Diastereoselective Pd(II)-Catalyzed sp3 C-H Arylation Followed by Ring Opening of Cyclopropanecarboxamides: Construction of anti β-Acyloxy Carboxamide Derivatives

Article abstract of DOI:10.1021/acs.joc.6b01635

The diastereoselective Pd(OAc)₂-catalyzed, bidentate ligand-directed sp³ C-H activation/arylation followed by ring opening of cyclopropanecarboxamides, which were assembled from cyclopropanecarbonyl chlorides and bidentate ligands (e.g., 8-aminoquinoline and 2-(methylthio)aniline), has been investigated. The treatment of various cyclopropanecarboxamides with excess amounts of aryl iodides in the presence of the Pd(OAc)₂ catalyst, AgOAc and AcOH directly afforded the corresponding multiple β-C-H arylated open-chain carboxamides (anti β-acyloxy amides). This method has led to the construction of several anti β-acyloxy amides that possess vicinal stereocenters with a high degree of stereocontrol with the formation of a new C-O bond and three new C-C bonds. A plausible mechanism for the formation of multiple β-C-H arylated open-chain carboxamides from the Pd-catalyzed, bidentate ligand-directed β-C-H arylation and the ring opening of cyclopropanecarboxamides is proposed based on several control experiments. The observed diastereoselectivity and anti stereochemistry of the β-acyloxy amides were ascertained based on X-ray structural analysis of representative β-acyloxy amides.

Full text of DOI:10.1021/acs.joc.6b01635

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Article
Diastereoselective Pd(II)-Catalyzed sp3 C-H Arylation
Followed by Ring Opening of Cyclopropanecarboxamides:
Construction of anti beta-Acyloxy Carboxamide Derivatives
Bojan Gopalakrishnan, Sruthi Mohan, Ramarao Parella, and Srinivasarao Arulananda Babu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01635 • Publication Date (Web): 07 Sep 2016
Downloaded from http://pubs.acs.org on September 7, 2016
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Diastereoselective Pd(II)ꢀCatalyzed sp CꢀH Arylation Followed by Ring Opening of
Cyclopropanecarboxamides: Construction of anti βꢀAcyloxy Carboxamide Derivatives
Bojan Gopalakrishnan, Sruthi Mohan, Ramarao Parella and Srinivasarao Arulananda Babu*
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
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ABSTRACT
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The diastereoselective Pd(OAc)
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ꢀcatalyzed, bidentate ligandꢀdirected sp
CꢀH
activation/arylation followed by ring opening of cyclopropanecarboxamides, which were
assembled from cyclopropanecarbonyl chlorides and bidentate ligands (e.g., 8ꢀaminoquinoline and
2
ꢀ(methylthio)aniline, has been investigated. The treatment of various cyclopropanecarboxamides
with excess amounts of aryl iodides in the presence of the Pd(OAc) catalyst, AgOAc and AcOH
2
directly afforded the corresponding multiple βꢀCꢀH arylated openꢀchain carboxamides (anti βꢀ
acyloxy amides). This method has led to the construction of several anti βꢀacyloxy amides that
possess vicinal stereocenters with a high degree of stereocontrol with the formation of a new CꢀO
bond and three new CꢀC bonds. A plausible mechanism for the formation of multiple βꢀCꢀH
arylated openꢀchain carboxamides from the Pdꢀcatalyzed, bidentate ligandꢀdirected βꢀCꢀH
arylation and the ring opening of cyclopropanecarboxamides is proposed based on several control
experiments. The observed diastereoselectivity and anti stereochemistry of the βꢀacyloxy amides
were ascertained based on Xꢀray structural analysis of representative βꢀacyloxy amides.
