Nickel-Catalyzed Annulation of Aliphatic Amides with Alkynyla silanes: An Expeditious Approach to Five-Membered Lactams

Article abstract of DOI:10.1055/s-0037-1610756

An expeditious approach for the synthesis of diverse five-membered lactams through nickel-catalyzed annulation of the C(sp ³)-H bonds of aliphatic amides with alkynylsilanes assisted by an 8-Aminoquinolinyl directing group is reported, delivering the corresponding lactam derivatives in moderate to high yields. It is worth noting that alkynylsilanes are employed for the first time as coupling partners in the transition-metal-catalyzed functionalization of C(sp ³)-H bonds of aliphatic amides. Equimolar amounts of alkynylsilanes and aliphatic amides are utilized, which greatly increases the efficiency of this protocol.

Full text of DOI:10.1055/s-0037-1610756

SYNLETT
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© Georg
Thieme Ver-
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2020, 52,
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C. Lin et al.
Letter
Synlett
Nickel-Catalyzed Annulation of Aliphatic Amides with Alkynyl-
silanes: An Expeditious Approach to Five-Membered Lactams
Cong Lin*
Yiqing Xu
0
0
0
0-0
0
0
2-4
4
0
4-
5
2
4
9
Q
Q
HN
N
Q =
Ni/Ag
R3
O
R3
TMS
O
+
Qiuxun Teng
Jingyi Lin
H
R2
N
1 R2
R1
R
R1, R2, R3 = aryl, alkyl, acyl
Fei Gao
aliphatic amides/alkynylsilanes = 1:1
23 examples, up to 99% yield
E-configuration
inexpensive Ni(II) as the catalyst
Liang Shen*
tolerance of various aliphatic amides and alkynylsilanes
Jiangxi Engineering Laboratory of Waterborne Coatings,
College of Chemistry and Chemical Engineering, Jiangxi
Science & Technology Normal University, Nanchang
330013, P. R. of China
conglin0127@jxstnu.com.cn
Received: 25.12.2019
Accepted after revision: 20.02.2020
Published online: 05.03.2020
amides was independently reported by Chatani,9 Yu,10
Gaunt11 and Wang12 by using different transition-metal cat-
alysts. Recently, Zhang and co-workers demonstrated an ef-
ficient approach to prepare five-membered lactams
through Co- and Ni-catalyzed annulations of aliphatic am-
ides with readily available alkynes and propiolic acids
(Scheme 1, a).13 However, two or more equivalents of the
terminal alkynes and propiolic acids were required due to
the relatively high reactivity and the tendency of self-di-
merization or self-trimerization of the terminal alkynes, re-
sulting in an increase in the cost of the system and a reduc-
tion in the efficiency of the reactions. In some cases, alky-
nylsilanes are better coupling reagents than terminal
alkynes, because their unique character is exemplified not
only in the silyl protection of the terminal C–H of the acety-
lene, but also in the ability of the silyl group to dictate and
improve the regioselectivity of reactions at the triple
bond.14 Thus, achieving the direct C–H annulation of inert
C(sp3)–H bonds with alkynylsilanes by using inexpensive
metal catalysts remains an important challenge.
DOI: 10.1055/s-0037-1610756; Art ID: st-2019-b0690-l
Abstract An expeditious approach for the synthesis of diverse five-
membered lactams through nickel-catalyzed annulation of the C(sp3)–
H bonds of aliphatic amides with alkynylsilanes assisted by an 8-amino-
quinolinyl directing group is reported, delivering the corresponding lac-
tam derivatives in moderate to high yields. It is worth noting that alky-
nylsilanes are employed for the first time as coupling partners in the
transition-metal-catalyzed functionalization of C(sp3)–H bonds of ali-
phatic amides. Equimolar amounts of alkynylsilanes and aliphatic am-
ides are utilized, which greatly increases the efficiency of this protocol.
