7.56–
7.60 (m, 1H), 7.37–7.42 (m, 2H), 7.26–7.35 (m, 9H), 7.18–
7.23 (m, 3H), 7.04–7.07 (m, 3H), 6.99–7.01 (m, 2H), 5.30 (s,
1H), 5.05 (s, 1H), 2.81–3.46 (m, 7H), 1.61 (s, 3H), 1.40 (s,
3H). 13C NMR (CDCl3, 100 MHz) d 180.3, 179.7, 151.2,
151.1, 144.3, 144.3, 142.8, 142.8, 137.6, 137.6, 137.0, 136.9,
136.2, 133.3, 133.2, 130.8, 130.4, 130.4, 130.3, 129.6, 129.5,
129.4, 129.3, 128.4, 128.3, 127.6, 126.9, 126.6, 126.4, 125.3,
125.2, 122.0, 121.9, 104.9, 104.1, 46.0, 45.6, 44.3, 43.2, 37.7,
37.3, 25.7, 24.0. HRMS (EI-TOF) calcd for C28H24N2O (M+):
404.1889, found: 404.1892.
(E)-5-Benzylidene-3-methyl-3-(4-methylbenzyl)-1-(quino-
lin-8-yl)pyrrolidin-2-one (4h): Rf1 0.52, Rf2 0.50 (hexane/
EtOAc=2:1). Yellow oil. Isolated yield: 35.9 mg, 85%. The
ratio of two isomers was 1:2 as determined by 1H NMR.
1H NMR (CDCl3, 400 MHz, a mixture of two isomers) d
8.85–8.88 (m, 2H), 8.17–8.22 (m, 2H), 7.89–7.94 (m, 2H),
7.68–7.70 (m, 1H), 7.58–7.62 (m, 1H), 7.39–7.44 (m, 2H),
7.34–7.36 (m, 1H), 7.16–7.23 (m, 6H), 7.11–7.13 (m, 3H),
7.04–7.08 (m, 3H), 7.00–7.02 (m, 2H), 5.30 (s, 1H), 5.07 (s,
1H), 2.78–3.46 (m, 6H), 2.36 (s, 5H), 1.59 (s, 3H), 1.39 (s,
3H). 13C NMR (CDCl3, 100 MHz) d 180.4, 179.8, 151.2,
151.1, 144.3, 144.3, 142.9, 137.0, 136.9, 136.3, 136.1, 136.0,
134.4, 133.2, 130.7, 130.4, 130.3, 129.6, 129.5, 129.3, 129.2,
129.0, 128.9, 128.3, 128.2, 127.6, 127.5, 126.4, 125.2, 125.1,
121.9, 121.8, 104.8, 104.1, 45.9, 45.5, 43.7, 42.8, 37.7, 37.2,
25.6, 23.9, 21.2. HRMS (EI-TOF) calcd for C29H26N2O (M+):
418.2045, found: 418.2045.
(E)-5-Benzylidene-3-methyl-3-phenethyl-1-(quinolin-8-yl)-
pyrrolidin-2-one (4e): Rf1 0.53, Rf2 0.51 (hexane/EtOAc=
2:1). Yellow oil. Isolated yield: 29.2 mg, 70%. The ratio of
1
1
two isomers was 1.3:1 as determined by H NMR. H NMR
(CDCl3, 400 MHz, a mixture of two isomers) d 8.86 (dd, J1 =
1.6 Hz, J2 =4.0 Hz), 8.81 (dd, J1 =1.6 Hz, J2 =4.0 Hz), 8.17 (s,
1H), 8.15 (s, 1H), 7.90 (s, 1H), 7.88 (s, 1H), 7.61–7.71 (m,
4H), 7.05–7.10 (m, 4H), 7.35–7.39 (m, 2H), 7.15–7.30 (m,
14H), 7.05–7.10 (m, 6H), 5.29–5.30 (m, 2H), 2.71–3.40 (m,
8H), 1.97–2.18 (m, 4H), 1.59 (s, 3H), 1.48 (s, 3H). 13C NMR
(CDCl3, 100 MHz) d 180.3, 180.2, 151.2, 151.1, 144.3, 143.1,
142.7, 141.9, 137.0, 136.2, 133.5, 133.3, 130.5, 130.4, 129.6,
129.4, 129.3, 128.6, 128.5, 128.4, 128.4, 127.7, 126.4, 126.4,
126.0, 125.8, 125.3, 122.0, 104.4, 104.3, 44.4, 44.4, 41.2, 40.8,
39.0, 38.7, 31.2, 31.1, 24.9, 24.6. HRMS (EI-TOF) calcd for
C29H26N2O (M+): 418.2045, found: 418.2006.
(E)-5-Benzylidene-3-(4-fluorobenzyl)-3-methyl-1-(quino-
lin-8-yl)pyrrolidin-2-one (4i): Rf1 0.52, Rf2 0.51 (hexane/
EtOAc=2:1). Yellow oil. Isolated yield: 30.4 mg, 72%. The
1
ratio of two isomers was 1:1.4 as determined by H NMR.
1H NMR (CDCl3, 400 MHz, a mixture of two isomers) d
8.81 (s, 2H), 7.86–7.92 (m, 2H), 7.42–7.47 (m, 2H), 7.24–
7.35 (m, 6H), 7.12–7.19 (m, 2H), 7.00–7.06 (m, 6H), 6.51–
6.57 (m, 2H), 6.32–6.45 (m, 6H), 6.12–6.13 (m, 2H), 5.67 (s,
1H), 5.54 (s, 1H), 2.65–3.26 (m, 8H), 1.56 (s, 3H), 1.39 (s,
3H). 13C NMR (CDCl3, 100 MHz) d 181.0, 180.7, 163.0,
161.1, 150.0, 149.9, 143.7, 143.6, 138.4, 138.2, 135.7, 135.6,
134.9, 134.8, 134.3, 134.1, 133.3, 132.2, 132.1, 131.9, 131.9,
129.2, 128.8, 128.7, 128.0, 127.9, 126.1, 126.0, 125.6, 125.5,
125.0, 124.8, 121.2, 121.1, 115.2, 115.0, 114.8, 104.0, 103.3,
45.4, 45.3, 43.4, 42.4, 40.5, 39.7, 25.0, 23.3. HRMS (EI-TOF)
calcd for C28H23FN2O (M+): 422.1794, found: 422.1798.
