Palladium-Catalyzed Direct Arylation of C(sp3)-H Bonds of α-Cyano Aliphatic Amides

Article abstract of DOI:10.1021/acs.joc.5b02138

Pd(OAc)₂-catalyzed arylation of C(sp³)-H bonds in α-cyano-α-methyl aliphatic amides is achieved in the presence of 8-aminoquinoline, as a removable directing group, using Mn(OAc)₂ and Na₂CO₃. The current strategy enables the placement of an aryl/heteroaryl group at the β-position of α-cyano aliphatic acids for the first time. Wide functional group tolerance and easily accessible starting materials provide an efficient protocol for the synthesis of arylated α-cyano amides. Furthermore, the synthetic utility of the products has been demonstrated by their efficient conversions to medicinally important α,α-dialkylated acid and β-amino acid derivatives.

Full text of DOI:10.1021/acs.joc.5b02138

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Article
Palladium-Catalyzed Direct Arylation of C(sp3)-
H Bonds of alpha-Cyano Aliphatic Amides
M. Damoder Reddy, and E. Blake Watkins
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02138 • Publication Date (Web): 29 Oct 2015
Downloaded from http://pubs.acs.org on October 30, 2015
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Page 1 of 42
The Journal of Organic Chemistry
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Palladium-Catalyzed Direct Arylation of C(sp3)-H Bonds of
Cyano Aliphatic Amides
α-
M. Damoder Reddy and E. Blake Watkins*
Department of Pharmaceutical Sciences, School of Pharmacy, Union University, Jackson, Tennessee,
United States 38305
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Eꢀmail: bwatkins@uu.edu
ABSTRACT: Pd(OAc)2ꢀcatalyzed arylation of C(sp3)ꢀH bonds in
is achieved in the presence of 8ꢀaminoquinoline, as a removable directing group, using Mn(OAc)2 and
Na2CO3. The current strategy enables the placement of an aryl/heteroaryl group at the −position of
−cyano aliphatic acids for the first time. Wide functional group tolerance and easily accessible starting
α−cyano−α−methyl aliphatic amides
β
α
materials provide an efficient protocol for the synthesis of arylated α−cyano amides. Furthermore, the
synthetic utility of the products has been demonstrated by their efficient conversions to medicinally
important −dialkylated acid and −amino acid derivatives.
α,
α
β
INTRODUCTION
Transition metalꢀcatalyzed functionalization of carbonꢀhydrogen bonds is an emerging topic in recent
years.1 The CꢀH bond activation protocol shortens the synthetic pathway and simplifies the
retrosynthetic strategy by elimination of preꢀfunctionalization of the starting materials. Over the years,
functionalization of C(sp2)ꢀH bonds has developed as a means to construct carbonꢀcarbon (CꢀC) and
carbonꢀheteroatom (CꢀX) bonds. Significant work has been done in the area of unactivated C(sp2)ꢀH
bond functionalization.2 The construction of CꢀC and CꢀX bonds using unactivated C(sp3)ꢀH bonds,
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however, is a challenging task in modern synthetic and organometallic chemistry due to the ubiquity of
C(sp3)ꢀH bonds in nature.3 In this context, various transition metal catalysts have been extensively
utilized in metalꢀcatalyzed CꢀH functionalizations. Among these, palladium complexes play a significant
role in this field. More recently, a number of C(sp3)ꢀH bond to C(sp3)ꢀC and C(sp3)ꢀX transformations
have been reported on carboxylic acid derivatives.4ꢀ10 In particular, arylation of acyclic and cyclic
aliphatic carboxylic acids4 (Scheme 1, eq 1), amino acids5 (Scheme 1, eq 2) and heterocyclic carboxylic
acid derivatives6 using a bidentate directing group have been reported, since a seminal article by
Daugulis in 2005.4g The pioneering work of Yu,11 Chatani,12 Daugulis,4g and others13 has demonstrated
that C(sp3)ꢀH bond functionalization could be accomplished through the use of an appropriate directing
group. Despite developments in C(sp3)ꢀH bond functionalization of various acid derivatives, the
functionalization of new classes of biologically significant synthons is beneficial, and further elucidation
of this method is warranted.
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2ꢀCyanoacetic acid derivatives are a class of active methylene compounds that can serve not only as
versatile intermediates in pharmaceuticals and functional materials,14 but also as handy precursors in
synthetic chemistry15 due to their ability to undergo a broad range of functional group transformations.16
Small molecules bearing a nitrile group comprise a considerable proportion of therapeutic drugs.17 It is
important to develop a substrate with diverse functional groups capable of further modification.
Inspired by the pioneering work and our interest in CꢀH functionalization, we envisioned that the
β
−C(sp3)ꢀH bonds of cyanoacetic acid derivatives could undergo arylation with bidentate auxiliary
assistance. In this line, herein, we disclose the direct arylation of unactivated C(sp3)ꢀH bonds in
α−cyano−α−methyl carboxylic acid amides using 8ꢀaminoquinoline (ꢀQ) as a directing group with
aryl/heteroaryl iodides under palladium catalysis (Scheme 1, eq 3).
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The Journal of Organic Chemistry
Previous work
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O
R
R1
O
R
R1
metal cat.
DG
DG
N
N
(eq 1)
(eq 2)
H
H
R, R1, R2 = alkyl/aryl/H
R2
R2 Ar
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O
O
PG
PG
metal cat.
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DG
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DG
N
N
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H
H
Ar
R
R
R = alkyl/aryl/H; PG = protecting group; DG=directing group
This work
O
O
NC
NC
Pd(OAc)2
(eq 3)
Q
N
N
R
R
Mn(OAc)2
H
H
N
Ar
R = alkyl/aryl/H
Q
Scheme 1. Transition metalꢀcatalyzed arylation of unactivated C(sp3)ꢀH bonds of aliphatic amides
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RESULTS AND DISCUSSION
We commenced our investigation with the reaction of 2ꢀcyanoꢀ2ꢀmethylꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide
(1a), (prepared from commercially available ethyl 2ꢀcyanopropanoate with 1ꢀbromodecane under
K2CO3/CH3CN conditions, followed by ester hydrolysis and amide formation, Scheme 7) and 4ꢀ
iodoanisole (2a), as a model substrate to establish the initial reaction parameters, in the presence of
Pd(OAc)2, Na2CO3 as base and AgOAc as additive at 120 οC in toluene for 24 h (entry 1, Table 1). The
expected mono arylated product 3a was isolated, although in only 18% yield. We then examined the
effects of various additives on product formation using Pd(OAc)2 as catalyst and either Cu(OAc)2,
K2S2O8 or Mn(OAc)2 at 130 οC in toluene for 24 h. Unsatisfactory yields were obtained with Cu(OAc)2
as well as K2S2O8 (entries 2 and 3). However, Mn(OAc)2 greatly aided the conversion of 1a, affording
3a in 54% yield (entry 4). This is significant since iodide scavenging is accomplished without the need
for silver salts. Next, prolongation of the reaction time with Pd(OAc)2 and Mn(OAc)2 in toluene
resulted in 3a in 68% yield (entry 5). Subsequently, based on the screening of a series of solvents
including 1,4ꢀdioxane, CF3CH2OH, tꢀAmOH and 1,2ꢀdichloroethane with Pd(OAc)2 and Mn(OAc)2 at
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different temperatures for 30 hours (entries 6ꢀ9), we concluded that tꢀAmOH was the solvent of choice,
providing 3a in 85% yield (entry 8, Table 1). In addition, employing coupling partners such as 4ꢀ
bromoanisole (23%) or 4ꢀchloroanisole (no reaction) instead of 2a was ineffective (entry 8, Table 1) and
replacing Pd(OAc)2 with Pd(TFA)2, Pd(OPiv)2 or PdCl2 resulted in lower yields (entries 10ꢀ12). From
the series of above examinations, the combination of 10 mol % of Pd(OAc)2, Mn(OAc)2 (2 equiv) and
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ο
Na2CO3 (2 equiv) in tꢀAmOH at 130 C for 30 hours was determined to be the optimal reaction
conditions.18
Table 1. Optimization of reaction conditionsa
O
I
O
catalyst (10 mol %)
additive (2 equiv)
NC
C9H19
N
NC
C9H19
N
H
N
H
solvent, temp, time
Na2CO3 (2 equiv)
N
OMe
1a
2a
3a
OMe
yield (%)b
temp (oC)
entry
catalyst
additive
AgOAc
solvent
time (h)
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2
Pd(OAc)2
Pd(OAc)2
toluene
toluene
120
130
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24
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15
Cu(OAc)2
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6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2S2O8
toluene
toluene
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130
130
130
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30
30
Trace
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Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
toluene
68
1,4-dioxane
72
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8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(OPiv)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
CF3CH2OH
t-AmOH
DCE
110
130
110
130
130
30
30
30
30
30
81
85, (23)c,(0)d
9
79
51
46
10
11
t-AmOH
t-AmOH
12
PdCl2
Mn(OAc)2
t-AmOH
130
30
40
aReaction conditions: Cyanoamide 1a (0.4 mmol), 4-iodoanisole (2a) (1.2 mmol), catalyst (10
mol %), additive (0.8 mmol), Na2CO3 (0.8 mmol), solvent (4 mL); bAll the products were
characterized by 1H, 13C NMR, IR and MS; c4-bromoanisole used as aryl halide; d4-chloroanisole
used as aryl halide.
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We next examined the scope and generality of an extensive range of aryl iodides with α−cyano amides
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1a and 1b using the optimized conditions. Results are summarized in Scheme 2. Substrates with
electron donating and electron withdrawing substituents are well tolerated under the optimal reaction
conditions. The 4ꢀOMe and 3,4,5ꢀtriꢀOMe iodobenzene derivatives (2a and 2b) reacted cleanly to give
the corresponding products in excellent yields (3a and 3b). Iodobenzene 2c was also subjected to the
optimized conditions and provided the corresponding product (3c) in 73% yield.
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Scheme 2. Reactivity of different aryl/heteroaryl iodides with 1a and 1ba
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Diverse electron withdrawing groups on the aryl iodide (2dꢀg, 4ꢀCO2Me, 4ꢀCOCH3, 4ꢀCN and 4ꢀNO2)
were all well tolerated with 1a to give the appropriate products in moderate to good yields (3dꢀ3g).
Importantly, ortho substituted aryl iodides (2ꢀOMe, 2h and 2,4ꢀdiꢀOMe, 2i) were also compatible in the
present protocol to afford the desired products in moderate to low yields (3h and 3i), presumably due to
steric effects. The 4ꢀchloroꢀ, 3ꢀfluoroꢀ5ꢀnitroꢀ and 3ꢀbromoꢀ5ꢀmethylcarboxylate aryl iodides (2j-l)
successfully gave the corresponding arylated products (3jꢀ3l) with reasonably good yields from 1a.
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Moreover,
α−cyano amide derivative 1b was also tested under these optimal conditions, with aryl
iodides (2a-f), bearing electron rich and electron poor groups, to afford the corresponding products in
good yields (4aꢀ4f). Auspiciously, the reaction of diverse heteroaromatic iodides (2m-s) with 1a
smoothly furnished the corresponding heteroaryl substituted,
α−cyano amides in synthetically useful
yields: substituted thiopheneꢀamide (3m, 62%), 1ꢀbenzylꢀ1Hꢀpyrazoleꢀamide (3n, 76%), 2ꢀpyridineꢀ
amide (3o, 60%), 6ꢀmethoxypyrazineꢀamide (3p, 62%), 2ꢀchloropyridineꢀamide (3q, 75%), Nꢀ
unprotected indoleꢀamide (3r, 81%), and 2,3ꢀdihydrobenzofuranꢀamide (3s, 79%), respectively. It is
noteworthy to mention here that the obtained products provide a critical handle for further structural
elaboration.
A variety of
α−cyano carboxylic acid derivatives were successfully arylated with 8ꢀaminoquinoline as a
directing group under the optimal reaction conditions with 2a (Table 2).
α−Cyano amides bearing
aliphatic long chains (1c and 1d) were well tolerated to afford the corresponding products 5a and 5b in
excellent yields. 2ꢀCyanoꢀ3ꢀcyclohexylpropanamide derivative 1e was coupled with 2a to give 5c in
78% yield, while 4ꢀphenylbutaramide (1f) and 5ꢀphenylpentanamide (1g) derivatives afforded the
arylated products 5d and 5e, respectively, in good yields. Interestingly, 2ꢀcyanoꢀ2ꢀmethylꢀNꢀ(quinolinꢀ8ꢀ
yl)propanamide (1h), treated with 2a under palladiumꢀcatalyzed conditions, furnished a mixture of
monoꢀarylated amide (5f) in 50% and diarylated amide (5g) in 29% yields. Further, the monoꢀarylated
product (5f) was treated separately with 2a under optimal conditions to afford 5g in 86% yield.
