Pd(II)-Catalyzed, Picolinamide-Assisted, Z-Selective γ-Arylation of Allylamines to Construct Z-Cinnamylamines

Article abstract of DOI:10.1021/acs.joc.7b00535

Investigations of Pd(II)-catalyzed, picolinamide-assisted, γ-C(sp²)-H activation and Z-selective arylation of allylamines are reported. The reactions of N-allylpicolinamides with various aryl iodides in the presence of the catalyst Pd(OAc)₂ and additive AgOAc have led to the selective γ-arylation of allylamines to construct various cinnamylamines with moderate to good yields and good to high E/Z ratios. To obtain good E/Z ratios, the Pd(II)-catalyzed arylation reaction of N-allylpicolinamides was probed using different additives, directing groups, and reaction conditions. The Pd(II)-catalyzed arylation of an allylamine containing both γ-C(sp²)-H and γ-C(sp³)-H bonds afforded moderate yields of the γ-C(sp²)-H and γ-C(sp³)-H bisarylated cinnamylamines. Although Heck-type γ-arylations of allylamines have generally afforded the E-cinnamylamines, the bidentate directing group picolinamide-directed arylations of allylamines were found to be Z-selective. A plausible mechanism was proposed for the observed regioselectivity and Z-selective arylation of N-allylpicolinamides. Additionally, the Pd(II)-catalyzed arylation of an N-allyl-5-methylisoxazole-3-carboxamide afforded the E-cinnamylamines plausibly via a ligand-free Heck-type reaction mechanism.

Full text of DOI:10.1021/acs.joc.7b00535

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Article
Pd(II)-Catalyzed, Picolinamide-Assisted, Z-Selective #-
Arylation of Allylamines to Construct Z-Cinnamylamines
Ramarao Parella, and Srinivasarao Arulananda Babu
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 25 May 2017
Downloaded from http://pubs.acs.org on May 25, 2017
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Pd(II)ꢀCatalyzed, PicolinamideꢀAssisted, ZꢀSelective γꢀArylation of Allylamines to
Construct ZꢀCinnamylamines
Ramarao Parella and Srinivasarao Arulananda Babu*
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Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER)
Mohali, Manauli P.O., Sector 81, SAS Nagar, Mohali, Knowledge City, Punjab 140306, India
sababu@iisermohali.ac.in
ABSTRACT
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Investigations of Pd(II)ꢀcatalyzed, picolinamideꢀassisted, γꢀC(sp )ꢀH activation and Zꢀ
selective arylation of allylamines are reported. The reactions of Nꢀallylpicolinamides with
various aryl iodides in the presence of the catalyst Pd(OAc) and additive AgOAc have led to the
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selective γꢀarylation of allylamines to construct various cinnamylamines with moderate to good
yields and good to high E/Z ratios. To obtain good E/Z ratios, the Pd(II)ꢀcatalyzed arylation
reaction of Nꢀallylpicolinamides was probed using different additives, directing groups and
2
reaction conditions. The Pd(II)ꢀcatalyzed arylation of an allylamine containing both γꢀC(sp )ꢀH
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2
3
and γꢀC(sp )ꢀH bonds afforded moderate yields of the γꢀC(sp )ꢀH and γꢀC(sp )ꢀH bisarylated
cinnamylamines. Although Heckꢀtype γꢀarylations of allylamines have generally afforded the Eꢀ
cinnamylamines, the bidentate directing group picolinamideꢀdirected arylations of allylamines
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were found to be Zꢀselective. A plausible mechanism was proposed for the observed
regioselectivity and Zꢀselective arylation of Nꢀallylpicolinamides. Additionally, the Pd(II)ꢀ
catalyzed arylation of an Nꢀallylꢀ5ꢀmethylisoxazoleꢀ3ꢀcarboxamide afforded the Eꢀ
cinnamylamines plausibly via a ligandꢀfree Heckꢀtype reaction mechanism.
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INTRODUCTION
Over the past few decades, organic synthesis generously experienced the advantages of
the celebrated transitionꢀmetalꢀcatalyzed CꢀC bond forming crossꢀcoupling reactions (e.g.,
1
ꢀ3
Kumada, Negishi, Stille, Suzuki, Hiyama and Heck reactions) of suitable coupling partners. In
recent years, the construction of CꢀC bonds via transitionꢀmetalꢀcatalyzed CꢀH bond
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ꢀ8
functionalization has received special attention because the CꢀH functionalization process
offers additional advantages. For example, transitionꢀmetalꢀcatalyzed CꢀH bond functionalization
is a direct method for forming CꢀC bonds and does not require the preassembling of
organometallic reagents. Often, CꢀH functionalization can be performed using commercially
available starting materials (e.g., arenes, alkenes, cycloalkanes, carbonyls, and amines). The
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3
functionalization of sp and sp CꢀH bonds of organic molecules has been performed with or
without the help of directing groups using transitionꢀmetalꢀbased catalysts (e.g., Pd, Ru, Rh, Cu,
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ꢀ10
and Ni).
Among the available CꢀH functionalization reactions, directingꢀgroupꢀassisted CꢀH
9,10
functionalization reactions have received substantial attention.
This is because high levels of
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,10
2
regioselectivity as well as stereoselectivity can be achieved.
CꢀH functionalization of sp or
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sp CꢀH bonds of organic molecules using Daugulis’ bidentate directing group (e.g., DGꢀa and
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DGꢀb), Yu’s monodentate directing group and other related/modified bidentate directing
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,10,13ꢀ21
groups have been extensively studied (Scheme 1).
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Scheme 1. Bidentate Directing GroupꢀAssisted CꢀH Functionalization of Carboxylic Acids
and Amines.
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Allylamine derivatives are an important class of compounds and are ubiquitous in
biologically active molecules and are considered important in medicinal chemistry research and
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pharmaceuticals.
Allylamine derivatives or allylamineꢀtethered molecules are notably useful
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synthetic building blocks for assembling various nitrogenꢀcontaining compounds.
Various γꢀ
arylated allylamine derivatives (cinnamylamines) have been found to exhibit a wide range of
biological activities and have been identified as potential drug candidates. Notably, some
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cinnamylamine molecules are currently being used as medicines (Figure 1).
For example,
naftifine is an antifungal drug used for the topical treatment of tinea pedis, tinea cruris and tinea
corporis. Flunarizine is a calcium antagonist, and flunarizine is effective in the prophylaxis of
migraine. Cinnarizine has been characterized as an antihistamine and calciumꢀchannel blocker
and is prescribed for nausea and vomiting. Additionally, the cinnamylamine derivative CPꢀ
724,714 was found to stop the growth of tumor cells.
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Figure 1. Biologically active allylamines/cinnamylamines (γꢀarylated allylamine derivatives).
In general, allylamine derivatives are synthesized using various methods and, given the
importance of cinnamylamines (γꢀarylated allylamine derivatives) in medicinal chemistry
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research, considerable efforts have been made to assemble cinnamylamines.
Notably, the
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celebrated MizorokiꢀHeckꢀtype reaction
partners (e.g., aryl halides or pseudohalides) is well utilized to assemble cinnamylamines.