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INTRODUCTION
Cyclopropane is the smallest ring in the cycloalkane family and is regularly encountered in
1,2
the core of numerous natural products and medicinally/biologically active molecules. The
chemistry of cyclopropanes is well understood, and cyclopropanes are one of the most versatile
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building blocks in organic synthesis. In addition, the release of the inherent ring strain associated
with the ring opening of the cyclopropane system has led to the discovery of numerous tandem
transformations. In general, the ringꢀopening reaction pathways depend on the electronic nature of
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ꢀ5
the functional groups or substituents that are present in the cyclopropane systems.
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a
3
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Cyclopropenes,
methylenecyclopropanes, alkylidenecyclopropanes, donor–acceptor
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6a,b
cyclopropanes and cyclopropyl ketones
are the most important classes of compounds in the
cyclopropane family. In general, cyclopropane systems readily undergo a wide range of
transformations including cyclodimerizations, cycloadditions, rearrangements, and ringꢀopening
(CꢀC cleavage) reactions under the influence of a variety of chemical reagents and suitable
1
ꢀ5
catalysts. The chemistry, usefulness and different modes of ring cleavage of these individual
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ꢀ
classes of cyclopropane systems have been well documented and summarized in various reviews.
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Although several types of cyclopropane ringꢀopening reactions are popularly known, the
transition metalꢀcatalyzed/promoted activation of the CꢀC bond and cleavage of the cyclopropane
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,3,5
5c
2a
ring has received unique attention.
The relevant reviews by Cramer, Rubin/Gevorgyan,
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a,b
3c
3d,e
3f
Pellissier,
Brandi,
Shi
and Marek provide an overview of transition metalꢀ
catalyzed/promoted activation and modes of cleavage of the CꢀC bonds of substituted
cyclopropanes, cyclopropenes, methylenecyclopropanes and alkylidenecyclopropanes, leading to
ringꢀopening reactions. For the reactions involving cyclopropanes, “the strainꢀdriven oxidative
addition of the C−C bond of cyclopropanes to a transitionꢀmetal leads to the formation of
5c
metallacyclobutane, which was shown to open the way to different reaction”. For the reactions
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involving cyclopropenes, methylenecyclopropanes and alkylidenecyclopropanes, “an unsaturated
tether facilitates the activation of the cyclopropane and directs the metal toward the cleavable C−C
5c
bond and can also participate in the postꢀactivation transformation”. Representative transition
metalꢀcatalyzed/promoted reactions consisting of activation and cleavage of the CꢀC bonds of
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cyclopropane, methylenecyclopropane and alkylidenecyclopropane are shown in Figure 1. Some
of the transition metalꢀcatalyzed/promoted reactions for donor–acceptor cyclopropane systems
(activated cyclopropanes) are also shown in Figure 1.
Figure 1. Representative MetalꢀCatalyzed/Promoted Ring Opening Reactions of
Cyclopropane Systems.
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Transition metalꢀcatalyzed CꢀH activation/functionalization reactions have received
significant attention in recent years, and in general, CꢀH functionalizationꢀbased crossꢀcoupling
10ꢀ14
reactions are considered to be stepꢀeconomical organic transformations.
Among the transition
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metal catalysts, the Pd(II) catalysts are frequently employed to perform sp and sp CꢀH
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activation/functionalization reactions.
Although the directing groupꢀassisted or directing
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groupꢀfree sp CꢀH activation/functionalization reactions have been extensively studied, the sp C–
H activation/functionalization reactions have received much attention after the seminal reports by
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2a,13a
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Daugulis,
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and other distinguished research groups.
Therefore, in recent years,
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the research area pertaining to the directing groupꢀaided sp C–H activation/functionalization of
10ꢀ16
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aliphatic/alicyclic carboxamides remains active.
Although sp C–H activation/functionalization
was investigated using a variety of aliphatic/alicyclic substrates, it is important to note that
cyclopropane, which is the smallest carbocyclic ring, was also successfully subjected to the Pd(II)ꢀ
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catalyzed C–H activation/functionalization. In this regard, our group recently reported the
diastereoselective Pd(II)ꢀcatalyzed, bidentate ligandꢀdirected βꢀCꢀH arylation of
cyclopropanecarboxamide derivatives.