α−Cyanoꢀ2,5ꢀdimethyl amide analog (1i) gave the arylated 5h in 81% yield. We further examined the
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utility of this method by examining the reactivity of monomethylene systems at the
1k). Treatment of 1j or 1k with 2a under standard reaction conditions failed to give the arylated
products (5i and 5j, respectively), presumably due to an active CꢀH proton at the ꢀposition of the
substrates. Only starting materials were recovered from the reaction. Interestingly, the reaction of 3a
(containing two methylene systems at the ꢀposition, 0.1 mmol) and 2a (0.15 mmol) did afford the
corresponding monoꢀarylated product 5k at the benzylic position, although in only 20% yield.
βꢀposition (1j and
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α
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β
Table 2. Arylation of various
α
−cyanoacetic acid derivatives with 2aa
O
O
NC
NC
R
2a, Pd(OAc)2, Mn(OAc)2
Na2CO3, t-AmOH, 130 oC
Q
Q
N
N
R
H
H
R1
Ar
R1
1c-k, 3a, 5f
5a-k
entry
product (5)
cyanoamide
yielda
77
1
2
1c, R = n-C5H11-; R1 = H
1d, R = n-C16H33-; R1 = H
5a, R = n-C5H11-; R1 = H
5b, R = n-C16H33; R1 = H
83
3
4
1e, R = Cyclohexylmethylene-;
5c, R = Cyclohexylmethylene-;
R1 = H
R1 = H
78
82
1f, R = PhCH2-; R1 = H
5d, R = PhCH2-; R1 = H
5
6
1g, R = Ph(CH2)2-; R1 = H
1h, R = CH3, R1 = H
5e, R = Ph(CH2)2-; R1 = H
5f, R = CH3, R1 = H
84
50b
86
81
0c
7
8
5f, R = 4-MeO-C6H4-; R1 = H
1i, R = i-Bu; R1 = H
5g, R = 4-MeO-C6H4-; R1 = H
5h, R = i-Bu; R1 = H
9
1j, R = H; R1 = PhCH2-
1k, R = H; R1 = C9H19-
5i, R = H; R1 = PhCH2-
5j, R = H; R1 = C9H19-
10
0d
11
3a, R = C10H21-; R1 = 4-MeO-C6H4-
5k, R = C10H21-; R1 = 4-MeO-C6H4- 20e
aReaction conditions: -cyanoamide (0.4 mmol), 2a (1.2 mmol), Pd(OAc)2 (10 mol %),
Mn(OAc)2 (0.8 mmol), Na2CO3 (0.8 mmol), t-AmOH (4 mL), 130 oC, 30 h; Ar- = 4-MeO-C6H4-.
All the products were characterized by 1H, 13C NMR, IR and MS. bdi-arylated product 5g also
c
d
e
formed in 29% yield. 45% of 1j was recovered, 89% of 1k was recovered, 0.1 mmol of 3a,
0.15 mmol of 2a were used.
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Encouraged by the successful utilization of various aryl iodides and
α−cyanoamide derivatives for
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2
3
4
5
palladiumꢀcatalyzed C(sp3)ꢀH functionalization, we turned our attention to the more challenging
intramolecular C(sp3)ꢀH arylation reaction (Scheme 3). We prepared an
α
−cyano substrate [2ꢀcyanoꢀ3ꢀ
6
7
8
(2ꢀiodophenyl)ꢀ2ꢀmethylꢀNꢀ(quinolinꢀ8ꢀyl)propanamide)] 1l, embedded with an iodoarene and treated it
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with 10 mol % Pd(OAc)2, Mn(OAc)2 (2 equiv) and Na2CO3 (2 equiv) in tꢀAmOH at 130 C for 48
hours. The reaction proceeded smoothly to give the 2ꢀcyanoꢀ2,3ꢀdihydroꢀ1Hꢀindeneꢀ2ꢀcarboxamide
derivative (6) in 65% yield.
O
O
Pd(OAc)2 (10 mol %)
Mn(OAc)2 (0.8 mmol)
NC
Q
NC
Q
N
N
H
H
Na2CO3 (0.8 mmol)
t-AmOH, 130 oC, 48 h
I
1l (0.4 mmol)
6, 65%
Scheme 3. Intramolecular C(sp3)ꢀH arylation reaction
Next, we used 5,5'ꢀdiiodoꢀ2,2'ꢀbisthiophene (2t) as an aryl iodide to test the structural generality of the
reaction under the optimized conditions, as shown in Scheme 4. The reaction of 1a (3 mmol) with 2t (1
mmol), proceeded smoothly to give the diꢀfunctionalized product (7) in 69% yield.
Scheme 4. Arylation of 1a with diiodoꢀbisthiophene
Remarkably, we also successfully applied the current protocol to the gramꢀscale synthesis of arylated
compounds 3a and 4a using 4 mmoles of 1a and 1b, separately, under the optimal conditions with 2a,
resulting in 1.36 g of 3a (72%) and 1.26 g of 4a (75%), respectively (Scheme 5). The synthetic
usefulness of these representative compounds was demonstrated through various functional group
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transformations. Initially, elimination of the nitrile group in 4a resulted in the dialkylated amide (8) in
45% yield. We also found that 4a under strongly basic conditions led to hydrolysis of both nitrile and
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4
5
6
amide groups, followed by decarboxylation of the acid functional group to afford the α,α−disubstituted
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8
9
amide (9a) in 77% yield and acid (9b) in 65% yield with longer reaction time. Additionally, in both
compounds 3a and 4a, the auxiliary 8ꢀaminoquinoline group was easily removed using KOH/tꢀAmOH
conditions to generate versatile acid motifs 10a (79%) and 10b (75%) in good yields, while the nitrile
group remained intact. Similarly, removal of the auxiliary in 3a and 4a using HCl/MeOH reflux
conditions gave the corresponding methyl esters in excellent yields (11a, 11b). Interestingly, cyanoacids
10a and 10b or cyanoesters 11a and 11b could be subjected to hydrogenation (PdꢀC in MeOH) to give
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the corresponding NꢀBocꢀ
β
ꢀamino acids, 12a (59%) and 12b (55%) or β−amino esters, 13a (82%) and
13b (80%), respectively.
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1a or 1b
(4 mmol)
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(a)
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H
COX
Ar
(b)
H
CONHQ
(c)/(d)
3a, 1.36 g, 72%
4a, 1.26 g, 75%
Bn
Bn
decyanation
hydrolysis
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Ar
8, 45%
9a, X = NH2, 77%
9b, X = OH, 65%
(f)
(e)
val
re
mo
DG
NC
CO2Me
NC
CO2H
R
R
11a, R = C10H21, 72%
11b, R = Bn, 81%
10a, R = C10H21, 79%
10b, R = Bn, 75%
Ar
Ar
(g)
(h)
NHBoc
CO2H
NH2
CO2Me
R
R
Ar
Ar
12a, R = C10H21, 59%
12b, R = Bn, 55%
13a, R = C10H21, 82%
13b, R = Bn, 80%
Reaction conditions: (a) 2a, Pd(OAc)2, Mn(OAc)2, Na2CO3, t-AmOH, 130 C, 30 h. (b) SmI2, HMPA: THF, 0 C-
rt, 6 h. (c) KOH, t-AmOH, 120 C, 24 h. (d) KOH, t-AmOH, 130 C, 40 h. (e) KOH, t-AmOH, 90 C, 3 h. (f) HCl,
MeOH, reflux, 20 h. (g) 10% Pd-C, H2, (Boc)2O, DIPEA, MeOH, rt, 36-40 h. (h) 10% Pd-C, H2, HCl, MeOH, rt,
24 h.
Scheme 5. Gramꢀscale syntheses of 3a and 4a and their synthetic utility
To further elaborate the applicability of the obtained products, compound 4c was subjected to LiAlH4 to
provide the 1,3ꢀamino alcohol 14 in 72% yield (Scheme 6).
OH
LiAlH4, THF, rt-reflux, 8 h
H2N
4c
Ph
Ph
14, 72%
Scheme 6. Synthesis of 1,3ꢀamino alcohol 14
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CONCLUSION
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In summary, we have developed an 8ꢀaminoquinolineꢀdirected arylation of unactivated C(sp3)ꢀH bonds
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of
wide functional group compatibility, broad substrate scope (including heterocyclic substrates) and
provides arylated −cyano amides in good to excellent yields, even on gram scale. The obtained
products can be utilized for the development of various synthetically useful compounds and privileged
motifs in pharmaceuticals, such as disubstituted −cyano acids, −dialkylated acid derivatives,
−amino acid derivatives and amino alcohols. Further applications of this method are underway in our
α−cyano aliphatic amides with aryl/heteroaryl iodides under palladium catalysis. The reaction offers
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α
α
α,α
β
laboratory.
EXPERIMENTAL SECTION
General Methods. Unless otherwise noted, materials obtained from commercial suppliers were used
without further purification. All reactions were conducted in glassware that was dried in an oven (120
°C), heated under reduced pressure, and cooled under a stream of argon before use. Reactions were
monitored by thinꢀlayer chromatography on silica gel plates using UVꢀlight (254 nm) and ceric sulfate
or βꢀnaphthol for visualization. Column chromatography was performed on a flash chromatography
system with silica gel columns using nꢀhexane and ethyl acetate as eluent. Evaporation of solvents was
conducted under reduced pressure at 50 °C using rotary evaporators. FTIR spectra were recorded neat,
wave numbers are indicated in cm−1. NMR spectra were recorded at 400 MHz (1H) and 100 MHz (13C).
Deuterated chloroform was used as the solvent, and spectra were calibrated against the residual solvent
peak 7.26 ppm for 1H and 77.0 ppm for 13C or against TMS. Chemical shifts (δ) and coupling constants
(J) are given in ppm (parts per million) and Hz (Hertz), respectively. The following abbreviations were
used to explain multiplicities: s=singlet, d=doublet, t=triplet, m=multiplet, bs=broad singlet. Low
resolution mass spectra were obtained by electrospray ionization (ESI) in positive mode. High resolution
mass spectra (HRMS) were performed with an orbitrap mass analyzer by electrospray ionization (ESI).
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General Procedure for the Preparation of Starting Materials:19
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Scheme 7. Preparation of starting compounds 1a-i, 1l
To a solution of ethyl 2ꢀcyanopropionate (635 mg, 0.629 mL, 5 mmol) in acetonitrile (20 mL) was
added K2CO3 (1.38 g, 10 mmol) and alkyl halide (6 mmol). After the addition, the mixture was warmed
ο
to 70 C and stirred overnight. The mixture was cooled to room temperature (RT), and the solvent was
removed under vacuum. Water (20 mL) was added and the product extracted with ethyl acetate (20 ml x
2). The combined organic layers were washed with brine, dried over MgSO4, and evaporated under
vacuum. The crude residue was purified by flash column chromatography to provide the corresponding
ester. The ester was dissolved in THF (15 mL), and treated with a solution of NaOH (800 mg, 20 mmol,
9 mL of water). The mixture was stirred at RT for 12 h. After removal of THF in vacuo, the pH of the
aqueous layer was adjusted to 4.0 with 2.0 M HCl. The mixture was extracted with DCM (20 mL x 2).
The combined organic layers were washed with brine, dried over MgSO4, and evaporated in vacuo to
give the crude carboxylic acid, which was used in the next reaction without further purification.
SOCl2 (0.51 mL, 7 mmol) was added slowly to a stirred solution of the carboxylic acid in toluene (15
mL) and DMF (0.1 mL) at room temperature. The mixture was stirred for 3 h at 110 °C and the solvent
evaporated in vacuo. The residue was then dissolved in toluene (5 mL), evaporated in vacuo twice to
give the crude acid chloride. The acid chloride was added dropwise to a solution of 8ꢀaminoquinoline
ο
(720 mg, 5 mmol) and DIPEA (1.26 g, 1.74 mL, 10 mmol) in CH2Cl2 (20 mL) at ꢀ10 C over 15 min.
The resulting solution was warmed to RT and stirred overnight. The mixture was diluted with CH2Cl2
(15 mL) and washed successively with water (20 mL), saturated aqueous NaHCO3 (20 mL), HCl (0.5 M,
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20 mL), and brine (20 mL). 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 (1:9, v/v), to afford the corresponding 2ꢀcyanoꢀ2ꢀmethylꢀ8ꢀaminoquinolinyl amides 1.