(E)-5-Benzylidene-3-methyl-3-(naphthalen-2-ylmethyl)-1-
(quinolin-8-yl)pyrrolidin-2-one (4j): Rf1 0.50, Rf2 0.48
(hexane/EtOAc=2:1). Yellow oil. Isolated yield: 38.5 mg,
85%. The ratio of two isomers was 1:1.5 as determined by
(E)-5-Benzylidene-3-(3-(2,5-dimethylphenoxy)propyl)-3-
methyl-1-(quinolin-8-yl)pyrrolidin-2-one (4 f): Rf1 0.52, Rf2
0.50 (hexane/EtOAc=2:1). Yellow oil. Isolated yield:
30.4 mg, 64%. The ratio of two isomers was 1.1:1 as deter-
1
1
mined by H NMR. H NMR (CDCl3, 400 MHz, a mixture
of two isomers) d 8.87 (d, J=3.2 Hz), 8.79 (d, J=3.2 Hz,
1H), 8.17–8.20 (m, 2H), 7.90–7.92 (m, 2H), 7.62–7.70 (m,
4H), 7.37–7.42 (m, 2H), 7.21–7.24 (m, 4H), 7.06–7.11 (m,
6H), 6.99–7.01 (m, 2H), 6.63–6.67 (m, 4H), 5.26–5.29 (m,
2H), 3.99–4.06 (m, 2H), 3.05–3.39 (m, 4H), 2.30 (s, 3H),
2.28 (s, 3H), 2.19–2.20 (m, 6H), 1.91–2.16 (m, 8H), 1.57 (s,
3H), 1.46 (s, 3H). 13C NMR (CDCl3, 100 MHz) d 181.5,
181.4, 157.2, 157.0, 150.1, 150.0, 143.8, 143.7, 136.7, 136.6,
1
1H NMR. H NMR (CDCl3, 400 MHz, a mixture of two iso-
mers) d 8.85 (s, 2H), 8.13–8.23 (m, 4H), 7.93 (d, J=8.0 Hz),
Adv. Synth. Catal. 2016, 358, 792 – 807
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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FULL PAPERS
Jitan Zhang et al.
7.72–7.85 (m, 5H), 7.64–7.68 (m, 1H), 7.33–7.55 (m, 10H),
7.09–7.17 (m, 4H), 6.94–7.02 (m, 4H), 6.78–6.80 (m, 2H),
5.34 (s, 1H), 5.00 (s, 1H), 3.67–4.03 (m, 2H), 3.32–3.52 (m,
4H), 2.78–3.04 (m, 2H), 1.68 (s, 3H), 1.47 (s, 3H). 13C NMR
(CDCl3, 100 MHz) d 180.6, 179.8, 151.1, 144.4, 144.2, 143.1,
142.7, 136.8, 136.7, 136.2, 136.1, 134.0, 133.9, 133.5, 133.1,
133.0, 130.4, 130.2, 129.7, 129.5, 129.3, 129.2, 129.1, 128.8,
128.7, 128.6, 128.2, 128.1, 127.6, 127.5, 127.4, 126.4, 126.3,
126.0, 126.0, 125.5, 125.4, 125.3, 125.2, 125.1, 124.4, 124.3,
122.0, 121.8, 105.0, 104.1, 46.5, 46.4, 39.3, 38.3, 37.7, 37.5,
25.7, 23.8. HRMS (EI-TOF) calcd for C32H26N2O (M+):
454.2045, found: 454.2048.
400 MHz) d 8.87 (dd, J1 =1.6 Hz, J2 =4.4 Hz, 1H), 7.90 (dd,
J1 =1.6 Hz, J2 =8.4 Hz, 1H), 7.48 (dd, J1 =1.2 Hz, J2 =
8.4 Hz, 1H), 7.37 (dd, J1 =1.2 Hz, J2 =7.6 Hz, 1H), 7.27–7.30
(m, 1H), 7.19 À7.23 (m, 1H), 7.54–6.57 (m, 1H), 6.42–6.45
(m, 2H), 6.35 (J=7.2 Hz, 2H), 5.69 (s, 1H), 3.11–3.39 (m,
2H), 1.48–1.53 (m, 1H), 1.39–1.43 (m, 1H), 1.02–1.08 (m,
2H). 13C NMR (CDCl3, 100 MHz) d 179.1, 150.1, 143.7,
138.8, 135.8, 135.0, 134.7, 129.5, 128.8, 128.2, 128.0, 126.0,
125.6, 124.8, 121.1, 103.1, 35.2, 21.8, 15.8, 15.4. HRMS (EI-
TOF) calcd for C22H18N2O (M+): 326.1419, found: 326.1423.
(E)-7-Benzylidene-6-(quinolin-8-yl)-6-azaspiro[3.4] octan-
5-one (4o): Rf 0.50 (hexane/EtOAc =2:1). White solid. Iso-
lated yield: 23.1 mg, 68%. 1H NMR (CDCl3, 500 MHz) d
8.88 (d, J=3.0 Hz, 1H), 8.21 (d, J=8.5 Hz, 1H), 7.93 (dd,
J1 =1.5 Hz, J2 =7.0 Hz, 1H), 7.64–7.69 (m, 2H), 7.41–7.44
(m, 1H), 7.22–7.26 (m, 2H), 7.07–7.12 (m, 3H), 5.25 (s, 1H),
3.39–3.57 (m, 2H), 2.81–2.85 (m, 1H), 2.67–2.71 (m, 1H),
2.14–2.25 (m, 3H), 2.04–2.08 (m, 1H). 13C NMR (CDCl3,
100 MHz) d 179.8, 151.2, 144.2, 143.2, 137.0, 136.3, 133.4,
130.5, 129.6, 129.2, 128.3, 127.6, 126.4, 125.2, 121.9, 104.0,
45.5, 40.2, 32.3, 31.8, 16.4. HRMS (EI-TOF) calcd for
C23H20N2O (M+): 340.1576, found: 340.1579.