Cinnamylamines have also been prepared via the metalꢀcatalyzed CꢀH functionalization of
comprising allylamines and suitable coupling
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allylamines by using arenes
and the oxidative Heckꢀtype reaction comprising allylamines and
Typically, in these reactions, the corresponding cinnamylamines with Eꢀ
geometries are obtained as predominant isomers. Consequently, the construction of Zꢀ
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aryl boronic acids.
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cinnamylamines as the predominant isomers has been less frequently encountered.
Furthermore, in some of the reactions, the MizorokiꢀHeckꢀtype arylation of allylamines was
found to afford both the γꢀ and βꢀarylated allylamines.
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Scheme 2. Bidentate Directing GroupꢀAssisted CꢀH Functionalization of Acrylamide and
Allylamine.
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A survey of the literature revealed that noteworthy investigations have been performed to
accomplish regioselectivity in the MizorokiꢀHeckꢀtype arylation of allylamines. Most of these
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reactions afforded Eꢀcinnamylamines as the major isomers.
Apart from the report by
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Xu/Deng, the construction of Zꢀcinnamylamines via the reaction of aryl halides and allylamines
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involving the transitionꢀmetalꢀcatalyzed direct arylation technique (e.g., Heck and CꢀH activation
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44a
reactions)
has not been explored well. Recently, Liu reported the stereoselective synthesis
of Zꢀallylic amines via a Cp TiCl ꢀcatalyzed cisꢀhydroalumination of propargylic amines with
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RedꢀAl. Consequently, there exist only limited reports dealing with the construction of Zꢀ
cinnamylamines.
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Our group recently reported
the stereoselective construction of Zꢀcinnamamide
scaffolds via a Pd(OAc) ꢀcatalyzed, bidentate directing group 8ꢀaminoquinolineꢀassisted Zꢀ
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selective βꢀC(sp )ꢀHꢀarylation of acrylamides (eq 1, Scheme 2). Taking an impetus from this
reaction and the existing developments regarding bidentate directing groupꢀassisted CꢀH
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functionalization,
we envisaged the construction of Zꢀcinnamylamines via a Pd(II)ꢀ
catalyzed, bidentate directing groupꢀ and chelationꢀassisted Zꢀselective CꢀH activation followed
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by a γꢀC(sp )ꢀH arylation of allylamines. To date, only two examples of bidentate directing group
oxalylamideꢀ, and chelationꢀassisted Zꢀselective CꢀH functionalization of allylamines have been
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reported.
Yao/Zhao reported an example comprising the synthesis of pyrrolidones via the
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γꢀC(sp )ꢀH carbonylation of allylamines (eq 2, Scheme 2). Wen/Zhao reported an example
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comprising the γꢀC(sp )ꢀH silylation of allylamines (eq 2, Scheme 2). Herein, we report our
investigations on the Pd(OAc) /AgOAc catalytic system, picolinamideꢀ and chelationꢀassisted Zꢀ
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selective γꢀC(sp )ꢀH arylation of Nꢀallylpicolinamides (eq 3, Scheme 2). This work divulges a
contemporary method for the regioselective γꢀarylation of allylamines involving relatively simple
reaction conditions, in which aryl iodide is a coupling partner, Pd(OAc) is the catalyst, and
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AgOAc acts as an additive to regenerate the catalyst.
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RESULTS AND DISCUSSION
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To begin our investigation on the Zꢀselective γꢀC(sp )ꢀH arylation of allylamines, we
assembled various Nꢀallylcarboxamides to use them as substrates in the Pd(OAc) /AgOAcꢀ,
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bidentate directing groupꢀassisted γꢀC(sp )ꢀH arylation reactions. Accordingly, the Nꢀ
allylcarboxamide substrates 1aꢀm were prepared from the corresponding allylamines and
carboxylic acids (Scheme 3). After preparing the required Nꢀallylcarboxamides 1aꢀm, we
attempted the construction of Zꢀcinnamylamine 3a via the Pd(II)ꢀcatalyzed arylation of Nꢀ
allylpicolinamide 1a. Table 1 shows the optimization of the reaction conditions of the reaction of
Nꢀallylpicolinamide 1a with aryl halides 2aꢀc in the presence of various palladium catalysts,
additives and solvents.
Table 1. Optimization of the Reaction of Allylamine 1a
Entry PdL2
Additive
Solvent
T (°C) 3a Yield E:Z ratio
(
10 mol%)
(%)
(3aʹ:3a)
21:79
11:89
8:92
b
1
2
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
AgOAc
AgOAc
Ag CO
Toluene
Toluene
Toluene
110
110
110
51
64
36
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Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
PhI(OAc)2
Toluene
Toluene
Toluene
Toluene
Toluene
1,2ꢀDCE
tꢀBuOH
tꢀAmlOH
Toluene
Toluene
Toluene
Toluene
Toluene
110
110
110
110
110
80
0
ꢀ
KOAc
K CO
<10
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37
31
19
18
37
69
48
25
0
69:31
70:30
11:89
11:89
21:79
16:84
12:88
4:96
16:84
18:82
ꢀ
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AgOAc
Pd(MeCN) Cl AgOAc
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2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
AgOAc
0
AgOAc
85
11
AgOAc
105
110
110
110
110
110
c
d
e
f
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13
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AgOAc
AgOAc
AgOAc
AgOAc
g
h
16
AgOAc
0
ꢀ
17
dppp (6 mol%)
Ethylene glycol 145
(1.5 mL)
traces
ꢀ
(
3 mol%)
Pd(OAc)2
2 mol%)
Et N (0.5 mmol)
3
i
18
PPh (4 mol%)
DMF
120
120
105
traces
traces
traces
ꢀ
ꢀ
ꢀ
3
(
TMEDA (0.5 mmol) (1.5 mL)
PPh (8 mol%) DMF
Cs CO (0.5 mmol) (1.5 mL)
j
1
9
0
Pd(OAc)2
(4 mol%)
Pd(OAc)2
3
2
3
k
2
K CO (1 mmol)
tꢀAmlOH
2
3
(10 mol%)
(3 mL)
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a
The E/Z ratios were determined from the NMR spectra of the corresponding crude reaction
mixtures. All the reactions were performed using PdL (5ꢀ10 mol%), additive (0.55 mmol),
2
b
c
solvent (3 mL) for 36 h unless otherwise stated. Five mol% of Pd(OAc) was used. Six equiv
2
d
e
(1.5 mmol) of 2a was used. Three equiv (0.75 mmol) of 2a was used. Two equiv (0.5 mmol)
f
g
of 2a was used. The reaction was performed using 2b instead of 2a. The reaction was
h
i
performed using 2c instead of 2a.
0.27 mmol of 2a and the reaction time was 5 h. The
j
k
reaction time was 5 h. 0.83 mmol of 2a and the reaction time was 24 h. 1 mmol of 2a and the
reaction time was 24 h.