2ꢀCyanoꢀ2ꢀmethylꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide (1a): 1ꢀBromodecane (1.32 g, 1.23 mL, 6 mmol) was
used as the alkyl halide and the product was obtained as a brown oil, 1.44 g, 79%; 1H NMR (400 MHz,
CDCl3): δ 10.88 (s, 1H), 8.89 (dd, J = 4.2, 2.4 Hz, 1H), 8.75 (dd, J = 7.1, 1.8 Hz, 1H), 8.19 (dd, J = 8.3,
1.6 Hz, 1H), 7.60ꢀ7.53 (m, 2H), 7.49 (dd, J = 8.3, 4.2 Hz, 1H), 2.13 (td, J = 12.3, 4.5 Hz, 1H), 1.85 (td,
J = 12.2, 4.5 Hz, 1H), 1.74 (s, 3H), 1.68ꢀ1.57 (m, 1H), 1.51ꢀ1.40 (m, 1H), 1.38ꢀ1.20 (m, 14H), 0.85 (t, J
= 6.9 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): δ 166.6, 148.9, 138.8, 136.2, 133.5, 127.9, 127.1,
122.7, 121.9, 121.4, 116.7, 45.5, 38.6, 31.8, 29.5, 29.4, 29.3, 29.3, 29.2, 25.6, 24.1, 22.6, 14.1; FTIR
(neat): 3307, 2924, 2853, 2235, 1688, 1529, 1486, 1424, 1327, 1132, 1057, 825, 791, 698 cmꢀ1; MS
(ESI): m/z 366 (M+H)+; HRMS (ESI): m/z calcd for C23H32ON3 (M+H)+: 366.2540, found: 366.2539.
2ꢀCyanoꢀ2ꢀmethylꢀ3ꢀphenylꢀNꢀ(quinolinꢀ8ꢀyl)propanamide (1b): Benzyl bromide (1.02 g, 0.71 mL, 6
mmol) was used as the alkyl halide and the product was obtained as a brown solid, mp = 82ꢀ84 οC, 1.27
g, 81%; 1H NMR (400 MHz, CDCl3): δ 10.70 (s, 1H), 8.79 (dd, J = 4.2, 1.7 Hz, 1H), 8.71 (dd, J = 6.3,
2.7 Hz, 1H), 8.14 (dd, J = 8.3, 1.6 Hz, 1H), 7.57ꢀ7.51 (m, 2H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H), 7.38ꢀ7.33
(m, 2H), 7.30ꢀ7.18 (m, 3H), 3.44 (d, J = 13.5 Hz, 1H), 3.12 (d, J = 13.5 Hz, 1H), 1.77 (s, 3H);
13C{1H}NMR (100 MHz, CDCl3): δ 166.6, 148.8, 138.7, 136.1, 134.5, 133.5, 130.1, 130.0, 128.6,
127.8, 127.0, 122.7, 121.9, 120.9, 116.7, 46.9, 43.9, 23.7; FTIR (neat): 3275, 3028, 2928, 2234, 1687,
1539, 1485, 1331, 1205, 1174, 1072, 882, 792, 699 cmꢀ1; MS (ESI): m/z 316 (M+H)+; HRMS (ESI): m/z
calcd for C20H18ON3 (M+H)+: 316.1444, found: 316.1440.
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2ꢀCyanoꢀ2ꢀmethylꢀNꢀ(quinolinꢀ8ꢀyl)heptanamide (1c): 1ꢀIodopentane (1.18 g, 0.781 mL, 6 mmol) was
1
used as the alkyl halide and the product was obtained as a dark brown oil, 1.06 g, 72%; H NMR (400
MHz, CDCl3): δ 10.89 (s, 1H), 8.89 (dd, J = 4.2, 1.6 Hz, 1H), 8.72 (dd, J = 7.1, 1.8 Hz, 1H), 8.19 (dd, J
= 8.2, 1.6 Hz, 1H), 7.60ꢀ7.53 (m, 2H), 7.49 (dd, J = 8.3, 4.2 Hz, 1H), 2.13 (td, J = 12.3, 4.5 Hz, 1H),
1.87 (td, J = 12.3, 4.5 Hz, 1H), 1.74 (s, 3H), 1.70ꢀ1.57 (m, 1H), 1.52ꢀ1.42 (m, 1H), 1.36ꢀ1.28 (m, 4H),
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0.87 (t, J = 7.2 Hz, 3H); C{1H}NMR (100 MHz, CDCl3): δ 166.6, 148.8, 138.8, 136.2, 133.6, 127.9,
127.1, 122.6, 121.9, 121.4, 116.7, 45.5, 38.5, 31.4, 25.3, 24.1, 22.3, 13.9; FTIR (neat): 3274, 3062,
2929, 2234, 1687, 1537, 1486, 1266, 1174, 1072, 824, 792, 699 cmꢀ1; MS (ESI): m/z 296 (M+H)+;
HRMS (ESI): m/z calcd for C18H22ON3, (M+H)+: 296.1757, found: 296.1753.
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2ꢀCyanoꢀ2ꢀmethylꢀNꢀ(quinolinꢀ8ꢀyl)octadecanamide (1d): 1ꢀBromohexadecane (1.83 g, 1.83 mL, 6
mmol) was used as the alkyl halide and the product was obtained as a pale yellow solid, mp = 48ꢀ49 οC,
1.84 g, 82%; 1H NMR (400 MHz, CDCl3): δ 10.88 (s, 1H), 8.89 (dd, J = 4.2, 1.7 Hz, 1H), 8.72 (dd, J =
7.1, 1.8 Hz, 1H), 8.19 (dd, J = 8.3, 1.6 Hz, 1H), 7.60ꢀ7.53 (m, 2H), 7.49 (dd, J = 8.3, 4.2 Hz, 1H), 2.13
(td, J = 12.3, 4.5 Hz, 1H), 1.86 (td, J = 12.3, 4.4 Hz, 1H), 1.74 (s, 3H), 1.68ꢀ1.58 (m, 1H), 1.52ꢀ1.41 (m,
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1H), 1.39ꢀ1.19 (m, 26H), 0.87 (t, J = 13.7 Hz, 3H); C{1H}NMR (100 MHz, CDCl3): δ 166.6, 148.9,
138.8, 136.2, 133.6, 127.9, 127.1, 122.6, 121.9, 121.4, 116.7, 45.5, 38.6, 31.9, 29.7, 29.7, 29.6, 29.6,
29.6, 29.5, 29.5, 29.5, 29.4, 29.3, 29.2, 25.6, 24.1, 22.7, 14.1; FTIR (neat): 3306, 2914, 2850, 2230,
1709, 1693, 1532, 1466, 1330, 1151, 822, 782 cmꢀ1; MS (ESI): m/z 450 (M+H)+; HRMS (ESI): m/z
calcd for C29H44ON3 (M+H)+: 450.3479, found: 450.3482.
2ꢀCyanoꢀ3ꢀcyclohexylꢀ2ꢀmethylꢀNꢀ(quinolinꢀ8ꢀyl)propanamide (1e): (Bromomethyl)cyclohexane (1.06
g, 0.834 mL, 6 mmol) was used as the alkyl halide and the product was obtained as a pale yellow oil,
1.25 g, 78%; 1H NMR (400 MHz, CDCl3): δ 10.93 (s, 1H), 8.89 (dd, J = 4.2, 1.6 Hz, 1H), 8.71 (dd, J =
7.1, 1.8 Hz, 1H), 8.18 (dd, J = 8.3, 1.6 Hz, 1H), 7.60ꢀ7.52 (m, 2H), 7.49 (dd, J = 8.3, 4.2 Hz, 1H), 2.13
(dd, J = 14.7, 7.2 Hz, 1H), 1.91 (d, J = 12.8 Hz, 1H), 1.79ꢀ1.53 (m, 8H), 1.30ꢀ0.93 (m, 6H);
13C{1H}NMR (100 MHz, CDCl3): δ 166.8, 148.9, 138.8, 136.2, 133.6, 127.9, 127.1, 122.6, 121.9,
121.7, 116.7, 45.3, 44.1, 35.4, 34.0, 33.0, 26.0, 25.9, 25.9, 25.8; FTIR (neat): 3308, 2922, 2850, 2234,
1690, 1526, 1424, 1326, 1260, 1132, 922, 825, 755 cmꢀ1; MS (ESI): m/z 322 (M+H)+; HRMS (ESI): m/z
calcd for C20H24ON3 (M+H)+: 322.1914, found: 322.1915.
2ꢀCyanoꢀ2ꢀmethylꢀ4ꢀphenylꢀNꢀ(quinolinꢀ8ꢀyl)butanamide (1f): (2ꢀBromoethyl)benzene (1.11 g, 0.82
mL, 6 mmol) used as the alkyl halide and the product was obtained as a pale yellow oil, 1.40 g, 85%; 1H
NMR (400 MHz, CDCl3): δ 10.94 (s, 1H), 8.90 (dd, J = 5.8, 2.6 Hz, 1H), 8.72 (dd, J = 7.2, 1.7 Hz, 1H),
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8.19 (dd, J = 8.3, 1.6 Hz, 1H), 7.61ꢀ7.53 (m, 2H), 7.49 (dd, J = 8.3, 4.2 Hz, 1H), 7.28ꢀ7.14 (m, 5H), 2.94
(td, J = 12.6, 4.8 Hz, 1H), 2.79 (td, J = 12.6, 5.0 Hz, 1H), 2.57 (td, J = 12.4, 5.0 Hz, 1H), 2.13 (td, J =
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12.6, 4.8 Hz, 1H), 1.79 (s, 3H); C{1H}NMR (100 MHz, CDCl3): δ 166.1, 148.9, 139.8, 138.7, 136.2,
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133.4, 128.5, 128.4, 127.8, 127.0, 126.3, 122.8, 121.9, 121.1, 116.8, 45.3, 40.3, 32.0, 24.4; FTIR (neat):
3306, 3029, 2934, 2233, 1687, 1527, 1485, 1326, 1261, 1156, 1055, 790, 697 cmꢀ1; MS (ESI): m/z 330
(M+H)+; HRMS (ESI): m/z calcd for C21H20ON3 (M+H)+: 330.1601, found: 330.1602.
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2ꢀCyanoꢀ2ꢀmethylꢀ5ꢀphenylꢀNꢀ(quinolinꢀ8ꢀyl)pentanamide (1g): (3ꢀBromopropyl)benzene (1.19 g, 0.915
mL, 6 mmol) was used as the alkyl halide and the product was obtained as a pale yellow oil, 1.39 g,
81%; 1H NMR (400 MHz, CDCl3): δ 10.88 (s, 1H), 8.86 (dd, J = 4.2, 1.6 Hz, 1H), 8.71 (dd, J = 7.0, 1.9
Hz, 1H), 8.15 (dd, J = 8.3, 1.6 Hz, 1H), 7.58ꢀ7.50 (m, 2H), 7.46 (dd, J = 8.3, 4.2 Hz, 1H), 7.27ꢀ7.22 (m,
2H), 7.19ꢀ7.13 (m, 3H), 2.78ꢀ2.61 (m, 2H), 2.22ꢀ2.14 (m, 1H), 2.02ꢀ1.76 (m, 3H), 1.72 (s, 3H);
13C{1H}NMR (100 MHz, CDCl3): δ 166.3, 148.8, 141.0, 138.7, 136.2, 133.5, 128.4, 128.3, 127.8,
127.0, 126.0, 122.7, 121.9, 121.3, 116.7, 45.3, 38.0, 35.3, 27.2, 24.1; FTIR (neat): 3308, 3063, 2935,
2962, 2235, 1687, 1527, 1485, 1326, 1262, 1132, 1029, 929, 825, 750 cmꢀ1; MS (ESI): m/z 344 (M+H)+;
HRMS (ESI): m/z calcd for C22H22ON3 (M+H)+: 344.1757, found: 344.1764.
2ꢀCyanoꢀ2ꢀmethylꢀNꢀ(quinolinꢀ8ꢀyl)propanamide (1h): Iodomethane (0.85 g, 0.373 mL, 6 mmol) was
used as the alkyl halide and the product was obtained as a brown oil, 0.78 g, 65%; 1H NMR (400 MHz,
CDCl3): δ 10.81 (s, 1H), 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.70 (dd, J = 7.0, 1.9 Hz, 1H), 8.19 (dd, J = 8.3,
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1.6 Hz, 1H), 7.60ꢀ7.52 (m, 2H), 7.49 (dd, J = 8.3, 4.2 Hz, 1H), 1.78 (s, 6H); C{1H}NMR (100 MHz,
CDCl3): δ 166.6, 148.8, 138.7, 136.3, 133.6, 127.9, 127.1, 122.7, 122.0, 121.9, 116.7, 40.0, 25.3; FTIR
(neat): 3276, 2984, 2235, 1686, 1531, 1485, 1424, 1327, 1243, 1156, 918, 899, 791, 640 cmꢀ1; MS
(ESI): m/z 240 (M+H)+; HRMS (ESI): m/z calcd for C14H14ON3 (M+H)+: 240.1131, found: 240.1132.