Inspired by the transition metalꢀcatalyzed ring opening of cyclopropanes including the Cꢀ
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6g
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a,3,5ꢀ9
16g
H/CꢀC bond activation strategy
as well as our previous work, we envisioned a oneꢀpot
method involving Pd(II)ꢀcatalyzed, bidentate directing groupꢀaided βꢀCꢀH arylation followed by
ring opening of cyclopropanecarboxamide derivatives. Accordingly, the reaction of unsubstituted
cyclopropanecarboxamide 1 with excess amounts of aryl iodide 2 in the presence of Pd(OAc) as a
2
catalyst, AgOAc and AcOH as the additive afforded the openꢀchain carboxamide derivatives 5/6
with a high degree of stereocontrol (Scheme 1). Herein, the results from our investigations
including a plausible mechanism for the formation of the openꢀchain carboxamide derivatives 5/6
from the Pd(II)ꢀcatalyzed CꢀH arylation followed by ring opening of cyclopropanecarboxamides 1
are reported.
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Scheme 1. Diastereoselective Pd(II)ꢀCatalyzed CꢀH Arylation Followed by Ring Opening of
Cyclopropanecarboxamides 1.
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RESULTS AND DISCUSSION
To initially explore the Pd(II)ꢀcatalyzed CꢀH arylation followed by ring opening of
cyclopropanecarboxamides, we performed optimization reactions using unsubstituted
cyclopropanecarboxamide 1a, which was prepared from the 2ꢀaminothioanisole bidentate ligand.
Table 1 shows the results for the Pd(OAc)
2
–catalyzed reaction of 1a with excess amounts of pꢀ
tolyl iodide in the presence of various additives. Upon treatment of cyclopropanecarboxamide 1a
with excess amounts of pꢀtolyl iodide in the presence of the Pd(OAc) catalyst and AgOAc, we
2
expected that compound 1a would undergo mono/bis CꢀH arylation followed by ring opening to
afford the corresponding openꢀchain carboxamide derivatives. Accordingly, the reaction of 1a
(0.25 mmol) with excess amounts of pꢀtolyl iodide (0.38ꢀ2.0 mmol) in the presence of the
Pd(OAc) catalyst and AgOAc afforded bisꢀarylated cyclopropanecarboxamide 3a (yields up to
2
37%) and monoꢀarylated cyclopropanecarboxamide 4a (yields up to 40%) along with anticipated
ringꢀopened product 5a (yields up to 20%, entries 1ꢀ7, Table 1).
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Table 1. Optimization Reactions. Pd(II)ꢀCatalyzed CꢀH Arylation/Ring Opening of
Cyclopropanecarboxamide 1a.
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To obtain ringꢀopened product 5a as the major compound in satisfactory yield, we
performed the Pd(II)ꢀcatalyzed reaction of 1a with 2a in the presence of additional additives (e.g.,
Na
a and 5a) without much selectivity (entries 8ꢀ12, Table 1). Next, we performed the Pd(II)ꢀ
catalyzed reaction of 1a with 2a in the presence of PivOH or TfOH, which was also ineffective
2 4
SO , NaOAc and KOAc). These reactions also afforded the corresponding three products (3a,
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(
entries 13 and 14, Table 1). Fortunately, the Pd(OAc) /AgOAc catalytic systemꢀbased reaction of
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1a with excess amounts of aryl iodide 2a in the presence of AcOH directly afforded multiple βꢀCꢀ
17a,b
H arylated openꢀchain carboxamide (anti βꢀacyloxy amide ) 5a in 47ꢀ86% yields (entries 15ꢀ19,
Table 1). It is important to note that this process, which consists of the Pd(OAc) /AgOAcꢀcatalytic
systemꢀbased reaction of 1a with excess amounts of aryl iodide 2a in the presence of AcOH, has
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led to the construction of anti βꢀacyloxy amide 5a, possessing vicinal stereocenters with a high
degree of stereocontrol with the formation of a new CꢀO bond and three new CꢀC bonds.