The CꢀH arylation reaction of a mixture of Nꢀallylpicolinamide 1a (1 equiv), 1ꢀiodoꢀ4ꢀ
methoxybenzene (2a, 4 equiv), Pd(OAc) (5 mol%) and AgOAc (2.2 equiv) in toluene at 110 °C
2
2
afforded the γꢀC(sp )ꢀH arylated allylamine derivatives 3aʹ/3a (E/Z isomers) with a yield of 51%
and an E/Z ratio of 21:79 (entry 1, Table 1). As was envisioned, this reaction afforded the γꢀCꢀH
arylated allylamine derivative 3a with Zꢀstereochemistry as the major isomer, and this result
indicated the involvement of a chelationꢀassisted mechanism of Nꢀallylpicolinamide 1a. We next
performed the same reaction using 10 mol% of the Pd(OAc) catalyst, which afforded 3aʹ/3a
2
(E/Z isomers) with an improved yield (64%) and E/Z ratio of 11:89 (entry 2, Table 1).
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Scheme 3. Directing Groups and Substrates Employed for Investigating the γꢀC(sp )ꢀH
a,44b
Arylation.
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a
General reaction conditions used for performing the arylations of substrates 1aꢀm: substrate
(
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2
24 h, and 110 °C.
We then determined whether the yield and E/Z ratio of 3aʹ/3a could be further improved
2
using various palladium catalysts, additives and solvents. The Pd(II)ꢀcatalyzed γꢀC(sp )ꢀH
arylation of 1a with 2a in the presence of Ag CO afforded 3aʹ/3a with a yield of only 36% and
2
3
an E/Z ratio of 8:92 (entry 3, Table 1). The arylation of 1a with 2a in the presence of PhI(OAc)2
or KOAc failed to afford 3aʹ/3a (entries 4 and 5, Table 1). The arylation of 1a with 2a in the
presence of K CO afforded 3aʹ/3a with a yield of only 29% and an E/Z ratio of 70:30 (entry 6,
2
3
Table 1). Notably, this reaction afforded the γꢀCꢀH arylated allylamine derivative 3aʹ with Eꢀ
stereochemistry as the major isomer, indicating the involvement of a conventional Heckꢀtype
3
1,32,45a
reaction mechanism.
We next attempted the arylation of 1a with 2a using PdCl and
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Pd(CH CN) Cl as the catalysts instead of Pd(OAc) . The reaction of 1a with 2a in the presence
3
2
2
2
of PdCl or Pd(CH CN) Cl (10 mol%) and AgOAc (2.2 equiv) afforded 3aʹ/3a with yields of
2
3
2
2
only 31ꢀ37% and an E/Z ratio of 11:89 (entries 7 and 8, Table 1). We also performed the
arylation of 1a with 2a in different solvents, e.g., 1,2ꢀdichloroethane (1,2ꢀDCE), tertꢀbutanol (tꢀ
BuOH) and tertꢀamyl alcohol (tꢀAmylOH). The Pd(II)ꢀcatalyzed reactions of 1a with 2a in 1,2ꢀ
DCE and tꢀBuOH solvents were not fruitful (entries 9 and 10, Table 1). The Pd(II)ꢀcatalyzed
reaction of 1a with 2a in tꢀAmylOH afforded 3aʹ/3a with a yield of only 37% and an E/Z ratio of
12:88 (entry 11, Table 1).
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60
To improve the yield and E/Z ratio of 3aʹ/3a, we screened the Pd(II)ꢀcatalyzed arylation
of 1a using different equiv of 2a. Accordingly, the arylation of 1a (1 equiv) with 6 equiv of 2a
afforded 3aʹ/3a in a marginally improved yield (69%) with an E/Z ratio of 4:96 (entry 12, Table
1). The arylation of 1a (1 equiv) with 2ꢀ3 equiv of 2a afforded low yields of 3aʹ/3a (25ꢀ48%)
with slightly decreased E/Z ratios (E/Z ratio up to 16:84, entries 13 and 14, Table 1). The
arylation of 1a with the coupling partners 1ꢀbromoꢀ4ꢀmethoxybenzene (2b) and 1ꢀchloroꢀ4ꢀ
methoxybenzene (2c) instead of 2a did not afford 3aʹ/3a (entries 15 and 16, Table 1). We also
performed the arylation of 1a using various standard Heckꢀtype reaction conditions, and these
reactions were not fruitful (entries 17ꢀ20, Table 1). The optimization reactions revealed that the
isomers 3aʹ/3a were formed with different E/Z ratios under the experimental conditions. While
we cannot ignore the occurrence of thermal cisꢀtrans (Z/E) isomerization as discussed in our
45a
previous work,
a control reaction was performed to check whether the cisꢀtrans (Z/E)
isomerization is occurring under the thermal condition or the Eꢀisomer is formed under via a
conventional Heckꢀtype reaction pathway. Accordingly, the isomers 3aʹ/3a (E/Z = 1:99) were
treated with the catalyst Pd(OAc) and additive AgOAc in the absence of 2a. The crude NMR of
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this reaction revealed a minor change in the E/Z ratio and the E/Z ratio was found to be 11:89 (eq
1, Table 1). Additionally, to check whether a second arylation of 3aʹ/3a occurs under the
experimental conditions, we performed the arylation of 3aʹ/3a (E/Z = 11:89) with iodobenzene.
This reaction afforded a complex mixture and purification of the crude mixture did not give the
expected bisarylated product 3aA (eq 2, Table 1). After successfully achieving the arylations of
substrates 1aꢀg, we then performed the Pd(II)ꢀcatalyzed arylations of substrates 1hꢀj, which were
lacking the corresponding bidentate directing groups, and these reactions did not give the
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0
44b
corresponding arylated products in characterizable amounts (Scheme 3). These experiments
indicated that, in substrates 1aꢀg, the corresponding bidentate directing groups played an
important role in the Pd(II)ꢀcatalyzed CꢀH arylation process to afford the corresponding Zꢀ
isomers 3ꢀ7 (major isomers).
With the reaction conditions optimized, we next wished to explore the generality and
substrate scope of this protocol. Accordingly, Scheme 4 shows the arylation of 1a with a wide
range of aryl iodides under the optimized reaction conditions (entry 2, Table 1). The arylation of
1a with aryl iodides containing an alkyl substituent at the para position afforded the
corresponding γꢀCꢀH arylated allylamines 3bꢀg with yields of 50ꢀ82% and moderate to good E/Z
ratios (E/Z up to 9:91). The arylation of 1a with various disubstituted aryl iodides and an aryl
iodide containing a substituent at the meta position (e.g., COOEt) afforded the corresponding
allylamines 3hꢀk with yields of 40ꢀ59% and low to moderate E/Z ratios (E/Z up to 22:79,
Scheme 4). We also performed the arylation of 1a using another optimized reaction conditions
(entry 12, Table 1) in which 6 equiv of ArI (2a) was used. Accordingly, the products 3b, 3c, 3g
and 3h were obtained from the arylation of 1a with the corresponding aryl iodides with relatively
good E/Z ratios (E/Z up to 15:85, Scheme 4).
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Scheme 4. Pd(II)ꢀCatalyzed, Picolinamideꢀ, ChelationꢀAssisted Construction of Zꢀ
Cinnamylamines 3bꢀm.