Key words five-membered lactams, nickel-catalyzed, annulations,
C(sp3)–H bonds, aliphatic amides, alkynylsilanes
Over the past few decades, significant headway has
been made in the transition-metal-catalyzed direct func-
tionalization of C–H bonds, and the process is widely used
to construct diverse C–C and C–X bonds as well as syntheti-
cally useful heterocycles.1 Among the many useful hetero-
cycles, lactams represent an important structural motif that
occur in a wide range of biologically active compounds,
pharmaceuticals and in natural products.2 In recent years,
the annulation of C(sp2)–H bonds has aroused considerable
attention due to the significant value of the synthesis of lac-
tams in organic chemistry.3 In contrast, protocols involving
the direct functionalization of inert sp3 C–H bonds are lim-
ited. An initial study on the synthesis of five-membered lac-
tams through palladium-catalyzed alkenylation/Michael
addition of aliphatic amides with electron-deficient alkenes
was described by Yu and co-workers in 2010.4 Later on, the
transition-metal-catalyzed intramolecular aminations of
the C(sp3)–H bonds of aliphatic amides for the formation of
four- or five-membered lactams were successfully devel-
oped by the groups of Chen,5 Shi,6 Kanai7 and Ge.8 The tan-
dem carbonylation/intramolecular amination of aliphatic
Nickel has been widely utilized as a catalyst in the realm
of C–H bond functionalization owing to its advantages of
being a cheap and sustainable metal. Several important
breakthroughs have been achieved in terms of nickel-
catalyzed C–H activation to construct C–C and C–X bonds, as
pioneered by Chatani and others,15 and further underscoring
the excellent catalytic performance of nickel catalysts. Re-
cently, a powerful strategy that involved bidentate directing
groups proved to be highly efficient in nickel-catalyzed
functionalization of inert C(sp3)–H bonds to realize a vari-
ety of useful transformations, including arylation,16 alke-
nylation,15i,j,17 alkynylation,18 alkylation,19 intramolecular
amination,8 thioetherification,20 and annulation.21 Inspired
by these encouraging achievements, we explored an expe-
ditious strategy to prepare five-membered lactams through
nickel-catalyzed annulation of the C(sp3)–H bonds of ali-
© 2020. Thieme. All rights reserved. Synlett 2020, 52, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
C. Lin et al.
Letter
Synlett
Table 1 Optimization of the Reaction Conditionsa
(a) Previous work:
Q
HN
Q
Ni/Ag
or Co/Ag
10 mol% Ni salt
Ag salt, additive
N
O
O
Ph
O
R1
R2
O
R
H
+
Ph
TMS
R1
R2
Q
Q =
Na2CO3 (2 equiv)
PhCF3, N2, 150 °C, 24 h
H
N
Q
N
+
H
2a
N
1a
H
3a
Cu/Ag
Ni/Ag
R
COOH
R
Entry
[Ni]
Ag salt
Ag2CO3
Additive
TBAI
Yield (%)b
(b) This work:
1
2
NiBr2
NiCl2
NiI2
11
trace
20
51
99
52
0
O
R1
R2
O
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2SO4
AgOAc
Ag2O
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
–
R1
R2
Q
Q =
Q
N
N
3
+
R
TMS
H
N
H
4
(Cy3P)2NiCl2
Ni(acac)2
Ni(OAc)2
–
R
5
Scheme 1 Transition-metal-catalyzed synthesis of five-membered lac-
tams: (a) previous work, (b) this work
6
7
8
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
trace
0
phatic amides with alkynylsilanes assisted by an 8-amino-
quinolinyl directing group. Notable features of our strategy
include (i) the use of alkynylsilanes14 as coupling reagents
for the first time in the functionalization of C(sp3)–H bonds,
(ii) high functional group tolerance, and (iii) equimolar
amounts of alkynylsilanes and aliphatic amides are em-
ployed, which greatly increases the efficiency of the process
(Scheme 1, b).