(E)-5-Benzylidene-3-methyl-3-phenyl-1-(quinolin-8-yl)
pyrrolidin-2-one (4k): Rf1 0.60, Rf2 0.57 (hexane/EtOAc=
2:1). Yellow oil. Isolated yield: 25.3 mg, 65%. The ratio of
1
1
two isomers was 1:1.1 as determined by H NMR. H NMR
(CDCl3, 400 MHz, a mixture of two isomers) d 8.90 (s, 2H),
8.20–8.21 (m, 2H), 7.93–7.94 (m, 2H), 7.81–7.83 (m, 2H),
7.58–7.77 (m, 6H), 7.37–7.43 (m, 6H), 7.21–7.29 (m, 6H),
7.06–7.11 (m, 6H), 5.36 (s, 1H), 5.31 (s, 1H), 3.42–3.73 (m,
4H), 1.95 (s, 3H), 1.86 (s, 3H). 13C NMR (CDCl3, 100 MHz)
d 179.2, 178.9, 151.2, 151.1, 144.3, 144.1, 142.5, 142.4, 136.8,
136.7, 136.3, 136.2, 133.4, 133.2, 130.6, 130.4, 129.6, 129.6,
129.4, 129.4, 128.7, 128.6, 128.4, 127.7, 127.6, 127.0, 126.9,
126.7, 126.4, 126.4, 126.1, 125.4, 122.0, 122.0, 104.7, 104.6,
48.5, 48.5, 43.6, 42.6, 25.8, 25.2. HRMS (EI-TOF) calcd for
C27H22N2O (M+): 390.1732, found: 390.1736.
(E)-3-Benzylidene-2-(quinolin-8-yl)-2-azaspiro[4.4]
nonan-1-one (4p): Rf 0.51 (hexane/EtOAc =2:1). White
solid. Isolated yield: 18.3 mg, 52%. 1H NMR (CDCl3,
400 MHz) d 8.88 (dd, J1 =1.6 Hz, J2 =4.4 Hz, 1H), 8.21 (dd,
J1 =1.6 Hz, J2 =8.4 Hz, 1H), 7.93 (dd, J1 =1.2 Hz, J2 =
8.0 Hz, 1H), 7.64–7.71 (m, 2H), 7.41–7.44 (m, 1H), 7.21–
7.26 (m, 2H), 7.06–7.11 (m, 3H), 5.27 (s, 1H), 3.14–3.32 (m,
2H), 2.33–2.37 (m, 1H), 2.22–2.25 (m, 1H), 1.86–1.93 (m,
3H), 1.78–1.84 (m, 1H). 13C NMR (CDCl3, 100 MHz) d
181.1, 151.2, 144.3, 143.5, 137.1, 136.2, 133.5, 130.4, 129.6,
129.2, 128.3, 127.6, 126.4, 125.2, 121.9, 104.1, 51.2, 41.1, 38.4,
38.0, 25.6, 25.5. HRMS (EI-TOF) calcd for C24H22N2O (M+):
354.1732, found: 354.1734.
(E)-3-Benzylidene-2-(quinolin-8-yl)-2-azaspiro[4.5] decan-
1-one (4q): Rf 0.55 (hexane/EtOAc =2:1). White solid. Iso-
lated yield: 33.0 mg, 90%. 1H NMR (CDCl3, 500 MHz) d
8.86 (d, J=2.5 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.92 (dd,
J1 =1.5 Hz, J2 =7.0 Hz, 1H), 7.64–7.68 (m, 2H), 7.40–7.43
(m, 1H), 7.23–7.26 (m, 2H), 7.07–7.14 (m, 3H), 5.25 (s, 1H),
3.10–3.31 (m, 2H), 1.89–1.95 (m, 3H), 1.82–1.84 (m, 2H),
1.69–1.72 (m, 2H), 1.38–1.52 (m, 3H). 13C NMR (CDCl3,
100 MHz) d 180.9, 151.1, 144.3, 143.4, 137.1, 136.2, 133.3,
130.5, 129.6, 129.2, 128.3, 127.6, 126.4, 125.1, 121.9, 104.1,
45.3, 37.1, 33.6, 33.6, 25.4, 22.4, 22.2. HRMS (EI-TOF) calcd
for C25H24N2O (M+): 368.1889, found: 368.1890.
(Z)-3-Benzylidene-2-(quinolin-8-yl)isoindolin-1-one (6a):
Rf 0.23 (hexane/EtOAc =2:1). White solid. Isolated yield:
33.7 mg, 97%. 1H NMR (CDCl3, 400 MHz) d 8.83 (d, J=
2.4 Hz, 1H), 7.94–7.99 (m, 2H), 7.87 (d, J=7.6 Hz, 1H),
7.65–7.68 (m, 1H), 7.52–7.57 (m, 2H), 7.46 (d, J=7.2 Hz,
1H), 7.25–7.29 (m, 2H), 6.79 (s, 1H), 6.65–6.68 (m, 1H),
6.50–6.54 (m, 4H). 13C NMR (CDCl3, 100 MHz) d 168.2,
150.4, 144.4, 138.7, 136.1, 135.9, 134.2, 133.6, 132.3, 130.1,
129.1, 128.9, 128.4, 128.3, 128.2, 126.3, 126.1, 125.7, 124.0,
121.2, 119.7, 107.4. HRMS (EI-TOF) calcd for C24H16N2O
(M+): 348.1263, found: 348.126.