10
11
12
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5
6
a
The E/Z ratios were determined from the NMR spectra of the corresponding crude
reaction mixtures, and in most cases, the corresponding major isomer (Z) was isolated in its pure
b
form. These reactions were performed using the conditions of entry 12 in Table 1, and some
0
1
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7
8
9
0
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9
0
c
other trials using the conditions of entry 12 in Table 1 were not fruitful. Two mmol of ArI was
d
used. In this case, compounds 3g′ (Eꢀisomer) and 3g (Zꢀisomer) were isolated in their pure
e
f
forms. Two mmol of ArI and 15 mol% of Pd(OAc) were used. Five mol% of Pd(OAc) was
2
2
used.
Then, we also performed the arylation of 1a using heteroaryl iodides to afford the
corresponding allylamine derivatives 3l and 3m with yields of 50ꢀ69% and high E/Z ratios (E/Z
up to 2:98, Scheme 4). Most of the allylamines 3ʹ/3 were obtained in satisfactory yields (>50%
yields) and E/Z ratios (E/Z ratios ranging from 38:62 to 2:98). After performing the Pd(II)ꢀ
catalyzed γꢀCꢀH arylation of allylamine 1a using picolinamide as the bidentate directing group to
determine other working directing groups and obtain an improved yield and E/Z ratio, we
attempted the γꢀCꢀH arylation of allylamine 1b by using 4ꢀchloropicolinamide as the bidentate
directing group. The arylation of 1b with PhI, aryl iodides containing a substituent at the para or
meta position (e.g., OMe, Me, Et, nꢀpentyl, nꢀhexyl, iꢀPr and COOEt), disubstituted aryl iodides
and heteroaryl iodides afforded the corresponding γꢀCꢀH arylated allylamine derivatives 4aꢀn
with yields of 41ꢀ63% and low to good E/Z ratios (E/Z up to 12:88, Scheme 5). Most of the
derivatives 4ʹ/4 were obtained with satisfactory yields (>50% yields) and E/Z ratios (E/Z ratios
ranging from 34:66 to 12:88). A comparison of the obtained yields and E/Z ratios of the products
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shown in Schemes 4 and 5 revealed that, except for some cases, the efficacy of the bidentate
directing group 4ꢀchloroꢀ2ꢀpicolinamide was comparable to that of 2ꢀpicolinamide.
To extend the substrate scope of this method, we attempted the arylation of Nꢀ(2ꢀ
methylallyl)picolinamides 1c and 1d, which were derived from βꢀmethylallylamine and the
corresponding picolinic acids. Notably, Nꢀ(2ꢀmethylallyl)picolinamides 1c and 1d contain both
10
11
12
13
14
15
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60
3
2
γꢀC(sp )ꢀH and γꢀC(sp )ꢀH bonds, which can undergo the arylation under the experimental
conditions. Scheme 6 shows the arylation of 1c and 1d with various aryl iodides under the
optimized reaction conditions. We initially performed the Pd(II)ꢀcatalyzed reaction of 1c with
aryl iodides containing a substituent at the para position (e.g., Me, Et, Cl, COOMe and iꢀPr),
2
3
which afforded the corresponding γꢀC(sp )ꢀH and γꢀC(sp )ꢀH bisarylated allylamine derivatives
5aꢀe with yields of 36ꢀ50% (Scheme 6).
We then performed the Pd(II)ꢀcatalyzed reaction of 1c and 1d with various disubstituted
aryl iodides, an aryl iodide containing a substituent at the meta position (e.g., COOEt) and
2
3
heteroaryl iodides. These reactions also afforded the corresponding γꢀC(sp )ꢀH and γꢀC(sp )ꢀH
bisarylated allylamine derivatives 5fꢀk and 7a with yields of 34ꢀ47%. It should be noted that the
2
Pd(II)ꢀcatalyzed reaction of 1c with 2ꢀchloroꢀ4ꢀiodopyridine afforded the γꢀC(sp )ꢀH
2
3
monoarylated product 6a along with the expected γꢀC(sp )ꢀH and γꢀC(sp )ꢀH bisarylated
allylamine derivative 5k. Given this interesting result, we performed the Pd(II)ꢀcatalyzed
2
arylation of 1c and 1d with various iodopyridines, which afforded the corresponding γꢀC(sp )ꢀH
monoarylated products 6bꢀd with yields of 40ꢀ41% (Scheme 6).
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6
Scheme 5. Pd(II)ꢀCatalyzed, 4ꢀChloropicolinamideꢀ, ChelationꢀAssisted Construction of Zꢀ
a
Cinnamylamines 4aꢀn.
0
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2
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8
9
0
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0
a
The E/Z ratios were determined from the NMR spectra of the corresponding crude reaction
mixtures, and in most cases, the corresponding major isomer (Zꢀisomer) was isolated in pure
b
form. In this case, compounds 4c′ (Eꢀisomer) and 4c (Zꢀisomer) were isolated in their pure
c
d
forms. Fifteen mol% of Pd(OAc) was used. Two mmol of ArI was used.
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Scheme 6. Pd(II)ꢀCatalyzed, Picolinamideꢀ, ChelationꢀAssisted sp and sp γꢀCꢀH Arylation
to Construct ZꢀCinnamylamines 5aꢀk, 6aꢀd and 7a.
R
R
N
PdL (10 mol%)
2
N
10
11
12
13
14
15
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18
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20
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60
Ar
AgOAc (0.55 mmol)
H C
3
N
H
O
+
Ar I
N
H
O
toluene (3 mL)
H
H
o
Ar
t (h), 110 C
2
1c; R=H, 1d; R=Cl
(1 mmol)
5a-k / 6a-d / 7a
(Z-isomer, major)
(0.25 mmol)
R
Me
Me
O
O
N
N
N
5a; R = Me 43% (24 h)
5
5
5
5
b; R = Et 36% (36 h)
N
H
O
R
N
H
O
N
H
O
c; R = Cl 40% (24 h)
d; R = COOMe 50% (36 h)a
e; R = i-Pr 37% (24 h)
Me
O
Me
O
5f; 44% (24 h) 5g; 46% (36 h)
Cl
EtOOC
Cl
Me
Me
N
N
N
N
H
O
N
H
O
Me
N
O
H
Cl
Cl
Me
COOEt
5h; 45% (36 h)
5i; 47% (36 h)
5j; 41% (36 h)b
Cl
N
EtOOC
Cl
N
N
N
H C
3
N
H
O
N
H
O
N
O
H
N
N
Cl
Cl
COOEt
7a; 40% (10 h)
Cl
5k; 34% (36 h)
6a; 30% (36 h)
N
N
N
H C
H3C
H C
3
3
N
O
N
H
O
F
N
H
O
H
N
N
Br
N
Br
6c; 41% (24 h)
6b; 41% (48 h)
6d; 40% (48 h)
a
b
Fifteen mol% of Pd(OAc) was used. Twenty mol% of Pd(OAc) was used.
2
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Scheme 7. Pd(OAc) /AgOAcꢀCatalyzed EꢀSelective γꢀCꢀH Arylation of Allylamine
2
a
Substrates 1eꢀg.
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a
The E/Z ratios were determined from the NMR spectra of the corresponding crude
b
reaction mixtures. Compounds 10bꢀf were prepared using the conditions given in entry 3. A
complex mixture was obtained, and purification of the crude reaction mixture did not afford the
corresponding cinnamylamine in pure form.