2ꢀCyanoꢀ2,5ꢀdimethylꢀNꢀ(quinolinꢀ8ꢀyl)hexanamide (1i): 1ꢀBromoꢀ3ꢀmethylbutane (0.91 g, 0.758 mL, 6
1
mmol) was used as the alkyl halide and the product was obtained as a pale yellow oil, 1.16 g, 79%; H
NMR (400 MHz, CDCl3): δ 10.89 (s, 1H), 8.89 (dd, J = 5.8, 2.6 Hz, 1H), 8.73 (dd, J = 7.1, 1.8 Hz, 1H),
8.13 (dd, J = 8.2, 1.6 Hz, 1H), 7.60ꢀ7.52 (m, 2H), 7.48 (dd, J = 8.3, 4.2 Hz, 1H), 2.14 (td, J = 12.3, 4.6
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Hz, 1H), 1.85 (td, J = 12.8, 4.4 Hz, 1H), 1.75 (s, 3H), 1.65ꢀ1.55 (m, 1H), 1.54ꢀ1.47 (m, 1H), 1.41ꢀ1.31
(m, 1H), 0.91 (dd, J = 6.5, 3.4 Hz, 6H); 13C{1H}NMR (100 MHz, CDCl3): δ 166.6, 148.8, 138.8, 136.2,
133,6, 127.8, 127.1, 122.6, 121.9, 121.4, 116.7, 45.5, 36.6, 34.3, 28.0, 24.1, 22.4; FTIR (neat): 3310,
2956, 2870, 2235, 1688, 1527, 1486, 1466, 1326, 1154, 918, 825, 790, 755 cmꢀ1; MS (ESI): m/z 296
(M+H)+; HRMS (ESI): m/z calcd for C18H22ON3 (M+H)+: 296.1757, found: 296.1753.
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2ꢀCyanoꢀ3ꢀ(2ꢀiodophenyl)ꢀ2ꢀmethylꢀNꢀ(quinolinꢀ8ꢀyl)propanamide (1l): 2ꢀIodobenzyl bromide (1.78 g,
6 mmol) was used as the alkyl halide and the product was obtained as a pale yellow oil, 1.65 g, 75%; 1H
NMR (400 MHz, CDCl3): δ 10.80 (s, 1H), 8.79 (dd, J = 5.8, 2.5 Hz, 1H), 8.75 (dd, J = 6.4, 2.5 Hz, 1H),
8.16 (dd, J = 8.3, 1.6 Hz, 1H), 7.84 (dd, J = 7.9, 1.2 Hz, 1H), 7.60ꢀ7.53 (m, 2H), 7.48ꢀ7.43 (m, 2H), 7.25
(dd, J = 7.5, 1.2 Hz, 1H), 6.91 (dd, J = 7.7, 1.6 Hz, 1H), 3.62 (d, J = 14.2 Hz, 1H), 3.52 (d, J = 14.2 Hz,
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1H), 1.84 (s, 3H); C{1H}NMR (100 MHz, CDCl3): δ 165.7, 148.7, 140.1, 138.7, 137.8, 136.1, 133.4,
130.4, 130.3, 129.4, 128.5, 127.8, 127.0, 122.7, 121.8, 120.7, 116.7, 102.6, 46.4, 23.7; FTIR (neat):
3299, 3050, 2988, 2236, 1686, 1527, 1485, 1326, 1241, 1126, 1012, 904, 789 cmꢀ1; MS (ESI): m/z 442
(M+H)+; HRMS (ESI): m/z calcd for C20H17ION3 (M+H)+: 442.0411, found: 442.0416.
2ꢀCyanoꢀ4ꢀphenylꢀNꢀ(quinolinꢀ8ꢀyl)butanamide (1j): To a solution of ethyl 2ꢀcyanoacetate (565 mg,
0.538 mL, 5 mmol) in acetonitrile (20 mL) was added K2CO3 (138 mg, 1 mmol) and (2ꢀ
ο
bromoethyl)benzene (185 mg, 0.14 mL, 1 mmol). After the addition, the mixture was warmed to 70 C
and stirred overnight. The mixture was cooled to room temperature (RT), and the solvent was removed
under vacuum. Water (20 mL) was added and the product extracted with ethyl acetate (10 ml x 2). The
combined organic layers were washed with brine (20 mL), dried over MgSO4, and evaporated under
reduced pressure. The crude residue was purified by flash column chromatography to provide the
corresponding ester. The ester was dissolved in THF (5 mL), and treated with a solution of NaOH (160
mg, 4 mmol, 3 mL of water). The mixture was stirred at RT for 12 h. After removal of THF in vacuo,
the pH of the aqueous layer was adjusted to 4.0 with 2.0 M HCl. The mixture was extracted with DCM
(10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over MgSO4, and
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evaporated to give the crude carboxylic acid, which was used in the next reaction without further
purification.
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A mixture of the crude 2ꢀcyanoꢀ4ꢀphenylbutanoic acid (190 mg, 1 mmol), 8ꢀaminoquinoline (145 mg, 1
mmol), EDCI (163 mg, 1.05 mmol), HOBt•H2O (161 mg, 1.05 mmol), and DIPEA (387 mg, 3 mmol) in
anhydrous CH2Cl2 (10 mL) was stirred at RT overnight. Water (10 mL) was added and the mixture was
extracted with CH2Cl2 (10 mL x 2). The combined organic layers were washed with water (10 mL) and
brine (10 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by
flash chromatography on silica gel, eluting with EtOAc/hexane (1:9, v/v), to give the title compound 1j
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as a brown solid (233 mg, 74 % yield). mp = 62ꢀ63 C; 1H NMR (400 MHz, CDCl3): δ 10.50 (s, 1H),
8.84 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (dd, J = 7.2, 1.7 Hz, 1H), 8.18 (dd, J = 8.3, 1.6 Hz, 1H), 7.59ꢀ7.50
(m, 2H), 7.48 (dd, J = 8.3, 4.2 Hz, 1H), 7.34ꢀ7.19 (m, 5H), 3.65 (dd, J = 8.5, 5.9 Hz, 1H), 3.03ꢀ2.84 (m,
13
2H), 2.54ꢀ2.37 (m, 2H); C{1H}NMR (100 MHz, CDCl3): δ 162.6, 148.6, 139.2, 138.3, 136.5, 133.3,
128.7, 128.6, 127.8, 127.1, 126.7, 122.8, 121.9, 117.5, 116.9, 38.9, 32.8, 31.8; FTIR (neat): 3308, 2925,
2853, 2250, 1667, 1536, 1499, 1322, 1239, 827, 790 cmꢀ1; MS (ESI): m/z 316 (M+H)+; HRMS (ESI):
m/z calcd for C20H18ON3 (M+H)+: 316.1444, found: 316.1445.
2ꢀCyanoꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide (1k): To a solution of ethyl 2ꢀcyanoacetate (565 mg, 0.538 mL,
5 mmol) in acetonitrile (20 mL) was added K2CO3 (138 mg, 1 mmol) and 1ꢀbromodecane (220 mg, 0.20
ο
mL, 1 mmol). After the addition, the mixture was warmed to 70 C and stirred overnight. The mixture
was cooled to room temperature (RT), and the solvent was removed under vacuum. Water (20 mL) was
added and the product extracted with ethyl acetate (10 ml x 2). The combined organic layers were
washed with brine (20 mL), dried over MgSO4, and evaporated under vacuum. The crude residue was
purified by flash column chromatography to provide the corresponding ester. The ester was dissolved in
THF (5 mL), and treated with a solution of NaOH (160 mg, 4 mmol, 3 mL of water). The mixture was
stirred at RT for 12 h. After removal of THF in vacuo, the pH of the aqueous layer was adjusted to 4.0
with 2.0 M HCl. The mixture was extracted with DCM (10 mL x 2). The combined organic layers were
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washed with brine (10 mL), dried over MgSO4, and evaporated in vacuo to give the crude carboxylic
acid, which was used in the next reaction without further purification.
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A mixture of the crude 2ꢀcyanododecanoic acid (225 mg, 1 mmol), 8ꢀaminoquinoline (145 mg, 1 mmol),
EDCI (163 mg, 1.05 mmol), HOBt•H2O (161 mg, 1.05 mmol), and DIPEA (387 mg, 3 mmol) in
anhydrous CH2Cl2 (10 mL) was stirred at RT overnight. Water was added and the mixture was extracted
with CH2Cl2 (10 mL x 2). The combined organic layers were washed with water (10 mL) and brine (10
mL), dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel, eluting with EtOAc/hexane (1:9, v/v), to give the title compound 1k asa
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brown solid (245 mg, 70% yield). mp = 89ꢀ90 C; 1H NMR (400 MHz, CDCl3): δ 10.52 (s, 1H), 8.85
(dd, J = 4.2, 1.6 Hz, 1H), 8.69 (dd, J = 7.0, 1.8 Hz, 1H), 8.17 (dd, J = 8.2, 1.6 Hz, 1H), 7.60ꢀ7.51 (m,
2H), 7.48 (dd, J = 8.3, 4.2 Hz, 1H), 3.70 (dd, J = 7.6, 6.4 Hz, 1H), 2.19ꢀ2.07 (m, 2H), 1.67ꢀ1.54 (m,
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2H), 1.43ꢀ1.20 (m, 14H), 0.87 (t, J = 6.8 Hz, 3H); C{1H}NMR (100 MHz, CDCl3): δ 162.9, 148.7,
138.5, 136.3, 133.4, 127.8, 127.3, 122.7, 121.9, 117.8, 116.8, 40.0, 31.8, 30.4, 29.5, 29.4, 29.3, 29.2,
28.9, 26.9, 22.7, 14.1; FTIR (neat): 3303, 3006, 2929, 2250, 1948, 1663, 1552, 1492, 1295, 827, 640
cmꢀ1; MS (ESI): m/z 352 (M+H)+; HRMS (ESI): m/z calcd for C22H30ON3 (M+H)+: 352.2383, found:
352.2384.
General procedure for the synthesis of arylated cyanoacetic acid derivatives:
To an ovenꢀdried 10 mL screwꢀcapped vial, containing a magnetic stir bar were added the amide
derivative (1, 0.4 mmol), iodoarene (2, 1.2 mmol), Pd(OAc)2 (9 mg, 0.04 mmol), Mn(OAc)2 (138 mg,
0.8 mmol), Na2CO3 (85 mg, 0.8 mmol) and tꢀAmOH (4 mL). The mixture was stirred for 30 h at 130 °C
followed by cooling. The reaction mixture was diluted with EtOAc (10 mL) and filtered through a pad
of Celite and concentrated under reduced pressure. Water (10 mL) was added to the crude residue and
the product extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine
(20 mL), dried over MgSO4, and evaporated in vacuo. The residue was purified by column
chromatography on silica gel (eluent: hexane/EtOAc= 10/1 to 6/1) to afford the desired arylated product
(3a-s, 4a-f and 5a-5j).
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1
2ꢀCyanoꢀ2ꢀ(4ꢀmethoxybenzyl)ꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide (3a): 160 mg, 85%; brown oil; H NMR
(400 MHz, CDCl3): δ 10.64 (s, 1H), 8.78 (dd, J = 4.2, 1.6 Hz, 1H), 8.72 (dd, J = 5.9, 3.0 Hz, 1H), 8.12
(dd, J = 8.3, 1.7 Hz, 1H), 7.56ꢀ7.50 (m, 2H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 7.25 (d, J = 8.7 Hz, 2H),
6.74 (d, J = 8.7 Hz, 2H), 3.66 (s, 3H), 3.36 (d, J = 13.5 Hz, 1H), 3.06 (d, J = 13.5 Hz, 1H), 2.20 (td, J =
13.1, 4.4 Hz, 1H), 1.85 (td, J = 12.3, 4.2 Hz, 1H), 1.70ꢀ1.59 (m, 1H), 1.51ꢀ1.38 (m, 1H), 1.37ꢀ1.17 (m,
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14H), 0.85 (t, J = 6.9 Hz, 3H); C{1H}NMR (100 MHz, CDCl3): δ 165.7, 159.1, 148.8, 138.7, 136.0,
133.5, 131.0, 127.8, 127.1, 126.7, 122.7, 121.8, 120.5, 116.6, 113.9, 55.1, 53.2, 42.7, 37.4, 31.9, 29.6,
29.5, 29.5, 29.4, 29.3, 25.6, 22.7, 14.4; FTIR (neat): 3306, 2924, 2853, 2232, 1686, 1612, 1529, 1325,
1178, 1034, 909, 790 cmꢀ1; MS (ESI): m/z 472 (M+H)+; HRMS (ESI): m/z calcd for C30H38O2N3
(M+H)+: 472.2959, found: 472.2959.