(E)-5-Benzylidene-3-butyl-3-phenyl-1-(quinolin-8-yl) pyr-
rolidin-2-one (4l): Rf1 0.51, Rf2 0.51 (hexane/EtOAc=5:1).
Yellow oil. Isolated yield: 30.6 mg, 71%. The ratio of two
isomers was 1:1.1 as determined by 1H NMR. 1H NMR
(CDCl3, 400 MHz, a mixture of two isomers) d 8.89 (dd, J1 =
1.2 Hz, J2 =3.2 Hz, 1H), 8.85 (dd, J1 =1.2 Hz, J2 =3.2 Hz,
1H), 8.21 (s, 1H), 8.19 (s, 1H), 7.91–7.94 (m, 2H), 7.78–7.80
(m, 2H), 7.73–7.74 (m, 1H), 7.67–7.70 (m, 1H), 7.61–7.65
(m, 4H), 7.35–7.44 (m, 6H), 7.21–7.28 (m, 6H), 7.06–7.15
(m, 6H), 5.31 (s, 1H), 5.29 (s, 1H), 3.50–3.72 (m, 4H), 2.15–
2.37 (m, 4H), 1.50–1.59 (m, 4H), 1.37–1.48 (m, 4H), 0.92–
0.95 (m, 6H). 13C NMR (CDCl3, 100 MHz) d 178.1, 177.9,
151.1, 151.0, 144.3, 144.1, 142.8, 142.8, 142.8, 137.0, 136.9,
136.1, 136.1, 133.4, 130.5, 130.4, 129.6, 129.6, 129.3, 129.3,
128.6, 128.5, 128.4, 128.4, 127.7, 127.7, 126.9, 126.8, 126.7,
126.5, 126.4, 125.3, 125.3, 122.0, 121.9, 104.3, 104.0, 52.1,
52.0, 40.5, 39.2, 38.9, 26.9, 26.8, 23.3, 23.2, 14.2, 14.1. HRMS
(EI-TOF) calcd for C30H28N2O (M+): 432.2202, found:
432.2204.
(E)-5-Benzylidene-3,3-diphenyl-1-(quinolin-8-yl) pyrroli-
din-2-one (4m): Rf 0.47 (hexane/EtOAc=5:1). Yellow solid.
1
Isolated yield: 35.2 mg, 78%. H NMR (CDCl3, 400 MHz) d
8.86 (dd, J1 =1.6 Hz, J2 =4.0 Hz, 1H), 8.19 (dd, J1 =1.6 Hz,
J2 =8.0 Hz, 1H), 7.92 (dd, J1 =4.0 Hz, J2 =6.0 Hz, 1H), 7.59–
7.63 (m, 4H), 7.54–7.57 (m, 2H), 7.40–7.44 (m, 1H), 7.33–
7.39 (m, 4H), 7.26–7.32 (m, 3H), 7.23–7.25 (m, 2H), 7.15–
7.17 (m, 2H), 7.08–7.12 (m, 1H), 5.37 (s, 1H), 4.00–4.16 (m,
2H). 13C NMR (CDCl3, 100 MHz) d 176.3, 151.1, 144.6,
144.2, 142.7, 141.9, 136.6, 136.2, 133.3, 130.4, 129.5, 129.4,
128.6, 128.4, 128.4, 128.4, 128.0, 127.8, 127.3, 126.9, 126.4,
125.5, 122.0, 104.5, 57.4, 42.5. HRMS (EI-TOF) calcd for
C32H24N2O (M+): 452.1889, found: 452.1881.
(Z)-3-Benzylidene-5-methyl-2-(quinolin-8-yl)isoindolin-1-
one (6b): Rf 0.25 (hexane/EtOAc =2:1). White solid. Isolat-
(E)-6-Benzylidene-5-(quinolin-8-yl)-5-azaspiro[2.4]
1
heptan-4-one (4n): Rf 0.48 (hexane/EtOAc =2:1). Yellow
ed yield: 30.7 mg, 85%. H NMR (CDCl3, 400 MHz) d 8.87
oil. Isolated yield: 12.7 mg, 39%. 1H NMR (CDCl3,
(dd, J1 =1.6 Hz, J2 =3.6 Hz, 1H), 7.97 (dd, J1 =1.6 Hz, J2 =
802
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Cu(II)/Ag(I)-Catalyzed Sequential Alkynylation and Annulation
1
3.6 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.67 (s, 1H), 7.57 (dd,
J1 =1.2 Hz, J2 =4.0 Hz, 1H), 7.47 (dd, J1 =1.2 Hz, J2 =
7.6 Hz, 1H), 7.36–7.38 (m, 1H), 7.27–7.32 (m, 2H), 6.77 (s,
1H), 6.64–6.68 (m, 1H), 6.50–6.56 (m, 4H), 2.54 (s, 3H).
13C NMR (CDCl3, 100 MHz) d 168.3, 150.3, 144.3, 143.0,
139.1, 136.2, 136.0, 134.2, 133.6, 130.3, 130.2, 128.9, 128.3,
128.1, 126.3, 126.0, 125.7, 123.8, 121.2, 120.0, 107.0, 22.2.