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Next, to elaborate our investigation on the Pd(OAc) /AgOAcꢀcatalyzed γꢀCꢀH arylation
2
of allylamines, we performed the Pd(II)ꢀcatalyzed reaction of picolinamide 1e with 2a, which
gave derivative 8a with a yield of 40% with an E/Z ratio of 67:33 (eq 1, Scheme 7). We then
performed the Pd(II)ꢀcatalyzed reaction of Nꢀallylpyrazineꢀ2ꢀcarboxamide 1f with 2a, and this
reaction afforded the γꢀCꢀH arylated allylamine derivative 9a with a yield of only 35% and an
E/Z ratio of 62:38 (eq 2, Scheme 7). An initial attempt of the reaction of isoxazoleꢀ3ꢀ
carboxamide 1g (1 equiv) with pꢀtolyl iodide (1 equiv) in the presence of Pd(OAc) (10 mol%)
2
and AgOAc (2.2 equiv) in toluene at 110 °C afforded the γꢀCꢀH arylated allylamine derivative
1
0a with a yield of 48% and an E/Z ratio of 98:2 (entry 1, Scheme 7). Surprised by this reaction,
we then performed the arylation of 1g using different reaction conditions to see whether we
could obtain the Zꢀisomer as the major isomer. Accordingly, the reaction of 1g (1 equiv) with pꢀ
tolyl iodide (1 equiv) in the presence of Pd(OAc) (5 mol%) in toluene at rt afforded 10a in 33%
2
yield with E/Z ratio of 89:11 (entry 2, Scheme 7). The same reaction at 50 °C afforded 10a in an
improved yield (78%) with an E/Z ratio of 98:2 (entry 3, Scheme 7). Apart from these reactions,
other attempts to obtain the Zꢀisomer from the arylation of 1g under different reaction conditions
were not fruitful (entries 4ꢀ7, Scheme 7). These results indicate that the arylation reactions
comprising the substrates 1eꢀg underwent the conventional Heckꢀtype reaction mechanism
31,32,45a
without chelation assistance by the corresponding directing groups (Scheme 7).
We were
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6
interested to capitalize on the reaction conditions that afforded compound 10a with Eꢀ
stereochemistry (entry 3, Scheme 7) for synthesizing various γꢀCꢀH arylated allylamine
derivatives. Accordingly, treatment of 1g with various aryl iodides in the presence of Pd(OAc)2
0
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7
8
9
0
o
(
5 mol%) in toluene at 50 C afforded a series of γꢀCꢀH arylated allylamines 10bꢀf with Eꢀ
stereochemistry with yields of 60ꢀ75% (Scheme 7).
Scheme 8. Plausible Mechanism for the ZꢀSelective γꢀCꢀH Arylation of 1aꢀd.
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In the present work, the arylations of the picolinamide substrates 1aꢀd selectively
afforded the corresponding γꢀCꢀH arylated products 3ꢀ7 with Zꢀstereochemistry as the
II
predominant isomers (Table 1, Schemes 4ꢀ6). In concurrence with the generally proposed Pd ꢀ
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IV
Pd catalytic cycle mechanism pertaining to the Pd(OAc) /AgOAcꢀcatalyzed, bidentate
2
9ꢀ11,45
directing groupꢀassisted CꢀH functionalization,
aꢀd could be demonstrated via a plausible bidentate directing groupꢀassisted and chelationꢀ
controlled CꢀH activation mechanism (Scheme 8). In this process, it is believed that AgOAc
the observed Zꢀselective γꢀCꢀH arylations of
1
IV
9ꢀ11
helps in the ligandꢀexchange step to generate the Pd species 11d.
Furthermore, the picolinamide substrate 1e and pyrazineꢀ2ꢀcarboxamide substrate 1f were
expected to afford the corresponding products 8a and 9a with Zꢀstereochemistry as the
predominant isomers (Scheme 7); however, the corresponding products 8a and 9a with Eꢀ
stereochemistry were obtained as the predominant isomers. These results are likely due to the
absence of chelation assistance by the corresponding bidentate directing groups. Substrate 1eꢀg
appears to only weakly coordinate with palladium, and therefore, the reactions result in a mixture
46ꢀ49
of products formed through two different mechanisms, such as a Heckꢀtype mechanism
leading to the Eꢀregioisomer and a bidentate directing groupꢀassisted, chelationꢀcontrolled
4
5a
mechanism leading to the Zꢀregioisomer.
CONCLUSION
We investigated the Pd(II)ꢀcatalyzed, bidentate directing groupꢀ and chelationꢀassisted Zꢀ
2
selective γꢀC(sp )ꢀH arylation of allylamines. The reactions of Nꢀallylpicolinamides with various
2
aryl and heteroaryl iodides in the presence of Pd(OAc) and AgOAc led to the selective γꢀC(sp )ꢀ
2
H arylation to construct various Zꢀcinnamylamine derivatives with low to high E/Z ratios (E/Z
ratios up to 2:98). Additionally, the Pd(II)ꢀcatalyzed arylation of an allylamine containing both γꢀ
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C(sp )ꢀH and γꢀC(sp )ꢀH bonds afforded the γꢀC(sp )ꢀH and γꢀC(sp )ꢀH arylated cinnamylamine
scaffolds. Although Heckꢀtype γꢀarylations of allylamines have generally afforded Eꢀ
cinnamylamines, the present work demonstrated the construction of Zꢀcinnamylamine scaffolds
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with reasonably good E/Z ratios. The Pd(II)ꢀcatalyzed γꢀC(sp )ꢀH arylation of Nꢀ
allylpicolinamides was probed using different additives, directing groups and reaction
conditions. In concurrence with the generally proposed mechanism pertaining to the
Pd(OAc) /AgOAcꢀcatalyzed, bidentate directing groupꢀassisted CꢀH functionalization, the
2
2
observed Zꢀselective γꢀC(sp )ꢀH arylations of 1aꢀd were demonstrated via a plausible bidentate
directing groupꢀ and chelationꢀassisted CꢀH activation mechanism. Finally, the
Pd(OAc) /AgOAcꢀcatalyzed arylation of Nꢀallylꢀ5ꢀmethylisoxazoleꢀ3ꢀcarboxamide 1g was
2
found to afford the Eꢀcinnamylamine derivatives 10aꢀf, and it is assumed that the arylations of
1
g occurred via a ligandꢀfree Heckꢀtype reaction mechanism to afford the corresponding Eꢀ
cinnamylamine derivatives 10aꢀf.
EXPERIMENTAL SECTION
General Considerations. IR spectra of allylamines were recorded as thin films or KBr pellets.
1
13
H and C NMR spectra of samples were recorded on 400 MHz and 100 MHz spectrometers,
respectively (using TMS as an internal standard). HRMS measurements reported in this work
were obtained from QTOF mass analyzer using electrospray ionization method (ESI). Column
chromatography was carried out using silica gel (100ꢀ200 mesh) or neutral alumina. Starting
materials preparation and CꢀH functionalization reactions were performed in anhydrous solvents
under a nitrogen atmosphere wherever necessary. Isolated yields of all the compounds were
reported and yields were not optimized. Thin layer chromatography (TLC) analysis was
performed on silica gel or alumina plates and the components were visualized by observation
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under iodine vapor. Amide starting materials used in the Pd(II)ꢀcatalyzed CꢀH arylation reactions
were prepared (from their corresponding acids and amines) using the standard literature
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procedures.