2ꢀCyanoꢀNꢀ(quinolinꢀ8ꢀyl)ꢀ2ꢀ(3,4,5ꢀtrimethoxybenzyl)dodecanamide (3b): 178 mg, 84%; pale yellow
1
oil; H NMR (400 MHz, CDCl3): δ 10.59 (s, 1H), 8.77 (dd, J = 4.2, 1.6 Hz, 1H), 8.71 (dd, J = 6.9, 1.9
Hz, 1H), 8.12 (dd, J = 8.3, 1.6 Hz, 1H), 7.56ꢀ7.48 (m, 2H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 6.53 (s, 2H),
3.67 (s, 6H), 3.56 (s, 3H), 3.31 (d, J = 13.4 Hz, 1H), 3.05 (d, J = 13.4 Hz, 1H), 2.25 (td, J = 12.9, 4.4
Hz, 1H), 1.89 (td, J = 12.3, 4.2 Hz, 1H), 1.75ꢀ1.63 (m, 1H), 1.55ꢀ1.43 (m, 1H), 1.41ꢀ1.20 (m, 14H), 0.85
(t, J = 6.9 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): δ 165.5, 152.9, 148.8, 138.6, 137.2, 136.0, 133.4,
130.2, 127.8, 126.8, 122.7, 121.9, 120.5, 116.4, 106.7, 60.5, 55.9, 53.2, 44.2, 37.4, 31.9, 29.5, 29.4,
29.4, 29.3, 29.2, 25.6, 22.6, 14.1; FTIR (neat): 3302, 2960, 2924, 2853, 2232, 1686, 1590, 1529, 1422,
1326, 1240, 1123, 1007, 826, 791 cmꢀ1; MS (ESI): m/z 532 (M+H)+; HRMS (ESI): m/z calcd for
C32H42O4N3 (M+H)+: 532.3170, found: 532.3172.
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2ꢀBenzylꢀ2ꢀcyanoꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide (3c): 128 mg, 73%; pale yellow oil; H NMR (400
MHz, CDCl3): δ 10.66 (s, 1H), 8.78 (dd, J = 4.2, 1.6 Hz, 1H), 8.72 (dd, J = 6.1, 2.8 Hz, 1H), 8.12 (dd, J
= 8.3, 1.6 Hz, 1H), 7.56ꢀ7.50 (m, 2H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 7.36ꢀ7.32 (m, 2H), 7.25ꢀ7.20 (m,
2H), 7.19ꢀ7.14 (m, 1H), 3.42 (d, J = 13.4 Hz, 1H), 3.11 (d, J = 13.4 Hz, 1H), 2.21 (td, J = 13.1, 4.1 Hz,
1H), 1.86 (td, J = 12.3, 4.2 Hz, 1H), 1.71ꢀ1.58 (m, 1H), 1.51ꢀ1.40 (m, 1H), 1.37ꢀ1.17 (m, 14H), 0.85 (t,
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J = 6.9 Hz, 3H); C{1H}NMR (100 MHz, CDCl3): δ 165.5, 148.8, 138.7, 136.0, 134.6, 133.4, 130.0,
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128.5, 127.7, 127.5, 126.9, 122.6, 121.8, 120.3, 116.6, 52.9, 43.4, 37.5, 31.8, 29.6, 29.5, 29.4, 29.3,
29.2, 25.6, 22.6, 14.1; FTIR (neat): 3303, 3030, 2924, 2853, 2235, 1686, 1529, 1485, 1326, 1206, 1170,
910, 825, 699 cmꢀ1; MS (ESI): m/z 442 (M+H)+; HRMS (ESI): m/z calcd for C29H36ON3 (M+H)+:
442.2855, found: 442.2854.
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Methyl 4ꢀ(2ꢀcyanoꢀ2ꢀ(quinolinꢀ8ꢀylcarbamoyl)dodecyl)benzoate (3d): 125 mg, 63%; pale yellow oil; H
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NMR (400 MHz, CDCl3): δ 10.64 (s, 1H), 8.76 (dd, J = 4.2, 1.6 Hz, 1H), 8.70 (dd, J = 6.8, 2.1 Hz, 1H),
8.12 (dd, J = 8.3, 1.6 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.58ꢀ7.50 (m, 2H), 7.44ꢀ7.39 (m, 3H), 3.82 (s,
3H), 3.48 (d, J = 13.3 Hz, 1H), 3.14 (d, J = 13.3 Hz, 1H), 2.24 (td, J = 13.0, 4.5 Hz, 1H), 1.88 (td, J =
12.3, 4.2 Hz, 1H), 1.70ꢀ1.58 (m, 1H), 1.53ꢀ1.40 (m, 1H), 1.37ꢀ1.18 (m, 14H), 0.85 (t, J = 6.9 Hz, 3H);
13C{1H}NMR (100 MHz, CDCl3): δ 166.7, 165.0, 148.8, 139.8, 138.9, 136.0, 133.2, 130.0, 129.8,
129.4, 127.8, 126.9, 122.8, 121.8, 120.0, 116.7, 52.6, 52.0, 43.2, 37.7, 31.8, 29.5, 29.4, 29.3, 29.2, 29.2,
25.6, 22.7, 14.1; FTIR (neat): 3304, 2924, 2854, 2234, 1721, 1687, 1529, 1486, 1325, 1276, 1106, 1021,
791, 637 cmꢀ1; MS (ESI): m/z 500 (M+H)+; HRMS (ESI): m/z calcd for C31H38O3N3 (M+H)+: 500.2908,
found: 500.2908.
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2ꢀ(4ꢀAcetylbenzyl)ꢀ2ꢀcyanoꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide (3e): 119 mg, 62%; pale yellow oil; H
NMR (400 MHz, CDCl3): δ 10.63 (s, 1H), 8.76 (dd, J = 4.2, 1.6 Hz, 1H), 8.70 (dd, J = 6.8, 2.2 Hz, 1H),
8.13 (dd, J = 8.3, 1.6 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.58ꢀ7.51 (m, 2H), 7.46ꢀ7.40 (m, 3H), 3.48 (d, J
= 13.3 Hz, 1H), 3.15 (d, J = 13.3 Hz, 1H), 2.47 (s, 3H), 2.26 (td, J = 13.0, 4.4 Hz, 1H), 1.89 (td, J =
12.3, 4.2 Hz, 1H), 1.71ꢀ1.61 (m, 1H), 1.52ꢀ1.41 (m, 1H), 1.38ꢀ1.17 (m, 14H), 0.85 (t, J = 6.9 Hz, 3H);
13C{1H}NMR (100 MHz, CDCl3): δ 197.7, 165.0, 148.8, 140.1, 138.6, 136.3, 136.1, 133.2, 132.5,
130.2, 128.7, 128.5, 127.8, 126.9, 122.8, 121.9, 120.0, 116.7, 52.6, 43.1, 37.8, 31.8, 29.5, 29.5, 29.4,
29.3, 29.2, 26.5, 25.6, 22.6, 14.1; FTIR (neat): 3303, 2954, 2924, 2853, 2234, 1682, 1529, 1486, 1325,
1263, 1018, 826, 611 cmꢀ1; MS (ESI): m/z 484 (M+H)+; HRMS (ESI): m/z calcd for C31H38O2N3
(M+H)+: 484.2959, found: 484.2954.
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2ꢀCyanoꢀ2ꢀ(4ꢀcyanobenzyl)ꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide (3f): 102 mg, 55%; pale yellow oil; H
NMR (400 MHz, CDCl3): δ 10.60 (s, 1H), 8.78 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (dd, J = 7.3, 1.6 Hz, 1H),
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8.15 (dd, J = 8.3, 1.6 Hz, 1H), 7.65ꢀ7.39 (m, 7H), 3.48 (d, J = 13.3 Hz, 1H), 3.13 (d, J = 13.3 Hz, 1H),
2.25 (td, J = 13.0, 4.4 Hz, 1H), 1.90 (td, J = 12.3, 4.2 Hz, 1H), 1.74ꢀ1.61 (m, 1H), 1.53ꢀ1.41 (m, 1H),
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1.39ꢀ1.17 (m, 14H), 0.85 (t, J = 6.9 Hz, 3H); C{1H}NMR (100 MHz, CDCl3): δ 164.7, 148.9, 140.1,
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138.6, 136.1, 133.0, 132.2, 131.1, 127.8, 126.9, 123.0, 122.0, 119.8, 118.5, 116.7, 111.6, 52.6, 43.1,
37.8, 31.8, 29.5, 29.4, 29.3, 29.2, 29.2, 25.5, 22.6, 14.1; FTIR (neat): 3303, 2924, 2853, 2229, 1686,
1529, 1485, 1425, 1326, 1170, 910, 825, 790, 608 cmꢀ1; MS (ESI): m/z 467 (M+H)+; HRMS (ESI): m/z
calcd for C30H35ON4 (M+H)+: 467.2805, found: 467.2791.
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2ꢀCyanoꢀ2ꢀ(4ꢀnitrobenzyl)ꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide (3g): 140 mg, 72%; pale yellow solid, mp =
140ꢀ141 οC; 1H NMR (400 MHz, CDCl3): δ 10.62 (s, 1H), 8.75 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (dd, J =
7.2, 1.6 Hz, 1H), 8.14 (dd, J = 8.3, 1.6 Hz, 1H), 8.06 (d, J = 8.7 Hz, 2H), 7.59ꢀ7.53 (m, 2H), 7.51 (d, J =
8.7 Hz, 2H), 7.43 (dd, J = 8.3, 4.2 Hz, 1H), 3.53 (d, J = 13.3 Hz, 1H), 3.18 (d, J = 13.3 Hz, 1H), 2.26
(td, J = 13.1, 4.4 Hz, 1H), 1.92 (td, J = 12.3, 4.3 Hz, 1H), 1.74ꢀ1.64 (m, 1H), 1.54ꢀ1.42 (m, 1H), 1.39ꢀ
1.18 (m, 14H), 0.85 (t, J = 6.9 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): δ 164.6, 148.9, 147.4, 142.1,
138.6, 136.1, 133.0, 130.9, 127.8, 126.9, 123.7, 123.0, 122.0, 119.8, 116.7, 52.6, 42.8, 37.9, 31.8, 29.5,
29.4, 29.3, 29.2, 29.2, 25.6, 22.6, 14.1; FTIR (neat): 3320, 2924, 2853, 2236, 1690, 1530, 1487, 1425,
1299, 1007, 827, 792, 757 cmꢀ1; MS (ESI): m/z 487 (M+H)+; HRMS (ESI): m/z calcd for C29H35O3N4
(M+H)+: 487.2704, found: 487.2707.
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(400 MHz, CDCl3): δ 10.67 (s, 1H), 8.79ꢀ8.73 (m, 2H), 8.13 (dd, J = 8.3, 1.6 Hz, 1H), 7.56ꢀ7.51 (m,
2H), 7.43 (dd, J = 8.3, 4.2 Hz, 1H), 7.28ꢀ7.25 (m, 1H), 7.15 (td, J = 15.6, 1.7 Hz, 1H), 6.82 (td, J = 7.4,
1.0 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 3.69 (s, 3H), 3.35 (dd, J = 14.9, 13.6 Hz, 2H), 2.25 (td, J = 12.5,
4.4 Hz, 1H), 1.86 (td, J = 12.2, 4.2 Hz, 1H), 1.70ꢀ1.59 (m, 1H), 1.51ꢀ1.40 (m, 1H), 1.37ꢀ1.18 (m, 14H),
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0.85 (t, J = 6.9 Hz, 3H); C{1H}NMR (100 MHz, CDCl3): δ 166.0, 157.9, 148.7, 138.7, 136.0, 133.7,
131.6, 129.0, 127.7, 127.0, 123.3, 122.4, 121.8, 120.4, 120.3, 116.5, 110.4, 55.1, 52.2, 37.2, 37.0, 31.8,
29.7, 29.5, 29.4, 29.3, 29.2, 25.6, 22.6, 14.4; FTIR (neat): 3305, 2923, 2855, 2233, 1687, 1529, 1425,
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1291, 1157, 825, 757 cmꢀ1; MS (ESI): m/z 472 (M+H)+; HRMS (ESI): m/z calcd for C30H38O2N3
(M+H)+: 472.2959, found: 472.2959.