HRMS (EI-TOF) calcd for C25H18N2 (M+): 362.1419, found:
362.1423.
ed yield: 25.2 mg, 66%. H NMR (CDCl3, 400 MHz) d 8.83
(dd, J1 =1.6 Hz, J2 =4.0 Hz, 1H), 7.96(dd, J1 =1.6 Hz, J2 =
8.4 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.86 (d, J=1.6 Hz,
1H), 7.58 (dd, J1 =1.2 Hz, J2 =7.2 Hz, 1H), 7.52 (dd, J1 =
1.6 Hz, J2 =6.4 Hz, 1H), 7.47 (dd, J1 =1.6 Hz, J2 =6.0 Hz,
1H), 7.27–7.31 (m, 2H), 6.77 (s, 1H), 6.66–6.71 (m, 1H),
6.53(d, J=4.8 Hz, 4H). 13C NMR (CDCl3, 100 MHz) d
167.2, 150.4, 144.2, 140.2, 138.7, 135.9, 135.1, 133.9, 133.1,
130.0, 129.5, 128.9, 128.6, 128.1, 126.7, 126.4, 126.3, 125.7,
125.2, 121.3, 120.1, 108.6. HRMS (EI-TOF) calcd for
C24H15ClN2O (M+): 382.0873, found: 382.0869.
(Z)-3-Benzylidene-6-methyl-2-(quinolin-8-yl)isoindolin-1-
one (6c): Rf 0.34 (hexane/EtOAc=2:1). White solid. Isolat-
1
ed yield: 27.1 mg, 75%. H NMR (CDCl3, 400 MHz) d 8.84
(Z)-3-Benzylidene-2-(quinolin-8-yl)-5-(trifluoromethyl)-
isoindolin-1-one (6h): Rf 0.29 (hexane/EtOAc=2:1). Yellow
solid. Isolated yield: 25.4 mg, 61%. 1H NMR (CDCl3,
400 MHz) d 8.82 (dd, J1 =1.6 Hz, J2 =4.0 Hz, 1H), 8.10–8.15
(m, 2H), 7.97 (dd, J1 =1.6 Hz, J2 =8.4 Hz, 1H), 7.82 (d, J=
7.6 Hz, 1H), 7.60 (dd, J1 =1.2 Hz, J2 =8.4 Hz, 1H), 7.49–7.51
(m, 1H), 7.29–7.33 (m, 2H), 6.89 (s, 1H), 6.67–6.72 (m, 1H),
6.54–6.57 (m, 4H). 13C NMR (CDCl3, 100 MHz) d 166.8,
150.5, 144.1, 138.9, 135.9, 135.1, 134.3 (q, JCÀF =32.0 Hz),
(dd, J1 =1.6 Hz, J2 =4.0 Hz, 1H), 7.95 (dd, J1 =2.0 Hz, J2 =
8.4 Hz, 1H), 7.74–7.78 (m, 2H), 7.56 (dd, J1 =1.2 Hz, J2 =
8.4 Hz, 1H), 7.44–7.49 (m, 2H), 7.25–7.30 (m, 2H), 6.73 (s,
1H), 6.64–6.68 (m, 1H), 6.50–6.55 (m, 4H), 2.51 (s, 3H).
13C NMR (CDCl3, 100 MHz) d 168.3, 150.4, 144.5, 139.4,
136.3, 136.2, 135.8, 134.4, 133.7, 133.3, 130.1, 128.9, 128.5,
128.3, 128.2, 126.3, 125.9, 125.7, 124.0, 121.2, 119.5, 106.7,
21.6. HRMS (EI-TOF) calcd for C25H18N2O (M+): 362.1419,
found: 362.1418.
133.7, 132.9, 131.0, 130.0, 128.9, 128.7, 128.1, 126.8 (q, JCÀF
=
(Z)-3-Benzylidene-7-methyl-2-(quinolin-8-yl)isoindolin-1-
one (6d): Rf 0.46 (hexane/EtOAc =2:1). White solid. Isolat-
ed yield: 21.0 mg, 58%. H NMR (CDCl3, 400 MHz) d 8.87
304.4 Hz), 126.4, 126.4, 125.9 (q, JCÀF =3.4 Hz), 125.7, 124.6,
121.4, 117.1 (q, JCÀF =4.7 Hz), 109.3. HRMS (EI-TOF) calcd
for C25H15F3N2O (M+): 416.1136, found: 416.1139.
1
(dd, J1 =1.2 Hz, J2 =3.2 Hz, 1H), 7.97 (dd, J1 =1.2 Hz, J2 =
7.8 Hz, 1H), 7.70 (d, J=6.0 Hz, 1H), 7.51–7.58 (m, 2H),
7.44 (dd, J1 =1.2 Hz, J2 =6.0 Hz, 1H), 7.27–7.31 (m, 3H),
6.76 (s, 1H), 6.66 (t, J=5.6 Hz, 1H), 6.50–6.57 (m, 4H), 2.77
(s, 3H). 13C NMR (CDCl3, 100 MHz) d 168.9, 150.5, 144.5,
139.3, 138.1, 136.1, 135.8, 134.4, 133.8, 131.8, 131.1, 130.1,
128.9, 128.3, 128.2, 126.3, 125.9, 125.7, 125.6, 121.2, 117.1,
106.5, 17.6. HRMS (EI-TOF) calcd for C25H18N2O (M+):
362.1419, found: 362.1419.
(Z)-3-(4-Methylbenzylidene)-2-(quinolin-8-yl)isoindolin-1-
one (6i): Rf 0.29 (hexane/EtOAc =2:1). White solid. Isolated
yield: 28.2 mg, 78%. 1H NMR (CDCl3, 400 MHz) d 8.84
(dd, J1 =1.6 Hz, J2 =4.4 Hz, 1H), 7.97–7.99 (m, 2H), 7.87 (d,
J=8.0 Hz, 1H), 7.65–7.69 (m, 1H), 7.53–7.61 (m, 2H), 7.46
(dd, J1 =1.2 Hz, J2 =7.2 Hz, 1H), 7.27–7.32 (m, 2H), 6.79 (s,
1H), 6.42 (d, J=7.6 Hz, 2H), 6.32 (d, J=8.0 Hz, 2H), 2.00
(s, 3H). 13C NMR (CDCl3, 100 MHz) d 168.1, 150.4, 144.5,
138.8, 135.8, 135.7, 135.7, 134.4, 132.2, 130.5, 130.1, 129.0,
128.9, 128.3, 128.1, 128.0, 127.0, 125.7, 123.9, 121.2, 119.6,
107.6, 21.9. HRMS (EI-TOF) calcd for C25H18N2O (M+):
362.1419, found: 362.1424.