9
NaI
10
11
12
13
14
15
16c
KI
0
CsI
0
TBAI
TBAI
TBAI
TBAI
TBAI
33
26
0
–
0
Reaction optimization was performed by coupling
N-(quinolin-8-yl)pivalamide (1a) with trimethyl(phenyl-
ethynyl)silane (2a) as a model system. When the reaction
was carried out in the presence of NiBr2, Ag2CO3, Na2CO3,
and TBAI in PhCF3 at 150 °C under an N2 atmosphere for 24
hours, the desired product 3a was obtained in a low 11%
yield (Table 1, entry 1). Next, other commercially available
nickel catalysts were screened, including NiCl2, NiI2,
(Cy3P)2NiCl2, Ni(acac)2, and Ni(OAc)2. Gratifyingly, it was
observed that Ni(acac)2 showed the best catalytic reactivity,
giving the annulated product 3a in quantitative yield (Table
1, entries 2–6). The replacement of TBAI with other addi-
tives had a deleterious effect on the reaction efficiency (Ta-
ble 1, entries 9–11). Although the exact role of TBAI is un-
clear at this point, we speculate that it might play the role of
a phase-transfer catalyst to increase the solubility of Ag2CO3
in PhCF3. An investigation of alternative silver oxidants was
also conducted, but lower yields were obtained in each case
(Table 1, entries 12–14). Control experiments indicated that
the reaction did not occur in the absence of the nickel cata-
lyst, TBAI, the oxidant, or Na2CO3, respectively (Table 1, en-
tries 7, 8, 15 and 16). Further optimization with respect to
the solvent revealed that PhCF3 was superior compared to
other solvents (see the Supporting Information). Further-
more, the yield of product 3a was reduced when the tem-
perature or the reaction time was decreased (see the Sup-
porting Information).
Ag2CO3
0
a Reaction conditions: N-(quinolin-8-yl)pivalamide (1a) (0.1 mmol), trimeth-
yl(phenylethynyl)silane (2a) (0.1 mmol), Ni salt (0.01 mmol), Ag salt (0.3
mmol), Na2CO3 (0.3 mmol), additive (0.3 mmol), PhCF3 (1.5 mL), N2,
150 °C, 24 h. Q = 8-Quinolinyl, TBAI = tetrabutylammonium iodide.
b Yield of isolated product.
c Without Na2CO3.
nylsilanes 2, including examples with phenyl and alkyl
groups, were all compatible under the present reaction con-
ditions, giving the corresponding products 3a–d,g–h. It was
worth mentioning that a conjugated alkynylsilane could
participate in this transformation to provide the corre-
sponding lactam-containing conjugated diene 3f, which
may allow the synthesis of more complex molecules. More
significantly, 2-[(trimethylsilyl)ethynyl]pyridine was also
applicable under the current reaction conditions, affording
the desired product 3e in a moderate 41% yield.
After examining the compatibility of the annulation re-
action with a variety of alkynylsilane substrates, our atten-
tion turned toward the reactivity of different aliphatic am-
ides 1 (Scheme 3). A variety of aliphatic amides bearing a -
methyl group smoothly participated in the annulation reac-
tion to provide the corresponding E-configured products
4a–o in moderate to excellent yields. Different substituents
located at the -carbon of the aliphatic amides, such as al-
kyl, benzyl, and even phenyl, were all tolerated in the trans-
formation. Noteworthy was the fact that the formation of
two racemic pairs of enantiomers of 4a–k were observed
with regard to the different substituents at the -carbon of
With optimized reaction conditions in hand, we next in-
vestigated the scope of the alkynylsilanes (Scheme 2). Grat-
ifyingly, the results showed that different substituted alky-
© 2020. Thieme. All rights reserved. Synlett 2020, 52, A–F