After determining the suitable reaction conditions for obtaining multiple βꢀCꢀH arylated
openꢀchain carboxamide 5a from 1a, we investigated the generality of this protocol and performed
the diastereoselective CꢀH arylation followed by ring opening of substrate 1a using various aryl
iodides (Table 2). Using the optimized reaction conditions (entry 19, Table 1), we performed the
2
Pd(OAc) /AgOAc catalytic systemꢀbased diastereoselective CꢀH arylation followed by ring
opening of substrate 1a with different aryl iodides, which furnished the corresponding multiple βꢀ
CꢀH arylated openꢀchain carboxamides (anti βꢀacyloxy amides) 5aꢀl in 10ꢀ86% yields (Table 2).
We observed that the CꢀH arylation followed by ring opening of substrate 1a proceeded smoothly
and afforded products 5aꢀh and 5l when the Pd(II)ꢀcatalyzed reaction of substrate 1a was
i
performed with aryl iodides that possessed electronꢀdonating alkyl groups (e.g., Me, Et and Pr) at
the para or meta position of the aryl ring in the aryl iodides. However, we experienced some
difficulty when the Pd(II)ꢀcatalyzed CꢀH arylation reaction of substrate 1a was performed with
aryl iodides that possessed electronꢀwithdrawing groups (i.e., Br, F and NO ) at the para or meta
2
position of the aryl ring in the aryl iodides. Therefore, the Pd(OAc) /AgOAc catalytic systemꢀ
2
based reaction of substrate 1a with aryl iodides possessing electronꢀwithdrawing groups afforded
corresponding products 5iꢀk in low yields. Although a clear reason is not known at this stage, we
assume that the aryl iodides that possess electronꢀwithdrawing groups may be less reactive than
aryl iodides containing alkyl groups under our experimental conditions.
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Table 2.
Pd(II)ꢀCatalyzed CꢀH Arylation Followed by Ring Opening of
Cyclopropanecarboxamide 1a.
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Next, we investigated diastereoselective CꢀH arylation followed by ring opening of
cyclopropanecarboxamide using cyclopropanecarboxamide 1b, which was assembled from 8ꢀ
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aminoquinoline bidentate ligand (Table 3). The Pd(OAc) /AgOAc catalytic systemꢀbased
diastereoselective CꢀH arylation followed by ring opening of cyclopropanecarboxamide 1b with
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different aryl iodides in AcOH afforded the corresponding multiple βꢀCꢀH arylated openꢀchain
carboxamides 6aꢀe (anti βꢀacyloxy amides possessing vicinal stereocenters) in 20ꢀ75% yields
(Table 3). In these studies, we have revealed the concept of Pd(II)ꢀcatalyzed CꢀH arylation
followed by ring opening of cyclopropanecarboxamides using unsubstituted
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cyclopropanecarboxamides 1a and 1b as the substrates. Next, we examined the Pd(II)ꢀcatalyzed Cꢀ
H arylation followed by ring opening of cyclopropanecarboxamides using various monoꢀarylated
cyclopropanecarboxamides 4a/8/9/13/14/15b (cis isomers) and 15a (trans isomer) as the substrates
(Scheme 2).
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Table 3.
Pd(II)ꢀCatalyzed CꢀH Arylation Followed by Ring Opening of
Cyclopropanecarboxamide 1b.