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2ꢀCyanoꢀ2ꢀ(2,4ꢀdimethoxybenzyl)ꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide (3i): 112 mg, 56%; pale yellow oil;
1H NMR (400 MHz, CDCl3): δ 10.64 (s, 1H), 8.79ꢀ8.73 (m, 2H), 8.12 (dd, J = 8.3, 1.6 Hz, 1H), 7.57ꢀ
7.50 (m, 2H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.34 (dd, J = 8.3, 2.4 Hz, 1H),
6.29 (d, J = 2.4 Hz, 1H), 3.68 (s, 3H). 3.64 (s, 3H), 3.28 (dd, J = 17.6, 13.6 Hz, 2H), 2.24 (td, J = 13.1,
4.4 Hz, 1H), 1.84 (td, J = 12.3, 4.2 Hz, 1H), 1.70ꢀ1.58 (m, 1H), 1.50ꢀ1.39 (m, 1H), 1.37ꢀ1.18 (m, 14H),
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0.85 (t, J = 6.9 Hz, 3H); C{1H}NMR (100 MHz, CDCl3): δ 166.1, 160.4, 158.8, 148.6, 138.7, 136.0,
133.7, 132.0, 127.8, 127.0, 122.4, 121.7, 120.6, 116.5, 115.7, 104.1, 98.3, 55.2, 55.1, 52.5, 37.1, 36.7,
31.8, 29.5, 29.5, 29.4, 29.3, 29.2, 25.7, 22.7, 14.1; FTIR (neat): 3308, 2924, 2853, 2233, 1687, 1528,
1424, 1290, 1208, 1157, 1035, 825, 790, 756 cmꢀ1; MS (ESI): m/z 502 (M+H)+; HRMS (ESI): m/z calcd
for C31H40O3N3 (M+H)+: 502.3064, found: 502.3066.
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2ꢀ(4ꢀChlorobenzyl)ꢀ2ꢀcyanoꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide (3j): 140 mg, 74%; pale yellow oil; H
NMR (400 MHz, CDCl3): δ 10.62 (s, 1H), 8.79 (dd, J = 4.2, 1.6 Hz, 1H), 8.69 (dd, J = 6.9, 1.9 Hz, 1H),
8.13 (dd, J = 8.3, 1.6 Hz, 1H), 7.58ꢀ7.50 (m, 2H), 7.43 (dd, J = 8.3, 4.2 Hz, 1H), 7.27 (d, J = 8.5 Hz,
2H), 7.18 (d, J = 8.5 Hz, 2H), 3.39 (d, J = 13.5 Hz, 1H), 3.06 (d, J = 13.5 Hz, 1H), 2.21 (td, J = 12.9, 4.4
Hz, 1H), 1.86 (td, J = 12.9, 4.4 Hz, 1H), 1.73ꢀ1.59 (m, 1H), 1.52ꢀ1.39 (m, 1H), 1.37ꢀ1.16 (m, 14H), 0.85
(t, J = 6.9 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): δ 165.2, 148.8, 148.6, 138.6, 136.0, 133.6, 133.2,
133.1, 131.3, 128.6, 127.8, 126.9, 122.8, 121.9, 120.1, 116.6, 52.8, 42.6, 37.6, 31.8, 29.5, 29.4, 29.4,
29.3, 29.2, 25.6, 22.6, 14.1; FTIR (neat): 2924, 2853, 2233, 1686, 1529, 1486, 1326, 1092, 910, 806,
790 cmꢀ1; MS (ESI): m/z 476 (M+H)+; HRMS (ESI): m/z calcd for C29H35ClON3 (M+H)+: 476.2463,
found: 476.2466.
2ꢀCyanoꢀ2ꢀ(3ꢀfluoroꢀ5ꢀnitrobenzyl)ꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide (3k): 143 mg, 71%; pale yellow oil;
1H NMR (400 MHz, CDCl3): δ 10.66 (s, 1H), 8.78 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (dd, J = 7.1, 1.8 Hz,
1H), 8.15 (dd, J = 8.3, 1.6 Hz, 1H), 8.03 (s, 1H), 7.72 (dt, J = 8.2, 2.2 Hz, 1H), 7.60ꢀ7.52 (m, 2H), 7.47ꢀ
7.42 (m, 2H), 3.55 (d, J = 13.5 Hz, 1H), 3.16 (d, J = 13.5 Hz, 1H), 2.26 (td, J = 13.0, 4.5 Hz, 1H), 1.90
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(td, J = 12.3, 4.2 Hz, 1H), 1.75ꢀ1.66 (m, 1H), 1.55ꢀ1.43 (m. 1H), 1.40ꢀ1.17 (m, 14H), 0.85 (t, J = 6.9 Hz,
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3H); C{1H}NMR (100 MHz, CDCl3): δ 164.4, 163.3, 160.8, 148.9, 138.7, 136.2, 132.8,127.8, 127.1,
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123.5, 123.1, 121.9, 120.9, 119.5, 116.9, 110.8, 110.5, 52.4, 42.4, 37.8, 31.8, 29.7, 29.4, 29.4, 29.2,
29.2, 25.5, 22.6, 14.1; FTIR (neat): 3299, 2924, 2854, 2235, 1687, 1529, 1485, 1352, 1147, 882, 790
cmꢀ1; MS (ESI): m/z 505 (M+H)+; HRMS (ESI): m/z calcd for C29H34FO3N4 (M+H)+: 505.2609, found:
505.2610.
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Methyl 3ꢀbromoꢀ5ꢀ(2ꢀcyanoꢀ2ꢀ(quinolinꢀ8ꢀylcarbamoyl)dodecyl)benzoate (3l): 150 mg, 65%; pale
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yellow oil; H NMR (400 MHz, CDCl3): δ 10.60 (s, 1H), 8.77 (dd, J = 4.2, 1.6 Hz, 1H), 8.69 (dd, J =
6.6, 2.3 Hz, 1H), 8.14 (dd, J = 8.3, 1.6 Hz, 1H), 7.92 (dt, J = 12.0, 3.3 Hz, 1H), 7.66 (t, J = 1.6 Hz, 1H),
7.59ꢀ7.51 (m, 2H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H), 3.78 (s, 3H), 3.42 (d, J = 13.4 Hz, 1H), 3.10 (d, J =
13.4 Hz, 1H), 2.24 (td, J = 13.4, 4.5 Hz, 1H), 1.87 (td, J = 12.8, 4.2 Hz, 1H), 1.73ꢀ1.61 (m, 1H), 1.54ꢀ
1.41 (m. 1H), 1.40ꢀ1.19 (m, 14H), 0.85 (t, J = 6.9 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): δ 165.3,
164.9, 148.8, 138.6, 137.7, 137.0, 136.0, 133.0, 132.0, 131.9, 129.7. 126.9, 122.9, 122.5, 121.9, 119.7,
116.9, 52.6, 52.3, 42.7, 37.4, 31.8, 29.5, 29.4, 29.3, 29.2, 25.6, 22.6, 14.1; FTIR (neat): 2924, 2853,
1726, 1686, 1528, 1485, 1425, 1280, 1204, 886, 825, 763 cmꢀ1; MS (ESI): m/z 578 (M+H)+; HRMS
(ESI): m/z calcd for C31H37BrO3N3 (M+H)+: 578.2013, found: 578.2014.
2ꢀ((5ꢀAcetylthiophenꢀ2ꢀyl)methyl)ꢀ2ꢀcyanoꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide (3m): 121 mg, 62%; pale
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yellow oil; H NMR (400 MHz, CDCl3): δ 10.81 (s, 1H), 8.85 (dd, J = 4.2, 1.6 Hz, 1H), 8.74 (dd, J =
7.1, 1.8 Hz, 1H), 8.19 (dd, J = 8.3, 1.6 Hz, 1H), 7.63ꢀ7.55 (m, 1H), 7.52ꢀ7.46 (m, 2H), 7.10 (d, J = 3.8
Hz, 1H), 3.70 (d, J = 14.5 Hz, 3H), 3.35 (d, J = 14.5 Hz, 1H), 2.44 (s, 3H), 2.21 (td, J = 13.4, 4.4 Hz,
1H), 1.95 (td, J = 12.3, 4.3 Hz, 1H), 1.75ꢀ1.65 (m, 1H), 1.55ꢀ1.42 (m. 1H), 1.41ꢀ1.18 (m, 14H), 0.87 (t,
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J = 6.9 Hz, 3H); C{1H}NMR (100 MHz, CDCl3): δ 164.7, 148.9, 145.2, 144.1, 138.7, 136.1, 133.2,
132.6, 129.1, 127.8, 127.0, 122.9, 121.9, 119.8, 116.9, 52.7, 37.7, 37.7, 31.8, 29.5, 29.4, 29.4, 29.3,
29.2, 29.1, 26.6, 25.5, 22.6, 14.1; FTIR (neat): 2955, 2924, 2853, 2235, 1686, 1660, 1528, 1485, 1326,
1273, 928, 825, 790 cmꢀ1; MS (ESI): m/z 490 (M+H)+; HRMS (ESI): m/z calcd for C29H36N3O2S
(M+H)+: 490.2523, found: 490.2525.
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2ꢀ((1ꢀBenzylꢀ1Hꢀpyrazolꢀ4ꢀyl)methyl)ꢀ2ꢀcyanoꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide (3n): 158 mg, 76%; pale
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yellow oil; H NMR (400 MHz, CDCl3): δ 10.70 (s, 1H), 8.83 (dd, J = 4.2, 1.6 Hz, 1H), 8.69 (dd, J =
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7.4, 1.5 Hz, 1H), 8.16 (dd, J = 8.3, 1.6 Hz, 1H), 7.59ꢀ7.49 (m, 3H), 7.46 (dd, J = 8.3, 4.2 Hz, 1H), 7.37
(s, 1H), 7.14ꢀ7.09 (m, 1H), 7.07ꢀ7.01 (m, 2H), 6.99ꢀ6.96 (m, 2H), 5.14 (s, 2H), 3.28 (d, J = 14.3 Hz,
1H), 2.99 (d, J = 14.3 Hz, 1H), 2.16 (td, J = 13.1, 4.4 Hz, 1H), 1.87 (td, J = 12.2, 4.2 Hz, 1H), 1.70ꢀ1.59
(m, 1H), 1.51ꢀ1.38 (m, 1H), 1.36ꢀ1.16 (m, 14H), 0.85 (t, J = 6.9 Hz, 3H); 13C{1H}NMR (100 MHz,
CDCl3): δ 165.7, 148.8, 140.3, 138.7, 136.3, 136.1, 133.3, 129.3, 128.5, 127.8, 127.7, 127.3, 127.0,
122.7, 121.9, 120.7, 116.6, 114.6, 55.9, 53.1, 37.3, 33.0, 31.8, 29.5, 29.4, 29.3, 29.2, 29.2, 25.6, 22.6,
14.1; FTIR (neat): 3304, 2923, 2853, 2232, 1684, 1529, 1485, 1455, 1326, 1170, 909, 825, 790, 696 cmꢀ
1; MS (ESI): m/z 522 (M+H)+; HRMS (ESI): m/z calcd for C33H40ON5 (M+H)+: 522.3227, found:
522.3226.
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2ꢀCyanoꢀ2ꢀ(pyridinꢀ2ꢀylmethyl)ꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide (3o): 106 mg, 60%; pale yellow oil; H
NMR (400 MHz, CDCl3): δ 10.85 (s, 1H), 8.84 (dd, J = 4.2, 1.6 Hz, 1H), 8.73 (dd, J = 6.7, 2.2 Hz, 1H),
8.45 (d, J = 4.2 Hz, 1H), 8.15 (dd, J = 8.3, 1.6 Hz, 1H), 7.58ꢀ7.51 (m, 3H), 7.45 (dd, J = 8.3, 4.2 Hz,
1H), 7.27 (d, J = 8.4 Hz, 1H), 7.07 (ddd, J = 7.5, 4.9, 1.2 Hz, 1H), 3.66 (d, J = 14.2 Hz, 1H), 3.33 (d, J =
14.2 Hz, 1H), 2.26 (td, J = 13.3, 4.6 Hz, 1H), 1.96 (td, J = 12.5, 4.3 Hz, 1H), 1.77ꢀ1.63 (m, 1H), 1.57ꢀ
1.44 (m, 1H), 1.39ꢀ1.17 (m, 14H), 0.85 (t, J = 6.9 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): δ 165.9,
155.3, 149.4, 148.8, 138.8, 136.4, 136.0, 133.7, 127.8, 127.0, 123.8, 122.5, 122.2, 121.8, 120.3, 116.7,
51.0, 44.7, 37.9, 31.8, 29.5, 29.4, 29.4, 29.3, 29.2, 25.4, 22.6, 14.1; FTIR (neat): 3292, 2948, 2920,
2851, 2240, 1678, 1589, 1529, 1426, 1325, 1256, 910, 834, 778 cmꢀ1; MS (ESI): m/z 443 (M+H)+;
HRMS (ESI): m/z calcd for C28H35ON4 (M+H)+: 443.2805, found: 443.2806.