C
C. Lin et al.
Letter
Synlett
Q
Q
HN
Ni(acac)2 (10 mol%), Na2CO3 (3 equiv)
Ag2CO3 (3 equiv), TBAI (3 equiv)
N
R
O
O
R
TMS
+
PhCF3, N2, 150 °C, 24 h
Q = 8-quinolinyl
H
3
1a
2
Q
N
Q
Q
Q
Cl
N
N
N
O
O
O
O
O
MeO
Br
3d, 95%
3b, 87%
3c, 64%
3a, 99%
3e, 41%
Q
Q
N
Q
Q
N
N
N
N
O
O
O
3h, 55%
3g, 65%
3f, 51%
Scheme 2 Substrate scope of the alkynylsilanes. Reaction conditions: 1a (0.1 mmol), alkynylsilane 2 (0.1 mmol), Ni(acac)2 (0.01 mmol), Ag2CO3 (0.3
mmol), Na2CO3 (0.3 mmol), TBAI (0.3 mmol), PhCF3 (1.5 mL), N2, 150 °C, 24 h. Yields of isolated products are given
Q
Q
HN
Ni(acac)2 (10 mol%), Na2CO3 (3 equiv)
Ag2CO3 (3 equiv), TBAI (3 equiv)
N
Ph
O
O
Ph
TMS
+
R2
H
PhCF3, N2, 150 °C, 24 h
Q = 8-quinolinyl
1 R2
R1
R
4
1
2a
Q
N
Q
Q
N
N
Ph
Ph
Ph
O
O
O
4b, 98%
d.r. = 1.2:1
4c, 95%
d.r. = 1:1
4a, 91%
d.r. = 1.1:1
Q
Q
Q
N
N
O
N
O
Ph
Ph
Ph
O
Ph
F
4e, 87%
d.r. = 2:1
4f, 85%
d.r. = 2:1
4d, 87%
d.r. = 1.7:1
Q
Q
Q
N
O
N
O
Ph
N
O
Ph
Ph
CF3
Cl
4h, 73%
d.r. = 1.4:1
4i, 76%
d.r. = 1.1:1
4g, 82%
d.r. = 1.7:1
Q
Q
N
Q
N
N
Ph
O
Ph
Ph
Ph
O
O
O
O
Ph
Ph
Ph
4k, 97%
d.r. = 1:1
Q
4l, 94%
4j, 81%
d.r. = 1.1:1
Q
N
Q
N
N
Ph
O
Ph
O
4n, 70%
4o, 75%
4m, 55%
Scheme 3 Substrate scope of the aliphatic amides. Reaction conditions: 1 (0.1 mmol), trimethyl(phenylethynyl)silane (2a) (0.1 mmol), Ni(acac)2 (0.01
mmol), Ag2CO3 (0.3 mmol), Na2CO3 (0.3 mmol), TBAI (0.3 mmol), PhCF3 (1.5 mL), N2, 150 °C, 24 h. Yields of isolated products are given
© 2020. Thieme. All rights reserved. Synlett 2020, 52, A–F

D
C. Lin et al.
Letter
Synlett
Q
Q
HN
Ni(acac)2 (10 mol%), Na2CO3 (3 equiv)
Ag2CO3 (3 equiv), TBAI (3 equiv)
N
Ph
O
O
Ph
TMS
+
H
PhCF3, N2, 150 °C, 24 h
Q = 8-aminoquinolinyl
93%
3a, 305.2 mg
1a, 1.0 mmol
2a, 1.0 mmol
Scheme 4 Sub-gram-scale synthesis of 3a
the aliphatic amides, presumably due to axial chirality aris-
ing from hindered rotation around the N1–C(quinolinyl)
bond.13 It is worth mentioning that the site of C(sp3)–H an-
nulation occurred exclusively at the -methyl group instead
of the -methylene or -methyl groups of the amides,
thereby demonstrating the high regioselectivity of the pro-
tocol. The reason that the annulation does not occur at the
methylene C(sp3)–H bonds may be due to the fact that such
bonds are more inert and sterically hindered compared
with methyl C(sp3)–H bonds. Several -cyclic amides were also
compatible with the reaction system leading to the corre-
sponding spiral lactam products 4m–o with moderate effi-
ciency.