(Z)-3-Benzylidene-5-methoxy-2-(quinolin-8-yl)isoindolin-
1-one (6e): Rf 0.13 (hexane/EtOAc=2:1). White solid. Iso-
lated yield: 31.7 mg, 84%. 1H NMR (CDCl3, 400 MHz) d
8.85 (dd, J1 =1.6 Hz, J2 =4.0 Hz, 1H), 7.96 (dd, J1 =1.6 Hz,
J2 =8.4 Hz, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.56 (dd, J1 =
1.2 Hz, J2 =8.4 Hz, 1H), 7.47 (dd, J1 =1.2 Hz, J2 =7.6 Hz,
1H), 7.32 (d, J=2.0 Hz, 1H), 7.26–7.30 (m, 2H), 7.09 (dd,
J1 =2.0 Hz, J2 =8.4 Hz, 1H), 6.74 (s, 1H), 6.65–6.68 (m, 1H),
6.50–6.56 (m, 4H), 3.96 (s, 3H). 13C NMR (CDCl3,
100 MHz) d 166.9, 162.5, 149.2, 143.4, 139.9, 135.0, 134.8,
133.2, 132.5, 129.0, 127.8, 127.2, 127.1, 125.2, 124.9, 124.6,
124.4, 120.2, 120.1, 115.4, 106.0, 102.7, 54.8. HRMS (EI-
TOF) calcd for C25H18N2O2 (M+): 378.1368, found: 378.1367.
(Z)-3-Benzylidene-5-fluoro-2-(quinolin-8-yl)isoindolin-1-
one (6 f): Rf 0.13 (hexane/EtOAc=2:1). White solid. Isolat-
(Z)-3-(4-Methoxybenzylidene)-2-(quinolin-8-yl)isoindolin-
1-one (6j): Rf 0.16 (hexane/EtOAc =2:1). Pale yellow solid.
1
Isolated yield: 35.9 mg, 95%. H NMR (CDCl3, 400 MHz) d
8.86 (dd, J1 =1.6 Hz, J2 =4.0 Hz, 1H), 7.97–8.02 (m, 2H),
7.87 (d, J=7.6 Hz, 1H), 7.61–7.69 (m, 2H), 7.54 (t, J=
7.6 Hz, 1H), 7.47 (dd, J1 =1.2 Hz, J2 =7.2 Hz, 1H), 7.30–7.34
(m, 2H), 6.77 (s, 1H), 6.48 (d, J=8.8 Hz, 2H), 6.07 (d, J=
8.8 Hz, 2H), 3.55 (s, 3H). 13C NMR (CDCl3, 100 MHz) d
168.2, 157.8, 150.3, 144.4, 138.8, 135.9, 135.5, 134.3, 132.2,
130.1, 129.4, 128.9, 128.9, 128.3, 128.2, 126.0, 125.8, 123.9,
121.3, 119.6, 111.9, 107.4, 55.1. HRMS (EI-TOF) calcd for
C25H18N2O2 (M+): 378.1368, found: 378.1369.
1
ed yield: 25.3 mg, 69%. H NMR (CDCl3, 400 MHz) d 8.84
(Z)-3-(4-Fluorobenzylidene)-2-(quinolin-8-yl)isoindolin-1-
one (6k): Rf 0.23 (hexane/EtOAc =2:1). White solid. Isolat-
(dd, J1 =1.6 Hz, J2 =4.0 Hz, 1H), 7.95–7.98 (m, 2H), 7.58
(dd, J1 =1.2 Hz, J2 =8.4 Hz, 1H), 7.53 (dd, J1 =2.0 Hz, J2 =
8.4 Hz, 1H), 7.47 (dd, J1 =1.2 Hz, J2 =7.2 Hz, 1H), 7.23–7.32
(m, 3H), 6.75 (s, 1H), 6.66–6.71 (m, 1H), 6.51–6.54(m, 4H).
1
ed yield: 30.7 mg, 84%. H NMR (CDCl3, 400 MHz) d 8.83
(dd, J1 =1.6 Hz, J2 =4.0 Hz, 1H), 7.98–8.01 (m, 2H), 7.86 (d,
J=7.6 Hz, 1H), 7.66–7.70 (m, 1H), 7.63 (dd, J1 =1.2 Hz, J2 =
8.4 Hz, 1H), 7.54–7.58 (m, 1H), 7.49 (dd, J1 =1.6 Hz, J2 =
7.2 Hz, 1H), 7.29–7.35 (m, 2H), 6.72 (s, 1H), 6.49–6.53 (m,
2H), 6.19–6.23 (m, 2H). 13C NMR (CDCl3, 100 MHz) d
168.1, 160.9 (d, JCÀF =244.5 Hz), 159.7, 150.4, 144.4, 138.5,
136.5, 135.9, 134.1, 132.3, 130.1, 129.7 (d, JCÀF =8.4 Hz),
129.5 (d, JCÀF =3.2 Hz), 129.2, 128.9, 128.5, 128.3, 125.7,
124.0, 121.4, 119.7, 113.1 (d, JCÀF =21.2 Hz), 106.1. HRMS
(EI-TOF) calcd for C24H15FN2O (M+): 366.1168, found:
366.1169.