2ꢀCyanoꢀ2ꢀ((6ꢀmethoxypyrazinꢀ2ꢀyl)methyl)ꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide (3p): 117 mg, 62%; brown
solid, mp = 60ꢀ61 οC; 1H NMR (400 MHz, CDCl3): δ 10.90 (s, 1H), 8.85 (dd, J = 4.2, 1.6 Hz, 1H), 8.69
(dd, J = 7.3, 1.6 Hz, 1H), 8.17 (dd, J = 8.3, 1.6 Hz, 1H), 8.05 (s, 1H), 7.99 (s, 1H), 7.59ꢀ7.50 (m, 2H),
7.48 (dd, J = 8.3, 4.2 Hz, 1H), 3.66 (s, 3H), 3.65 (d, J = 15.1 Hz, 1H), 3.26 (d, J = 15.1 Hz, 1H), 2.23
(td, J = 13.1, 4.1 Hz, 1H), 1.99 (td, J = 12.6, 4.2 Hz, 1H), 1.88ꢀ1.68 (m, 1H), 1.59ꢀ1.46 (m, 1H), 1.41ꢀ
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1.19 (m, 14H), 0.85 (t, J = 6.9 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): δ 165.7, 159.7, 148.8, 147.4,
138.6, 136.2, 135.6, 134.1, 133.5, 127.8, 127.1, 122.6, 121.9, 120.3, 116.6, 53.7, 49.6, 40.7, 38.5, 31.8,
29.5, 29.4, 29.3, 29.2, 29.2, 25.3, 22.6, 14.1; FTIR (neat): 3299, 2924, 2854, 2236, 1686, 1541, 1485,
1302, 1245, 1009, 905, 799, 665 cmꢀ1; MS (ESI): m/z 474 (M+H)+; HRMS (ESI): m/z calcd for
C28H36O2N5 (M+H)+: 474.2864, found: 474.2864.
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2ꢀ((6ꢀChloropyridinꢀ3ꢀyl)methyl)ꢀ2ꢀcyanoꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide (3q): 143 mg, 75%; pale
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yellow oil; H NMR (400 MHz, CDCl3): δ 10.67 (s, 1H), 8.80 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (dd, J =
7.3, 1.5 Hz, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.15 (dd, J = 8.3, 1.6 Hz, 1H), 7.65 (dd, J = 8.2, 2.5 Hz, 1H),
7.60ꢀ7.50 (m, 2H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 3.44 (d, J = 13.7 Hz, 1H),
3.07 (d, J = 13.7 Hz, 1H), 2.23 (td, J = 12.9, 4.5 Hz, 1H), 1.91 (td, J = 12.9, 4.4 Hz, 1H), 1.75ꢀ1.61 (m,
1H), 1.53ꢀ1.41 (m, 1H), 1.40ꢀ1.18 (m, 14H), 0.86 (t, J = 6.9 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3):
δ 164.6, 151.0, 150.8, 148.9, 140.2, 138.6, 136.2, 129.4, 127.8, 126.9, 124.7, 123.2, 121.9, 119.7, 116.8,
52.5, 39.6, 37.8, 31.9, 29.5, 29.4, 29.4, 29.3, 29.2, 25.6, 22.6, 14.1; FTIR (neat): 2924, 2853, 2232,
1686, 1529, 1460, 1386, 1105, 825, 790 cmꢀ1; MS (ESI): m/z 477 (M+H)+; HRMS (ESI): m/z calcd for
C28H34ClON4 (M+H)+: 477.2416, found: 477.2416.
2ꢀ((1HꢀIndolꢀ5ꢀyl)methyl)ꢀ2ꢀcyanoꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide (3r): 155 mg, 81%; brown semiꢀ
solid; 1H NMR (400 MHz, CDCl3): δ 10.65 (s, 1H), 8.73 (dd, J = 6.7, 2.2 Hz, 1H), 8.60 (dd, J = 4.2, 1.6
Hz, 1H), 8.15 (s, 1H), 8.01 (dd, J = 8.3, 1.6 Hz, 1H), 7.60 (s, 1H), 7.51ꢀ7.44 (m, 2H), 7.29 (dd, J = 8.3,
4.2 Hz, 1H), 7.18ꢀ7.11 (m, 2H), 7.04 (t, J = 2.9 Hz, 1H), 6.39 (t, J = 4.5 Hz, 1H), 3.52 (d, J = 13.6 Hz,
1H), 3.21 (d, J = 13.6 Hz, 1H), 2.23 (td, J = 13.1, 4.5 Hz, 1H), 1.84 (td, J = 12.5, 4.2 Hz, 1H), 1.69ꢀ1.58
(m, 1H), 1.51ꢀ1.39 (m, 1H), 1.35ꢀ1.16 (m, 14H), 0.84 (t, J = 6.9 Hz, 3H); 13C{1H}NMR (100 MHz,
CDCl3): δ 166.1, 148.7, 138.7, 136.0, 135.3, 133.5, 128.0, 127.8, 127.0, 125.8, 124.6, 124.0, 122.6,
122.2, 121.7, 120.8, 116.7, 111.0, 102.5, 53.6, 43.8, 37.4, 31.9, 29.7, 29.5, 29.4, 29.3, 29.3, 25.7, 22.7,
14.2; FTIR (neat): 3379, 3304, 2923, 2853, 2233, 1686, 1528, 1485, 1326, 1965, 908, 825, 729 cmꢀ1;
MS (ESI): m/z 481 (M+H)+; HRMS (ESI): m/z calcd for C31H37ON4 (M+H)+: 481.2962, found:
481.2964.
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2ꢀCyanoꢀ2ꢀ((2,3ꢀdihydrobenzofuranꢀ5ꢀyl)methyl)ꢀNꢀ(quinolinꢀ8ꢀyl)dodecanamide (3s): 156 mg, 81%;
pale yellow oil; 1H NMR (400 MHz, CDCl3): δ 10.59 (s, 1H), 8.78 (dd, J = 4.2, 1.6 Hz, 1H), 8.70 (dd, J
= 6.1, 2.8 Hz, 1H), 8.12 (dd, J = 8.3, 1.6 Hz, 1H), 7.56ꢀ7.50 (m, 2H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 7.12
(s, 1H), 7.07 (dd, J = 8.2, 1.8 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 4.45ꢀ4.37 (m, 1H), 4.36ꢀ4.28 (m, 1H),
3.32 (d, J = 13.6 Hz, 1H), 3.12ꢀ3.03 (m, 1H), 3.02 (d, J = 13.6 Hz, 1H), 2.90ꢀ2.80 (m, 1H), 2.20 (td, J =
13.1, 4.4 Hz, 1H), 1.85 (td, J = 12.2, 4.2 Hz, 1H), 1.71ꢀ1.59 (m, 1H), 1.52ꢀ1.40 (m, 1H), 1.37ꢀ1.15 (m,
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133.5, 129.7, 127.8, 127.1, 126.9, 126.5, 122.6, 121.8, 120.5, 116.6, 109.1, 71.1, 53.3, 43.2, 37.2, 31.8,
29.7, 29.5, 29.4, 29.4, 29.3, 29.2, 29.2, 25.6, 22.7, 14.1; FTIR (neat): 3306, 2923, 2853, 2233, 1686,
1528, 1487, 1325, 1243, 1105, 982, 825, 790, 693 cmꢀ1; MS (ESI): m/z 484 (M+H)+; HRMS (ESI): m/z
calcd for C31H38O2N3 (M+H)+: 484.2959, found: 484.2954.
2ꢀBenzylꢀ2ꢀcyanoꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀNꢀ(quinolinꢀ8ꢀyl)propanamide (4a): 149 mg, 89%; brown solid,
mp = 117ꢀ118 οC; 1H NMR (400 MHz, CDCl3): δ 10.35 (s, 1H), 8.70ꢀ8.66 (m, 2H), 8.08 (d, J = 8.2 Hz,
1H), 7.52 (d, J = 4.2 Hz, 2H), 7.40ꢀ7.33 (m, 3H), 7.30ꢀ7.12 (m, 5H), 6.74 (d, J = 8.5 Hz, 2H), 3.66 (s,
3H), 3.51 (dd, J = 16.5, 13.1 Hz, 2H), 3.12 (dd, J = 15.7, 13.7 Hz, 2H); 13C{1H}NMR (100 MHz,
CDCl3): δ 164.9, 159.0, 148.6, 138.6, 135.9, 134.5, 133.3, 131.2, 130.0, 128.5, 127.6, 127.6, 126.9,
126.5, 122.6, 121.7, 119.8, 116.6, 113.9, 55.0, 54.7, 42.9, 42.4; FTIR (neat): 3304, 3030, 2942, 2830,
2233, 1686, 1530, 1426, 1325, 1179, 1035, 790 cmꢀ1; MS (ESI): m/z 422 (M+H)+; HRMS (ESI): m/z
calcd for C27H24O2N3 (M+H)+: 422.1863, found: 422.1863.
2ꢀBenzylꢀ2ꢀcyanoꢀNꢀ(quinolinꢀ8ꢀyl)ꢀ3ꢀ(3,4,5ꢀtrimethoxyphenyl)propanamide (4b): 159 mg, 83%; pale
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yellow oil; H NMR (400 MHz, CDCl3): δ 10.37 (s, 1H), 8.69 (dd, J = 5.6, 3.3 Hz, 1H), 8.66 (dd, J =
4.2, 1.6 Hz, 1H), 8.06 (dd, J = 8.3, 1.6 Hz, 1H), 7.52ꢀ7.47 (m, 2H), 7.40 (d, J = 7.0 Hz, 2H), 7.36 (dd, J
= 8.3, 4.2 Hz, 1H), 7.30ꢀ7.19 (m, 3H), 6.53 (s, 2H), 3.66 (s, 6H), 3.58 (d, J = 13.4 Hz, 1H), 3.53 (s, 3H),
3.43 (d, J = 13.4 Hz, 1H), 3.18 (d, J = 13.5 Hz, 1H), 3.08 (d, J = 13.4 Hz, 1H); 13C{1H}NMR (100
MHz, CDCl3): δ 164.9, 152.9, 148.7, 138.5, 137.2, 135.9, 134.5, 133.3, 130.2, 129.9, 128.6, 127.7,
127.6, 126.7, 122.7, 121.8, 119.8, 116.3, 106.7, 60.5, 55.9, 54.5, 43.8, 42.8; FTIR (neat): 2936, 2837,
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2248, 1683, 1590, 1528, 1485, 1326, 1240, 1124, 1004, 826, 698 cmꢀ1; MS (ESI): m/z 482 (M+H)+;
HRMS (ESI): m/z calcd for C29H28O4N3 (M+H)+: 482.2074, found: 482.2076.
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2ꢀBenzylꢀ2ꢀcyanoꢀ3ꢀphenylꢀNꢀ(quinolinꢀ8ꢀyl)propanamide (4c): 116 mg, 74%; brown solid, mp = 129ꢀ
130 οC; 1H NMR (400 MHz, CDCl3): δ 10.36 (s, 1H), 8.69 (dd, J = 5.4, 3.3 Hz, 1H), 8.64 (d, J = 2.9 Hz,
1H), 8.06 (d, J = 8.1 Hz, 1H), 7.55ꢀ7.49 (m, 2H), 7.40ꢀ7.32 (m, 5H), 7.27ꢀ7.12 (m, 6H), 3.55 (d, J =
13.4 Hz, 2H), 3.15 (d, J = 13.4 Hz, 2H); 13C{1H}NMR (100 MHz, CDCl3): δ 164.8, 148.6, 138.5, 135.8,
134.4, 133.2, 130.1, 128.5, 127.6, 127.5, 126.8, 122.6, 121.7, 119.7, 116.5, 54.4, 43.0; FTIR (neat):
3274, 3063, 2933, 2235, 1679, 1530, 1514, 1455, 1327, 1249, 1091, 1030, 910, 823, 758 cmꢀ1; MS
(ESI): m/z 392 (M+H)+; HRMS (ESI): m/z calcd for C26H22ON3 (M+H)+: 392.1757, found: 392.1755.