The Pd(II)ꢀcatalyzed CꢀH arylation followed by ring opening of cis
cyclopropanecarboxamides 8 and 9 with aryl iodides 2c/2b furnished the corresponding multiple
βꢀCꢀH arylated openꢀchain carboxamides 5c (61%) and 5b (39%, Scheme 2). It is important to
note that the substituents present at the para positions of the respective aryl iodides (2c/2b) and the
substituents present at the para positions of the aryl rings of the respective substrates (8/9) were
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identical. Therefore, the Pd(II)ꢀcatalyzed CꢀH arylation followed by ring opening of 8/9 with 2c/2b
furnished corresponding products 5c and 5b, in which the corresponding aryl rings had identical
substituents at the para positions. Similar to the reactions involving substrates 8 and 9, the Pd(II)ꢀ
catalyzed CꢀH arylation followed by ring opening of the cis cyclopropanecarboxamides 13 and 14
with para-substituted aryl iodides 2a and 2b afforded the corresponding multiple βꢀCꢀH arylated
openꢀchain carboxamides 6d (51%) and 6a (57%, Scheme 2). Additionally, the Pd(II)ꢀcatalyzed Cꢀ
H arylation followed by ring opening of the trans cyclopropanecarboxamide 15a with iodobenzene
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also furnished multiple βꢀCꢀH arylated openꢀchain carboxamides 5b in 30% yield (Scheme 2).
1
8
Scheme 2.
Pd(II)ꢀCatalyzed CꢀH Arylation Followed by Ring Opening of
a
Cyclopropanecarboxamides 4a, 8, 9, 13, 14 and 15a,b.
a
The reactions were performed using the corresponding carboxamide (0.25 mmol) and ArI (1.2
b
mmol). This reaction was performed using carboxamide 15b (0.25 mmol) and ArI (2 mmol).
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The Pd(II)ꢀcatalyzed CꢀH arylation followed by ring opening of cis
cyclopropanecarboxamides 4a and 8 with the corresponding aryl iodides 2aꢀc and 2l furnished the
respective multiple βꢀCꢀH arylated openꢀchain carboxamides 10,11 (43ꢀ60%) and 12aꢀc (52ꢀ63%,
1
8
Scheme 2). It is important to note that the substituents present at the para/meta positions of the
respective aryl iodides 2aꢀc and 2l and the substituents present at the para positions of the aryl
rings of the respective substrates 4a and 8 were not identical. Therefore, the Pd(II)ꢀcatalyzed CꢀH
arylation followed by ring opening of 4a and 8 with 2aꢀc and 2l furnished corresponding products
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10,11 and 12aꢀc, in which the corresponding aryl rings did not contain identical substituents at the
18
para positions. Along this line, the Pd(II)ꢀcatalyzed CꢀH arylation followed by ring opening of
cis cyclopropanecarboxamide 15b with 2a furnished the respective multiple βꢀCꢀH arylated openꢀ
chain carboxamide 12d in 26% yield (Scheme 2). The structure and stereochemistry of compound
12d were unambiguously established based on Xꢀray structure analysis (see SI for the Xꢀray
structure of the compound 12d).
We also performed synthetic transformations to remove the directing groups from the
representative multiple βꢀCꢀH arylated openꢀchain carboxamides that were obtained from the
Pd(II)ꢀcatalyzed CꢀH arylation followed by ring opening of cyclopropanecarboxamide. Initially,
we attempted the amide hydrolysis reaction of anti βꢀacyloxy amide 6d with 12 equiv of NaOH in
EtOH, and this reaction afforded carboxamide 16a, which contain the directing group, and
carboxylic acid 17a (formed from carboxamide 16a, Scheme 3). Similarly, the amide hydrolysis
reaction of anti βꢀacyloxy amide 5l with 12 equiv of NaOH in EtOH afforded carboxamide 16b
and carboxylic acid 17b (formed from carboxamide 16b, Scheme 3). Then, the treatment of anti βꢀ
acyloxy amide 5a with less NaOH (6 equiv) in EtOH only furnished carboxamide 16c, and in this
case, the corresponding carboxylic acid was not detected. In addition, we reacted carboxamides 10,
11 and 12b,c possessing different aryl groups at the 1,3ꢀpositions with less NaOH (6 equiv) to
afford corresponding carboxamides 16b,d,e (Scheme 3).