13C NMR (CDCl3, 100 MHz) d 167.1, 165.8 (d, JCÀF
=
249.6 Hz), 150.4, 144.2, 141.1 (d, JCÀF =11.4 Hz), 135.9, 135.3
(d, JCÀF =3.6 Hz), 133.9, 133.1, 130.1, 128.9, 128.5, 128.1,
126.4, 126.3, 126.2 (d, JCÀF =10.0 Hz), 125.7, 124.4 (d, JCÀF
=
1.7 Hz), 121.3, 116.9 (d, JCÀF =22.9 Hz), 108.4, 106.8 (d,
J
CÀF =24.9 Hz). HRMS (EI-TOF) calcd for C24H15FN2O
(M+): 366.1168, found: 366.1167.
(Z)-3-Benzylidene-5-chloro-2-(quinolin-8-yl)isoindolin-1-
one (6g): Rf 0.39 (hexane/EtOAc=2:1). White solid. Isolat-
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Jitan Zhang et al.
(Z)-3-(4-Chlorobenzylidene)-2-(quinolin-8-yl)isoindolin-1-
one (6l): Rf 0.26 (hexane/EtOAc=2:1). White solid. Isolat-
ed yield: 33.2 mg, 87%. H NMR (CDCl3, 400 MHz) d8.80
80 wt% in toluene, 44.88 mmol) in THF (21 mL) was then
added drop wise. The mixture was stirred overnight and
warm to room temperature. After quenching with NH4Cl
(aq. ~60 mL) the organic layer was separated and the aque-
ous layer extracted with Et2O (2”20 mL). The organic
layers were combined and washed with brine (20 mL), dried
over MgSO4, filtered and concentrated to brown oil. This oil
was purified by flash column chromatography on silica gel,
eluting with hexane, to afford 2, 2-dimethyl-ethyl penty-
noate.
Preparation of ethyl 2,2-dimethyl-5-phenylpentynoate:
ethyl 2,2-dimethylpentynoate (4.63 g, 30 mmol) was added
to a solution of dry, degassed triethylamine/acetonitrile
(100 mL, 1:4, 0.3m) and iodobenzene (6.71 mL, 60 mmol).
After stirring at room temperature for 10 min, Pd(PPh3)4
(243 mg, 0.21 mmol, 0.7 mol%) and CuI (286 mg, 1.5 mmol,
5 mol%) were added. The reaction mixture was stirred at
room temperature in the dark for 22 h. The crude mixture
was then filtered through a plug of celite and concentrated
to yellow oil. The oil was purified by flash chromatography,
eluting with hexane, to afford the product as colorless oil.
1H NMR (CDCl3, 400 MHz): d 7.37–7.39 (s, 2H), 7.25–7.28
(s, 3H), 4.16 (m, J=3.6 Hz, 2H), 2.65 (s, 2H), 1.33 (s, 6H),
1.26 (t, J=3.6 Hz, 3H). 13C NMR (CDCl3, 100 MHz): d
176.7, 131.6, 128.2, 127.7, 123.7, 86.8, 82.7, 60.7, 42.5, 30.6,
24.7, 14.3.
Preparation of 2,2-dimethyl-5-phenyl-4-pentynoic acid: To
a solution of NaOH (1.77 g, 44.4 mmol) in methanol/H2O
(2:1, 205 mL, 0.1m) was added the 2,2-dimethyl-5-phenyl
ethyl pentynoate (5.11 g, 22.2 mmol). The mixture was
heated at reflux (808C) for 4 h. After cooling back to room
temperature, the crude mixture was concentrated and then
diluted with H2O (15 mL). The aqueous mixture was ex-
tracted with Et2O (3”10 mL). The aqueous layer was acidi-
fied to pH 2 with concentrated HCl and extracted with ethyl
acetate (3”20 mL). These extracts were washed with brine
(~10 mL), dried over MgSO4 and concentrated to white
solid.
Oxalyl chloride (1.75 mL, 20 mmol) was added slowly to
a stirred solution of the 2, 2-dimethyl-5-phenyl-4-pentynoic
acid in CH2Cl2 (20 mL) and DMF (0.1 mL) at 08C. The mix-
ture was stirred for 1 h at 08C and another 4 h at room tem-
perature, and evaporated in vacuo. The residue was then
dissolved in toluene (5 mL), evaporated in vacuo twice, to
give the crude acid chloride, which was used directly for the
next step without further purification.
1
(d, J=3.2 Hz, 1H), 7.97–7.99 (m, 2H), 7.83 (d, J=7.6 Hz,
1H), 7.62–7.67 (m, 2H), 7.55 (t, J=7.2 Hz, 1H), 7.48 (d, J=
7.2 Hz, 1H), 7.27–7.35 (m, 2H), 6.68 (s, 1H), 6.42–6.47 (m,
4H). 13C NMR (CDCl3, 100 MHz) d 168.0, 150.4, 144.3,
138.4, 136.8, 135.9, 134.1, 132.4, 132.0, 131.8, 130.2, 129.3,
129.3, 128.9, 128.5, 128.3, 126.3, 125.8, 124.0, 121.4, 119.7,
105.8. HRMS (EI-TOF) calcd for C24H15ClN2O (M+):
382.0873, found: 382.0878.
(Z)-2-(Quinolin-8-yl)-3-(thiophen-2-ylmethylene)isoindo-
lin-1-one (6m): Rf 0.26 (hexane/EtOAc =2:1). Yellow solid.
1
Isolated yield: 33.2 mg, 94%. H NMR (CDCl3, 400 MHz) d
8.86 (dd, J1 =1.6 Hz, J2 =4.0 Hz, 1H), 8.10 (dd, J1 =1.2 Hz,
J2 =8.0 Hz, 1H), 7.98 (d, J=7.2 Hz, 1H), 7.86 (d, J=8.0 Hz,
1H), 7.77 (dd, J1 =1.2 Hz, J2 =8.4 Hz, 1H), 7.62–7.70 (m,
2H), 7.54–7.57 (m, 1H), 7.44–7.48 (m, 1H), 7.36 (q, J=
4.0 Hz, 1H), 6.75–6.76 (m, 2H), 6.25–6.28 (m, 1H), 5.97–
5.98 (m, 1H). 13C NMR (CDCl3, 100 MHz) d 168.1, 150.7,
144.9, 138.7, 136.0, 135.9, 135.7, 134.1, 132.3, 130.2, 129.2,
129.0, 128.8, 128.3, 128.0, 126.0, 125.8, 124.1, 121.5, 119.6,
99.8. HRMS (EI-TOF) calcd for C22H14N2OS (M+):
354.0827, found: 354.0823.