The E/Z ratios were determined from the NMR spectra of the corresponding
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crude reaction mixtures and in the cases of the Table 1 and Schemes 4, 5 and 7 the total yields of
E/Z isomers were reported. With regard to the CꢀH arylation reactions of 1aꢀd, the data given
here corresponds to the corresponding major isomers (Zꢀisomers) 3aꢀm, 4aꢀn, 5aꢀk, 7a and 6aꢀd.
In some cases, the corresponding minor isomers (Eꢀisomers) 3g′ and 4c′ were isolated and
characterized. With regard to the CꢀH arylation reactions of 1eꢀg, the data given here correspond
to the major isomers 8a, 9a and 10aꢀf (Eꢀisomers).
1
8c,d,43,45a
In concurrence with representative literature reports,
the Zꢀstereochemistry of 3aꢀm, 4aꢀ
n, 5aꢀk, 7a and 6aꢀd (major isomers) and the Eꢀstereochemistry of 3g′ and 4c′ (minor isomers)
were ascertained based on the observed characteristic coupling constant values of the
corresponding doublet peaks of the olefin protons (J = ∼ 11.5 Hz for the Zꢀisomers and J = ∼
15.8 Hz for the Eꢀisomers). The Eꢀstereochemistry of 8a, 9a and 10aꢀf were ascertained based on
the observed characteristic coupling constant values of the corresponding doublet peaks of the
olefin protons (J = ∼ 15.8 Hz). Additionally, the observed Eꢀstereochemistry of a representative
compound 10e was confirmed from the Xꢀray structure analysis (see the SI for the Xꢀray
structure of 10e).
The following points are with regard to separation of E/Z isomers. After the arylation of
the corresponding allylamines 1a,b, the purification of the crude reaction mixture afforded the
respective E/Z cinnamylamines as a mixture since the corresponding E/Z cinnamylamines (3′/3
and 4′/4) had similar/close R values. Hence, the respective E/Z cinnamylamines were subjected
f
to the repetitive column chromatographic purification to obtain the corresponding pure
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compounds. In some cases, we isolated the major isomers (Zꢀisomers) in pure form after the
repetitive column chromatographic purification and in some other cases, we got only a few
column fractions of the corresponding major isomers (Zꢀisomers) in pure forms, which were used
for characterization. Despite our repeated efforts to obtain the major isomers (Zꢀisomers) in pure
forms, in some cases, the Zꢀisomers were obtained with traces of corresponding minor isomers
due to similar Rf values of both major and minor isomers. With regard to isolation of minor
isomers (Eꢀisomers), except the minor isomers 3g′ and 4c′ (Eꢀisomers), our repeated efforts to
isolate the corresponding other Eꢀisomers 3′ and 4′ in pure forms for characterization were not
fruitful. The Pd(II)ꢀcatalyzed arylation of 1c,d afforded the corresponding double CꢀH arylated
compounds 5aꢀk and 7a (Zꢀisomers) as the major isomers. Though in some reactions the
corresponding crude NMRs indicated the formation of trace amounts minor compounds, except
the compound 6a, either we could not isolate any other corresponding minor isomers in pure
forms or the reactions did not give any other isomers in characterizable amounts.
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Procedure for the synthesis of Nꢀallylamide 1aꢀf, 1hꢀk and 1m: An ovenꢀdried roundꢀbottom
flask (25 mL capacity) was charged with an appropriate carboxylic acid (1.2 mmol, 1 equiv) and
anhydrous DCM (4ꢀ6 mL) and twoꢀthree drops of DMF. To this solution oxalyl chloride (1.5
mmol, 1.5 equiv, 190 mg) was added dropwise at 0 °C. The mixture was stirred at rt for 12 h and
then, the solvent was removed in vacuo and then dissolved in DCM (4ꢀ6 mL). The resulting acid
chloride solution was immediately used in the next step without further purification. Another
ovenꢀdried roundꢀbottom flask (25 mL capacity) was charged with an appropriate allylamine (1.0
mmol, 1 equiv), Et N (1.5 mmol, 1.5 equiv, 152 mg), DMAP (0.1 mmol, 0.1 equiv, 12 mg). To
3
this solution, the acid chloride solution (obtained in the previous step) was added dropwise at 0
°
C and after the addition the solution was warmed to rt and allow to stir overnight. Then, the
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reaction mixture was quenched with sat. aq. NaHCO solution (10ꢀ15 mL) and the organic layer
3
was separated, dried over anhydrous MgSO4 and evaporated in vacuo. The crude reaction
mixture was purified by column chromatography on silica gel (eluent: EtOAc:Hexanes = 30:70)
to afford the corresponding carboxamides 1aꢀf, 1hꢀk and 1m.
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Procedure for the synthesis of carboxamides 1g and 1l: An ovenꢀdried roundꢀbottom flask (25
mL capacity) was charged with 5ꢀmethylisoxazoleꢀ3ꢀcarboxylic acid (1 mmol, 1 equiv) and
DCM (6 mL) under a nitrogen atm. Then, EDCI (1.1 mmol, 1.1 equiv, 172 mg) and HOBt•H O
2
(1.1 mmol, 1.1 equiv, 168 mg) were added dropwise at 0 °C and the reaction mixture was stirred
for 15 min. Then, to the reaction mixture an appropriate allylamine (1 mmol, 1.1 equiv) was
added dropwise at 0 °C. Then, the solution was warmed to room temperature and the stirring was
continued for 12 h. After this period, water (4ꢀ7 mL) was added and extracted with DCM (4ꢀ7
mL, 2ꢀ3 times). The combined organic layers were washed with sat. aq. NaHCO (10 mL), dried
3
over anhydrous MgSO and the solvent was evaporated in vacuo. The crude reaction mixture
4
was purified by column chromatography on silica gel (eluent: EtOAc:Hexanes = 35:65) to afford
the corresponding products 1g and 1l.
General procedure for the Pd(II)ꢀcatalyzed arylation of Nꢀallylamide derivatives 1aꢀm and
the preparation of 3aꢀm/4aꢀn/5aꢀk/6aꢀd/7a/10aꢀf. An ovenꢀdried roundꢀbottom flask (10 mL
capacity) was charged with an appropriate Nꢀallylamide derivative (0.25 mmol, 1 equiv), an
appropriate aryl iodide (1.0 mmol, 4.0 equiv), Pd(OAc) (10 mol%, 5.6 mg,), AgOAc (0.55
2
o
mmol, 2.2 equiv, 91.8 mg) and toluene (3 mL). This reaction mixture was heated at 110 C for
24ꢀ48 h under a nitrogen atm. After this period, the reaction mixture was concentrated in vacuo
and purification of the resulting reaction mixture by column chromatography on silica gel
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furnished the corresponding γꢀCꢀH arylated allylamine derivatives 3aꢀm/4aꢀn/5aꢀk/6aꢀd/7a/10aꢀ
f (see the corresponding Tables/Schemes for specific examples).