Importantly, when the reaction was scaled up to 1.0
mmol on a sub-gram scale, the lactam product 3a was iso-
lated in 93% yield without any decrease in the efficiency of
the reaction, indicating the robustness of our protocol and
the potential synthetic applications of this method (Scheme
4). Unfortunately, the desired reaction did not occur when
we removed the directing group from the aliphatic amide 1.
To gain insights into the reaction mechanism, we carried
out several control experiments (Scheme 5). The addition of a
radical scavenger such as TEMPO (2,2,6,6-tetramethylpiperi-
dine 1-oxyl) hardly had any influence on the reaction, revealing
that a radical mechanism for this reaction may be excluded
(Scheme 5, eq 1). In addition, the reaction of trimethyl(phenyl-
ethynyl)silane (2a) with Na2CO3 was performed and ethynyl-
benzene (5) was not isolated (eq 2). Besides, ethynylbenzene (5)
was able to react with substrate 1a under the standard condi-
tions to give a mixture of products 3a and 3a′, albeit in low yield
(eq 3). This result illustrated that ethynylbenzene (5) was not a
suitable annulation coupling partner. Therefore, the mechanism
of this reaction is different to that previously reported by
Zhang.13 According to a reported method,22 we prepared the
alkynylated product 6, which reacted under the standard condi-
tions to form the pyrrolidinone 3a in 99% yield with E-configu-
ration (eq 4). It was thus speculated that the alkynylated
product 6 was a key intermediate in the reaction. Further
studies revealed that the use of Ag2CO3 was essential for the
cyclization process to occur (eq 5).
Q
HN
Q
N
Ni(acac)2 (10 mol%), Na2CO3 (3 equiv)
Ag2CO3 (3 equiv), TBAI (3 equiv)
Ph
O
O
Ph
TMS
+
(1)
H
PhCF3, N2, 150 °C, 24 h
Q = 8-aminoquinolinyl
3a
1a
2a
2a
TEMPO (2.0 equiv)
97%
Na2CO3 (2 equiv)
PhCF3, N2, 150 °C, 24 h
(2)
(3)
Ph
H
Ph
Ph
TMS
H
5
Q
HN
Ph
Q
Q
N
N
Ph
standard conditions
O
O
+
O
+
H
5 (1 equiv)
1a (1 equiv)
3a, 20%
3a', 11%
O
Q
N
O
Q
(4)
standard conditions
99%
Ph
N
H
Ph
3a
6
O
Ag2CO3 (30 mol%)
TBAI (3 equiv)
Q
Q
N
N
Ph
(5)
O
H
PhCF3, N2, 150 °C, 24 h
Ph
3a
6
standard conditions 99%
without Ag2CO3
without TBAI
no reaction
70%
Scheme 5 Control experiments
© 2020. Thieme. All rights reserved. Synlett 2020, 52, A–F

E
C. Lin et al.
Letter
Synlett
O
H
N
H
N
+
NaHCO3, NaX
Na2CO3
LnNiIIX2
Ag
O
N
NiII
N
Ag2CO3
LnNiIX
A
Ag2CO3
O
Ag
O
N
H
O
N
N
NiIII
N
N
NiIII
X
N
Ph
transmetalation
6
C
B
Ph
Ag2CO3
TBAI
Ph
TMS 2a
Na2CO3
+
Q
N
Ph
O
Q = 8-quinolinyl
Scheme 6 A plausible catalytic cycle
Based on these mechanistic results and previous re-
ports,13,18,21 a plausible catalytic cycle is depicted in Scheme
6. First, the cyclometalation of 1 with Ni(II) generates inter-
mediate A with the assistance of the 8-aminoquinoline aux-
iliary. Subsequent oxidation of Ni(II) to Ni(III)21 and trans-
metalation with trimethyl(phenylethynyl)silane (2a) forms
the intermediate C, which undergoes reductive elimination
to give the alkynylated product 6. Oxidation of Ni(I) gener-
ates the Ni(II) species through protonation to fulfill the cy-
cle. The silver salt in combination with TBAI promotes the
cyclization of alkynylated product 6 to deliver the final
product.