(Z)-3-(Cyclopropylmethylene)-2-(quinolin-8-yl)isoindolin-
1-one (6n): Rf 0.15 (hexane/EtOAc =2:1). White solid. Iso-
lated yield: 24.3 mg, 78%. 1H NMR (CDCl3, 400 MHz) d
9.19 (dd, J1 =1.6 Hz, J2 =4.4 Hz, 1H), 8.47 (dd, J1 =1.6 Hz,
J2 =8.0 Hz, 1H), 8.17–8.22 (m, 2H), 8.12 (dd, J1 =1.2 Hz,
J2 =7.2 Hz, 1H), 7.90–7.94 (m, 2H), 7.83–7.87 (m, 1H),
7.72–7.76 (m, 1H), 7.67–7.71 (m, 1H), 5.37–5.39 (m, 1H),
0.60–0.67 (m, 2H), 0.53–0.59 (m, 1H), 0.36–0.42 (m, 1H),
0.21–0.27 (m, 1H). 13C NMR (CDCl3, 100 MHz) d 168.0,
151.2, 145.4, 138.1, 136.1, 135.4, 135.2, 131.8, 130.6, 139.2,
129.1, 128.1, 127.8, 126.2, 123.7, 121.8, 118.9, 113.9, 8.7, 8.6.
HRMS (EI-TOF) calcd for C21H16N2O (M+): 312.1263,
found: 312.1266.
(Z)-3-Benzylidene-2-(quinolin-8-yl)-2,3,4,5,6,7-hexahydro-
1H-isoindol-1-one (6o): Rf 0.16 (hexane/EtOAc=2:1).
1
Yellow oil. Isolated yield: 26.0 mg, 74%. H NMR (CDCl3,
400 MHz) d 8.90 (dd, J1 =1.2 Hz, J2 =4.0 Hz, 1H), 7.97 (dd,
J1 =1.6 Hz, J2 =4.0 Hz, 1H), 7.53 (dd, J1 =0.8 Hz, J2 =
4.0 Hz, 1H), 7.35 (dd, J1 =1.2 Hz, J2 =7.2 Hz, 1H), 7.28–7.31
(m, 1H), 7.21–7.26 (m, 1H), 6.63–6.67 (m, 1H), 6.48–6.55
(m, 4H), 6.22 (s, 1H), 2.56–2.64 (m, 2H), 2.45–2.46 (m, 2H),
1.80–1.93 (m, 4H). 13C NMR (CDCl3, 100 MHz) d 171.3,
150.2, 146.3, 144.6, 140.0, 136.0, 134.5, 133.8, 130.2, 129.8,
128.9, 128.2, 127.8, 126.3, 126.1, 125.8, 121.1, 109.3, 22.3,
22.0, 21.5, 20.6. HRMS (EI-TOF) calcd for C24H20N2O (M+):
352.1576, found: 352.1575.
The acid chloride was added dropwise to a solution of 8-
aminoquinoline (1.01 g, 7.0 mmol) and Et3N (1.7 mL,
12 mmol) in CH2Cl2 (12 mL). The mixture was stirred over-
night at room temperature. Then the mixture was diluted
with CH2Cl2 (10 mL), washed successively with water, satu-
rated aqueous NaHCO3, and brine. The organic layer was
dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by flash column chromatography
on silica gel, eluting with EtOAc/hexane (1:20, v/v), to
afford 2, 2-dimethyl-5-phenyl-N-(quinolin-8-yl)pent-4-yn-
Synthesis of 2,2-Dimethyl-5-phenyl-N-(quinolin-8-
yl)pent-4-ynamide (7)
Preparation of ethyl 2,2-dimethylpentynoate: To a solution
of freshly prepared LDA (39.3 mmol) in THF (35 mL)
cooled to À788C was added a solution of ethyl isobutyrate
(5.0 mL, 37.4 mmol) in THF (42 mL) by addition funnel
over 1 h with stirring. After addition was completed, the re-
action mixture stirred for 20 min at À788C and then
warmed to 08C and stirred for 10 min before cooling back
1
amide (7) as a white solid. H NMR (400 MHz, CDCl3): d
10.45 (s, 1H), 8.83 (d, J=7.6 Hz, 1H), 8.66 (dd, J1 =1.6 Hz,
J2 =2.8 Hz, 1H), 8.12 (d, J=7.6 Hz, 1H), 7.47–7.55 (m, 2H),
7.37–7.41 (m, 1H), 7.32–7.34 (m, 2H), 7.17–7.23 (m, 3H),
2.85 (s, 2H), 1.59 (s, 3H). 13C NMR (100 MHz, CDCl3): d
175.3, 148.3, 138.8, 136.3, 134.6, 131.7, 128.1, 127.9, 127.7,
to À788C.
A solution of propargyl bromide (5.0 mL,
804
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Adv. Synth. Catal. 2016, 358, 792 – 807

FULL PAPERS
Cu(II)/Ag(I)-Catalyzed Sequential Alkynylation and Annulation
127.4, 123.7, 121.6, 121.5, 116.4, 86.8, 83.5, 43.8, 31.1, 25.2.
HRMS (EI-TOF) calcd for C22H20N2O (M+): 328.1576,
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Acknowledgements
We gratefully acknowledge the Natural Science Foundation
of China (21272205), the National Basic Research Program
of China (2011CB936003), and the Program for the Zhejiang
Leading Team of Science and Technology Innovation
(2011R50007) for their financial support.
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