5
0a
NꢀAllylpicolinamide (1a): The compound 1a was obtained after purification by column
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chromatography on silica gel (EtOAc:Hexanes = 30:70) as a brown colour liquid; R = 0.51
f
ꢀ1 1
(EtOAc/hexane = 1:4); Yield: 77% (126 mg); IR (DCM): 3446, 2064, 1642, 1529, 1465 cm ; H
NMR (400 MHz, CDCl ): δ 8.55 (dd, 1H, J = 4.8 Hz, J = 0.8 Hz), 8.21 (dd, 1H, J = 7.8 Hz, J
2
3
1
2
1
=
1.0 Hz), 8.17 (br. s, 1H), 7.85 (t, 1H, J = 7.7 Hz), 7.45ꢀ7.41(m, 1H), 5.99ꢀ5.89 (m, 1H), 5.30ꢀ
1
3
5.16 (m, 2H), 4.13ꢀ4.10 (m, 2H); C NMR (100 MHz, CDCl ): δ 164.2, 149.7, 148.0, 137.3,
3
+
1
34.0, 126.2, 122.2, 116.3, 41.7; HRMS (ESI): m/z [M + H] calcd for C H N O: 163.0871;
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found 163.0875.
5
0b
NꢀAllylꢀ4ꢀchloropicolinamide (1b): The compound 1b was obtained after purification by
column chromatography on silica gel (EtOAc:Hexanes = 30:70) as a pale yellow colour liquid;
Rf = 0.50 (EtOAc/hexane = 1:4); Yield: 67% (133 mg); IR (DCM): 3441, 2063, 1643, 1524,
ꢀ1 1
1
290 cm ; H NMR (400 MHz, CDCl ): δ 8.41 (d, 1H, J = 5.2 Hz), 8.17 (d, 1H, J = 2.0 Hz), 8.10
3
(
br. s, 1H), 7.41 (td, 1H, J = 5.2 Hz, J = 2.1 Hz), 5.95ꢀ5.85 (m, 1H), 5.26ꢀ5.13 (m, 2H), 4.09ꢀ
1 2
13
4.06 (m, 2H); C NMR (100 MHz, CDCl ): δ 163.0, 151.3, 149.0, 145.8, 133.8, 126.3, 122.9,
3
+
1
16.6, 41.9; HRMS (ESI): m/z [M + H] calcd for C H ClN O: 197.0482; found 197.0484.
9
10
2
Nꢀ(2ꢀMethylallyl)picolinamide (1c): The compound 1c was obtained after purification by
column chromatography on silica gel (EtOAc:Hexanes = 30:70) as a colourless liquid; R = 0.52
f
ꢀ1 1
(
EtOAc/hexane = 1:4); Yield: 69% (123 mg); IR (DCM): 3389, 1675, 1527, 1289 cm ; H NMR
(
400 MHz, CDCl ): δ 8.32ꢀ8.31 (m, 1H), 8.17 (br. s, 1H), 8.00 (dd, 1H, J = 7.8 Hz, J = 0.9 Hz),
3
1
2
7.61 (td, 1H, J = 7.7 Hz, J = 1.8 Hz), 7.21ꢀ7.19 (m, 1H), 4.69ꢀ4.63 (m, 2H), 3.82 (d, 2H, J = 6.4
13
Hz), 1.55 (s, 3H); C NMR (100 MHz, CDCl ): δ 164.1, 149.6, 147.9, 141.6, 137.2, 126.1,
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22.1, 110.8, 44.7, 20.2; HRMS (ESI): m/z [M + H] calcd for C H N O: 177.1028; found
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0
13
2
77.1023.
ꢀChloroꢀNꢀ(2ꢀmethylallyl)picolinamide (1d): The compound 1d was obtained after
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purification by column chromatography on silica gel (EtOAc:Hexanes = 30:70) as a colourless
liquid; R = 0.50 (EtOAc/Hexanes = 1:4); Yield: 35% (74 mg); IR (DCM): 3391, 1677, 1527,
f
ꢀ1 1
1
292 cm ; H NMR (400 MHz, CDCl ): δ 8.44 (d, 1H, J = 5.2 Hz), 8.21 (d, 1H, J = 1.4 Hz), 8.14
3
(br. s, 1H), 7.44ꢀ7.42 (m, 1H), 4.90 (s, 1H), 4.87 (s, 1H), 4.01 (d, 2H, J = 6.2 Hz), 1.78 (s, 3H);
1
3
C NMR (100 MHz, CDCl ): δ 163.1, 151.3, 149.0, 145.9, 141.6, 126.3, 123.0, 111.2, 45.1,
3
+
2
0.4; HRMS (ESI): m/z [M + H] calcd for C H ClN O: 211.0638; found 211.0629.
1
0
12
2
N ,N ꢀDiallylpyridineꢀ2,6ꢀdicarboxamide (1e): The compound 1e was obtained after
2
6
purification by column chromatography on silica gel (EtOAc:Hexanes = 30:70) as a colourless
liquid; R = 0.52 (EtOAc/Hexanes = 1:4); Yield: 65% (161 mg); IR (DCM): 3287, 1667, 1537,
f
ꢀ1 1
1
445 cm ; H NMR (400 MHz, CDCl ): δ 9.18 (t, 2H, J = 6.0 Hz), 8.28 (d, 2H, J = 7.8 Hz), 7.95
3
(t, 1H, J = 7.8 Hz), 5.69ꢀ5.59 (m, 2H), 4.96ꢀ4.91 (m, 2H), 4.83ꢀ4.81 (m, 2H), 3.86 (t, 4H, J = 5.8
13
Hz); C NMR (100 MHz, CDCl ): δ 164.0, 148.8, 138.9, 133.8, 124.9, 116.1, 42.0; HRMS
3
+
(ESI): m/z [M + Na] calcd for C H N NaO : 268.1062; found 268.1068.
1
3
15
3
2
NꢀAllylpyrazineꢀ2ꢀcarboxamide (1f): The compound 1f was obtained after purification by
column chromatography on silica gel (EtOAc:Hexanes = 40:60) as a colourless liquid; R = 0.50
f
ꢀ1
1
(EtOAc/Hexanes = 1:4); Yield: 70% (115 mg); IR (DCM): 3397, 1667, 1532, 1402 cm ; H
NMR (400 MHz, CDCl ): δ 9.41 (dd, 1H, J = 3.4 Hz, J = 1.3 Hz), 8.74 (dd, 1H, J = 5.1 Hz, J
2
3
1
2
1
=
2.5 Hz), 8.53 (br. s, 1H), 7.95 (br. s, 1H), 5.97ꢀ5.88 (m, 1H), 5.30ꢀ5.16 (m, 2H), 4.13ꢀ4.10 (m,
1
3
2
H); C NMR (100 MHz, CDCl ): δ 162.8, 147.3, 144.4, 144.4, 142.6, 133.6, 116.8, 41.8;
3
+
HRMS (ESI): m/z [M + H] calcd for C H N O: 164.0824; found 164.0822.