Methyl 4ꢀ(2ꢀbenzylꢀ2ꢀcyanoꢀ3ꢀoxoꢀ3ꢀ(quinolinꢀ8ꢀylamino)propyl)benzoate (4d): 115 mg, 64%; white
solid, mp = 191ꢀ192 οC; 1H NMR (400 MHz, CDCl3): δ 10.36 (s, 1H), 8.67 (t, J = 4.5 Hz, 1H), 8.62 (dd,
J = 4.2, 1.6 Hz, 1H), 8.06 (dd, J = 8.3, 1.6 Hz, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 4.2 Hz, 2H),
7.42 (d, J = 8.3 Hz, 2H), 7.39ꢀ7.31 (m, 3H), 7.26ꢀ7.21 (m, 2H), 7.20ꢀ7.15 (m, 1H), 3.81 (s, 3H), 3.51
(dd, J = 15.0, 13.4 Hz, 2H), 3.17 (dd, J = 13.3, 7.5 Hz, 2H); 13C{1H}NMR (100 MHz, CDCl3): δ 166.7,
164.4, 148.6, 139.7, 138.5, 135.9, 134.1, 133.0, 130.1, 130.1, 129.8, 129.4, 128.6, 127.8, 127.6, 126.8,
122.8, 121.7, 119.4, 116.6, 54.1, 52.0, 43.3, 42.7; FTIR (neat): 3340, 3048, 3009, 2941, 2233, 1690,
1712, 1524, 1487, 1289, 1172, 1111, 983, 823, 738 cmꢀ1; MS (ESI): m/z 450 (M+H)+; HRMS (ESI): m/z
calcd for C28H24O3N3 (M+H)+: 450.1812, found: 450.1814.
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2ꢀ(4ꢀAcetylbenzyl)ꢀ2ꢀcyanoꢀ3ꢀphenylꢀNꢀ(quinolinꢀ8ꢀyl)propanamide (4e): 121 mg, 70%; white solid, mp
= 172ꢀ173 οC; 1H NMR (400 MHz, CDCl3): δ 10.34 (s, 1H), 8.67 (dd, J = 5.1, 3.8 Hz, 1H), 8.60 (dd, J =
4.2, 1.6 Hz, 1H), 8.05 (dd, J = 8.3, 1.6 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.54ꢀ7.48 (m, 2H), 7.44 (d, J =
8.3 Hz, 2H), 7.37 (d, J = 7.0 Hz, 2H), 7.33 (dd, J = 8.2, 4.2 Hz, 1H), 7.26ꢀ7.21 (m, 2H), 7.20ꢀ7.15 (m,
1H), 3.59 (dd, J = 14.6, 13.4 Hz, 2H), 3.18 (dd, J = 13.2, 9.7 Hz, 2H), 2.44 (s, 3H); 13C{1H}NMR (100
MHz, CDCl3): δ 197.6, 164.4, 148.6, 139.9, 138.5, 136.3, 135.9, 134.1, 133.0, 130.3, 130.1, 128.6,
128.5, 127.8, 127.6, 126.8, 122.8, 121.7, 119.4, 116.6, 54.1, 43.3, 42.7, 26.5; FTIR (neat): 3337, 3042,
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2924, 2852, 223, 1691, 1675, 1523, 1486, 1269, 1172, 1089, 960, 822, 739, 632 cmꢀ1; MS (ESI): m/z
434 (M+H)+; HRMS (ESI): m/z calcd for C28H24O2N3 (M+H)+: 434.1863, found: 434.1863.
2ꢀBenzylꢀ2ꢀcyanoꢀ3ꢀ(4ꢀcyanophenyl)ꢀNꢀ(quinolinꢀ8ꢀyl)propanamide (4f): 101 mg, 61%; white solid, mp
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= 170ꢀ171 C; H NMR (400 MHz, CDCl3): δ 10.32 (s, 1H), 8.69ꢀ8.61 (m, 2H), 8.10 (dd, J = 8.3, 1.5
Hz, 1H), 7.55ꢀ7.51 (m, 2H), 7.50ꢀ7.43 (m, 4H), 7.42ꢀ7.35 (m, 3H), 7.29ꢀ7.17 (m, 3H), 3.59 (dd, J =
13.2, 10.9 Hz, 2H), 3.21 (d, J = 13.4 Hz, 1H), 3.13 (d, J = 13.4 Hz, 1H); 13C{1H}NMR (100 MHz,
CDCl3): δ 164.1, 148.7, 140.0, 138.5, 136.0, 133.9, 132.9, 132.3, 130.9, 130.1, 128.7, 128.0, 127.7,
126.8, 123.0, 121.9, 119.3, 118.5, 116.6, 111.7, 54.1, 43.4, 42.7; FTIR (neat): 3274, 3060, 2225, 1679,
1526, 1486, 1328, 1208, 1174, 1019, 915, 824, 699 cmꢀ1; MS (ESI): m/z 417 (M+H)+; HRMS (ESI): m/z
calcd for C27H21ON4 (M+H)+: 417.1710, found: 417.1712.
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2ꢀCyanoꢀ2ꢀ(4ꢀmethoxybenzyl)ꢀNꢀ(quinolinꢀ8ꢀyl)heptanamide (5a): 123 mg, 77%; brown oil; H NMR
(400 MHz, CDCl3): δ 10.63 (s, 1H), 8.78 (dd, J = 4.2, 1.6 Hz, 1H), 8.72 (dd, J = 5.9, 3.0 Hz, 1H), 8.12
(dd, J = 8.3, 1.6 Hz, 1H), 7.56ꢀ7.50 (m, 2H), 7.41 (dd, J = 8.3, 4.2 Hz, 1H), 7.25 (d, J = 8.7 Hz, 2H),
6.74 (d, J = 8.7 Hz, 2H), 3.66 (s, 3H), 3.36 (d, J = 13.5 Hz, 1H), 3.06 (d, J = 13.5 Hz, 1H), 2.20 (td, J =
13.6, 4.8 Hz, 1H), 1.85 (td, J = 12.2, 4.3 Hz, 1H), 1.70ꢀ1.59 (m, 1H), 1.51ꢀ1.39 (m, 1H), 1.37ꢀ1.26 (m,
4H), 0.85 (t, J = 7.0 Hz, 3H); C{1H}NMR (100 MHz, CDCl3): δ 165.6, 158.9, 148.7, 138.7, 136.0,
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133.4, 131.0, 127.6, 126.9, 126.6, 122.6, 121.8, 120.4, 116.6, 113.8, 55.0, 53.2, 42.7, 37.3, 31.5, 25.3,
22.3, 13.9; FTIR (neat): 3306, 2928, 2859, 2233, 1685, 1528, 1485, 1325, 1247, 1178, 1033, 909, 825,
790 cmꢀ1; MS (ESI): m/z 402 (M+H)+; HRMS (ESI): m/z calcd for C25H28O2N3 (M+H)+: 402.2176,
found: 402.2176.
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2ꢀCyanoꢀ2ꢀ(4ꢀmethoxybenzyl)ꢀNꢀ(quinolinꢀ8ꢀyl)octadecanamide (5b): 184 mg, 83%; brown oil; H
NMR (400 MHz, CDCl3): δ 10.63 (s, 1H), 8.77 (dd, J = 4.2, 1.6 Hz, 1H), 8.75 (dd, J = 5.2, 3.7 Hz, 1H),
8.10 (dd, J = 8.2, 1.6 Hz, 1H), 7.56ꢀ7.49 (m, 2H), 7.40 (dd, J = 8.3, 4.2 Hz, 1H), 7.25 (d, J = 8.7 Hz,
2H), 6.74 (d, J = 8.7 Hz, 2H), 3.65 (s, 3H), 3.36 (d, J = 13.6 Hz, 1H), 3.05 (d, J = 13.6 Hz, 1H), 2.20 (td,
J = 13.0, 4.4 Hz, 1H), 1.85 (td, J = 12.4, 4.2 Hz, 1H), 1.70ꢀ1.58 (m, 1H), 1.51ꢀ1.39 (m, 1H), 1.38ꢀ1.18
(m, 26H), 0.87 (t, J = 6.9 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): δ 165.6, 159.0, 148.7, 138.7,
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136.0, 133.4, 131.0, 127.7, 127.0, 126.7, 122.6, 121.8, 120.4, 116.6, 113.8, 55.0, 53.2, 42.7, 37.4, 31.9,
29.7, 29.7, 29.6, 29.6, 29.6, 29.5, 29.5, 29.5, 29.4, 29.3, 29.3, 25.6, 22.7, 14.1; FTIR (neat): 3337, 2922,
2852, 2233, 1689, 1528, 1513, 1486, 1327, 1250, 1178, 960, 824, 757 cmꢀ1; MS (ESI): m/z 556 (M+H)+;
HRMS (ESI): m/z calcd for C36H50O2N3 (M+H)+: 556.3898, found: 556.3894.
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2ꢀCyanoꢀ3ꢀcyclohexylꢀ2ꢀ(4ꢀmethoxybenzyl)ꢀNꢀ(quinolinꢀ8ꢀyl)propanamide (5c): 132 mg, 78%; pale
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yellow oil; H NMR (400 MHz, CDCl3): δ 10.60 (s, 1H), 8.77 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (dd, J =
5.7, 3.2 Hz, 1H), 8.11 (dd, J = 8.2, 1.6 Hz, 1H), 7.57ꢀ7.49 (m, 2H), 7.41 (dd, J = 8.2, 4.2 Hz, 1H), 7.23
(d, J = 8.6 Hz, 2H), 6.70 (d, J = 8.7 Hz, 2H), 3.62 (s, 3H), 3.32 (d, J = 13.5 Hz, 1H), 3.02 (d, J = 13.5
Hz, 1H), 2.21 (td, J = 13.9, 7.2 Hz, 1H), 1.92 (d, J = 12.6 Hz, 1H), 1.82ꢀ1.55 (m, 7H), 1.27ꢀ0.93 (m,
6H); 13C{1H}NMR (100 MHz, CDCl3): δ 165.9, 159.0, 148.7, 138.7, 136.0, 133.5, 131.1, 127.7, 127.0,
126.4, 122.6, 121.8, 120.6, 116.6, 113.8, 55.0, 51.7, 44.1, 43.9, 35.5, 34.0, 33.1, 26.0, 26.0, 25.9; FTIR
(neat): 3305, 2923, 2850, 2233, 1686, 1612, 1527, 1512, 1463, 1326, 1249, 1178, 1033, 908, 825, 608
cmꢀ1; MS (ESI): m/z 428 (M+H)+; HRMS (ESI): m/z calcd for C27H30O2N3 (M+H)+: 428.2333, found:
428.2332.
2ꢀCyanoꢀ2ꢀ(4ꢀmethoxybenzyl)ꢀ4ꢀphenylꢀNꢀ(quinolinꢀ8ꢀyl)butanamide (5d): 143 mg, 82%; pale yellow
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oil; H NMR (400 MHz, CDCl3): δ 10.69 (s, 1H), 8.77 (dd, J = 4.2, 1.6 Hz, 1H), 8.72 (dd, J = 5.4, 3.5
Hz, 1H), 8.09 (dd, J = 8.3, 1.6 Hz, 1H), 7.55ꢀ7.49 (m, 2H), 7.40 (dd, J = 8.3, 4.2 Hz, 1H), 7.28ꢀ7.12 (m,
7H), 6.73 (d, J = 8.7 Hz, 2H), 3.64 (s, 3H), 3.39 (d, J = 13.6 Hz, 1H), 3.09 (dd, J = 13.6 Hz, 1H), 2.94
(td, J = 12.9, 4.6 Hz, 1H), 2.77 (td, J = 12.7, 4.9 Hz, 1H), 2.54 (td, J = 13.4, 5.0 Hz, 1H), 2.13 (td, J =
12.5, 4.6 Hz, 1H); C{1H}NMR (100 MHz, CDCl3): δ 165.2, 159.0, 148.7, 139.9, 138.7, 136.0, 133.3,
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131.0, 128.5, 128.4, 127.7, 126.9, 126.4, 126.3, 122.7, 121.8, 120.2, 116.7, 113.9, 55.0, 52.9, 42.8, 39.0,
31.0; FTIR (neat): 3303, 3029, 2930, 2836, 2234, 1684, 1528, 1424, 1326, 1178, 908, 790, 697 cmꢀ1;
MS (ESI): m/z 436 (M+H)+; HRMS (ESI): m/z calcd for C28H26O2N3 (M+H)+: 436.2020, found:
436.2020.
2ꢀCyanoꢀ2ꢀ(4ꢀmethoxybenzyl)ꢀ5ꢀphenylꢀNꢀ(quinolinꢀ8ꢀyl)pentanamide (5e): 150 mg, 84%; pale yellow
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oil; H NMR (400 MHz, CDCl3): δ 10.62 (s, 1H), 8.75 (dd, J = 4.2, 1.6 Hz, 1H), 8.70 (dd, J = 5.8, 1.2
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