Funding Information
Funding from the Natural Science Foundation of China (Grant Nos.
51963010 and 21704036) and the Science Funds of the Education Of-
fice of Jiangxi Province (Grant No. GJJ180601) is acknowledged.
N
aturalS
c
i
e
n
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e
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n
d
ati
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n
of
C
h
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(5
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9
6
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i
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o
u
n
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ati
o
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i
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(2
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610756.
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References and Notes
In summary, we have reported a highly efficient method
for the direct nickel-catalyzed annulation of the C(sp3)–H
bonds of aliphatic amides with alkynylsilanes using an 8-
aminoquinolinyl auxiliary as a directing group to deliver di-
verse, structurally complex five-membered lactam deriva-
tives.23 Notable features of this protocol include broad sub-
strate scope, excellent regioselectivity and good functional
group compatibility. More significantly, alkynylsilanes have
been employed for the first time as coupling partners in the
transition-metal-catalyzed functionalization of C(sp3)–H
bonds of aliphatic amides. Further mechanistic studies and
investigations on extending the method to a range of other
coupling partners are currently underway in our laborato-
ries.
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Letter
Synlett
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A 25 mL sealed tube was charged with 2,2-disubstituted N-
(quinolin-8-yl)propionamide 1 (0.1 mmol), alkynylsilane 2 (0.1
mmol), Ni(acac)2 (2.57 mg, 0.01 mmol), Na2CO3 (31.8 mg, 0.3
mmol), Ag2CO3 (82.8 mg, 0.3 mmol), TBAI (110.8 mg, 0.3 mmol)
and PhCF3 (1.5 mL). The vial was then evacuated, filled with N2
and the reaction mixture stirred at 150 °C for 24 h. The mixture
was then cooled to room temperature, diluted with EtOAc (2
mL), filtered through a Celite pad, and concentrated in vacuo.
The residue was purified by flash column chromatography on
silica gel, eluting with EtOAc/PE (1:5 to 1:2, v/v), to afford the
desired alkylated product 3 or 4.
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Yield: 32.5 mg (99%); yellow solid; Rf = 0.51 (hexane/EtOAc,
2:1). 1H NMR (400 MHz, CDCl3):  = 8.87 (dd, J1 = 1.2 Hz, J2 = 3.2
Hz, 1 H), 8.20 (dd, J1 = 1.2 Hz, J2 = 6.8 Hz, 1 H), 7.92 (dd, J1 = 1.2
Hz, J2 = 6.4 Hz, 1 H), 7.63–7.69 (m, 2 H), 7.41 (dd, J1 = 3.2 Hz, J2 =
6.8 Hz, 1 H), 7.21–7.25 (m, 2 H), 7.06–7.10 (m, 3 H), 5.28 (s, 1 H),
3.25 (dd, J1 = 1.2 Hz, J2 = 14.4 Hz, 1 H), 3.13 (dd, J1 = 1.2 Hz, J2 =
14.4 Hz, 1 H), 1.53 (s, 3 H), 1.43 (s, 3 H). 13C NMR (100 MHz,
CDCl3):  = 181.1, 151.1, 144.3, 143.0, 137.0, 136.1, 133.4, 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): m/z [M]+ calcd for C22H20N2O:
328.1576; found: 328.1574.
© 2020. Thieme. All rights reserved. Synlett 2020, 52, A–F