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NꢀAllylꢀ5ꢀmethylisoxazoleꢀ3ꢀcarboxamide (1g): The compound 1g was obtained after
purification by column chromatography on neutral alumina (EtOAc:Hexanes = 35:65) as a
colourless liquid; R = 0.50 (EtOAc/hexane = 1:4); Yield: 50% (83 mg); IR (DCM): 3332, 1673,
f
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3
4
5
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7
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2
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3
4
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ꢀ1 1
1
599, 1458, 1280 cm ; H NMR (400 MHz, CDCl ): δ 7.07 (br. s, 1H), 6.43 (s, 1H), 5.92ꢀ5.83
3
13
(m, 1H), 5.26ꢀ5.14 (m, 2H), 4.04 (t, 2H, J = 5.8 Hz), 2.45 (s, 3H); C NMR (100 MHz, CDCl ):
3
+
δ 171.2, 159.0, 158.7, 133.4, 116.8, 101.4, 41.7, 12.3; HRMS (ESI): m/z [M + H] calcd for
C H N O : 167.0821; found 167.0815.
8
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2
NꢀAllylꢀ1ꢀnaphthamide (1h): The compound 1h was obtained after purification by column
chromatography on silica gel (EtOAc:Hexanes = 30:70) as a colourless liquid; Rf = 0.52
ꢀ1 1
(
EtOAc/Hexanes = 1:4); Yield: 65% (138 mg); IR (KBr): 3284, 1640, 1536, 1422 cm ; H NMR
(400 MHz, CDCl ): δ 8.13 (d, 1H, J = 8.1 Hz), 7.77ꢀ7.73 (m, 2H), 7.45ꢀ7.37 (m, 2H), 7.32 (d,
3
1
3
1
H, J = 7.0 Hz), 7.18 (t, 1H, J = 7.9 Hz), 6.99 (br. s, 1H), 5.80ꢀ5.71 (m, 1H), 5.12ꢀ5.01 (m, 2H),
13
.84 (t, 2H, J = 5.6 Hz); C NMR (100 MHz, CDCl ): δ 169.6, 139.1, 134.1, 133.5, 130.3,
3
+
30.1, 128.2, 126.8, 126.2, 125.5, 125.0, 124.6, 116.1, 42.2; HRMS (ESI): m/z [M + H] calcd
for C H NO: 212.1075; found 212.1082.
1
4
14
5
0c
NꢀAllylꢀ3ꢀphenylpropanamide (1i): The compound 1i was obtained after purification by
column chromatography on silica gel (EtOAc:Hexanes = 30:70) as a colourless liquid; R = 0.51
f
ꢀ1
(
EtOAc/Hexanes = 1:4); Yield: 72% (137 mg); IR (DCM): 3293, 1643, 1551, 1454, 1262 cm ;
1
H NMR (400 MHz, CDCl ): δ 7.30ꢀ7.26 (m, 2H), 7.22ꢀ7.19 (m, 3H), 6.28 (br. s, 1H), 5.82ꢀ5.72
3
(m, 1H), 5.10ꢀ5.06 (m, 2H), 3.83 (t, 2H, J = 5.6 Hz), 2.97 (t, 2H, J = 7.5 Hz), 2.52 (t, 2H, J = 7.5
1
3
Hz); C NMR (100 MHz, CDCl ): δ 172.3, 140.9, 134.2, 128.5, 128.3, 126.2, 116.1, 41.9, 38.3,
3
+
3
1.8; HRMS (ESI): m/z [M + H] calcd for C H NO: 190.1232; found 190.1228.
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Page 29 of 65
The Journal of Organic Chemistry
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50d
Nꢀ(2ꢀMethylallyl)ꢀ3ꢀphenylpropanamide (1j):
The compound 1j was obtained after
purification by column chromatography on silica gel (EtOAc:Hexanes = 30:70) as a colourless
liquid; R = 0.50 (EtOAc/hexane = 1:4); Yield: 74% (152 mg); IR (DCM): 3294, 1648, 1553,
f
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ꢀ1 1
1
454 cm ; H NMR (400 MHz, CDCl ): δ 7.30ꢀ7.27 (m, 2H), 7.22ꢀ7.20 (m, 3H), 6.00 (br. s,
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1H), 4.78 (s, 1H), 4.70 (s, 1H), 3.77 (d, 2H, J = 5.9 Hz), 2.99 (t, 2H, J = 7.9 Hz), 2.54 (t, 2H, J =
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.9 Hz), 1.67 (s, 3H); C NMR (100 MHz, CDCl ): δ 172.2, 141.9, 140.9, 128.5, 128.4, 126.2,
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10.8, 45.0, 38.4, 31.8, 20.3; HRMS (ESI): m/z [M + H] calcd for C H NO: 204.1388; found
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204.1379.
50e
Nꢀ(2ꢀ(Cyclohexꢀ1ꢀenꢀ1ꢀyl)ethyl)picolinamide (1k): The compound 1k was obtained after
purification by column chromatography on silica gel (EtOAc:Hexanes = 40:60) as a colourless
liquid; R = 0.50 (EtOAc/Hexanes = 1:4); Yield: 80% (184 mg); IR (DCM): 3392, 1665, 1590,
f
ꢀ1 1
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433 cm ; H NMR (400 MHz, CDCl ): δ 8.48 (dd, 1H, J = 4.7 Hz, J = 0.5 Hz), 8.14 (d, 1H, J
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=
7.8 Hz), 8.05 (br. s, 1H), 7.77 (td, 1H, J = 7.7 Hz, J = 1.7 Hz), 7.37ꢀ7.33 (m, 1H), 5.47 (s, 1H),
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.52ꢀ3.47 (m, 2H), 2.22ꢀ2.19 (m, 2H), 1.94ꢀ1.92 (m, 4H), 1.60ꢀ1.48 (m, 4H); C NMR (100
MHz, CDCl ): δ 164.1, 150.0, 148.0, 137.2, 134.5, 125.9, 123.4, 122.0, 37.7, 37.5, 28.0, 25.2,
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22.8, 22.3; HRMS (ESI): m/z [M + H] calcd for C H N O: 231.1497; found 231.1491.
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Nꢀ(2ꢀ(Cyclohexꢀ1ꢀenꢀ1ꢀyl)ethyl)ꢀ5ꢀmethylisoxazoleꢀ3ꢀcarboxamide (1l): The compound 1l
was obtained after purification by column chromatography on neutral alumina (EtOAc:Hexanes
= 35:65) as a colourless liquid; R = 0.52 (EtOAc/Hexanes = 1:4); Yield: 65% (153 mg); IR
f
ꢀ1 1
(
DCM): 3365, 1660, 1601, 1545, 1270 cm ; H NMR (400 MHz, CDCl ): δ 6.83 (br. s, 1H), 6.42
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(
s, 1H), 5.51 (s, 1H), 3.52ꢀ3.47 (m, 2H), 2.47 (s, 3H), 2.22 (t, 2H, J = 6.8 Hz), 1.99ꢀ1.95 (m, 4H),
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.65ꢀ1.53 (m, 4H); C NMR (100 MHz, CDCl ): δ 171.0, 159.0, 158.9, 134.2, 123.9, 101.4,
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