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2
3
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 3. Representative Synthetic Transformations.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Next, the amide hydrolysis reaction was investigated under mild reaction conditions. We
performed the amide hydrolysis of anti βꢀacyloxy amide 5a in the presence of K CO in MeOH,
and this reaction afforded βꢀhydroxy amide 18a and carboxamide 16c. In addition, the reaction
of anti βꢀacyloxy amide 5a in the presence of LiAlH afforded carboxamide 16c. We also
attempted the amide hydrolysis and removal of the directing groups (i.e., 8ꢀaminoquinoline and 2ꢀ
2
3
1
7c
4
(methylthio)aniline) under acidic conditions. However, these trials were not fruitful at this stage
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7
8
9
(see the SI for further trials in this regard). In the baseꢀmediated amide hydrolysis reactions of the
substrates investigated in Scheme 3, we expected the removal of the directing groups (i.e., 8ꢀ
aminoquinoline and 2ꢀ(methylthio)aniline) as well as the deprotection of the OAc group present in
the corresponding substrates. However, because the products (5/6/10ꢀ12) obtained from the Pd(II)ꢀ
catalyzed CꢀH arylation followed by ring opening of cyclopropanecarboxamides were aldolꢀtype
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
17b,c
derivatives, these compounds readily underwent retroꢀaldol type reactions
even under mild or
strongly basic conditions and furnished corresponding products 16 under the experimental
17e
conditions.
Because the Pdꢀcatalyzed reaction of cyclopropanecarboxamides with aryl iodides in
AcOH affords the corresponding openꢀchain carboxamides 5/6/10ꢀ12, control experiments were
performed to determine a plausible mechanism for the formation of products 5/6/10ꢀ12 from their
corresponding cyclopropanecarboxamide substrates shown in Tables 1ꢀ3 and Scheme 2. Initially,
we attempted the Pd(II)ꢀcatalyzed CꢀH arylation followed by ring opening of
cyclopropanecarboxamides 1d and 1e, which contain no directing groups, and
cyclopropanecarboxamides 1f and 1g, which were prepared using other bidentate ligands. The
Pd(II)ꢀcatalyzed CꢀH arylation followed by ring opening of substrates 1dꢀg failed to yield the
corresponding βꢀacyloxy amides (Scheme 4). These reactions revealed that 8ꢀaminoquinoline and
2ꢀ(methylthio)aniline were efficient bidentate ligands and essential for accomplishing the Pd(II)ꢀ
catalyzed CꢀH arylation followed by ring opening of the respective cyclopropanecarboxamides
shown in Tables 1ꢀ3 and Scheme 2.
Then, we performed control experiments to understand at what stage the CꢀC cleavage of
the corresponding cyclopropanecarboxamides occurs and how the openꢀchain carboxamides
5
/6/10ꢀ12 are formed with a high degree of stereocontrol. Initially, we performed the control
experiments using unsubstituted cyclopropanecarboxamide 1a. The reaction of 1a with only the
Pd(OAc)
2
catalyst, AgOAc and AcOH did not yield βꢀacyloxy amide 20 (i.e., the expected openꢀ
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
chain compound, entry 1, Scheme 4). The treatment of 1a with only AgOAc and AcOH did not
yield compound 20 (entry 2, Scheme 4). In addition, the reaction of 1a with only AcOH did not
yield expected compound 20 (entry 3, Scheme 4, see the SI for the crude NMR spectra of the
reactions of compound 1a).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. Screening of Other Ligands and Control Experiments Performed using Substrate
a
1a.
a
See the SI for the crude NMR spectra of the reactions of compound 1a.
Next, we performed control experiments using bisꢀarylated cyclopropanecarboxamide 3b.
We assembled compound 3b, which was subjected to a Pd(II)ꢀcatalyzed CꢀH arylation reaction
with iodobenzene in the presence of AcOH (Scheme 5). This reaction resulted in the formation of
product 5b, which was directly obtained from 1a (entry 19, Table 2). The reaction of 3b with only
the Pd(OAc) catalyst, AgOAc and AcOH afforded expected openꢀchain compound 21, which was
2
isolated in 25% yield and characterized (entry 1, Scheme 5). The treatment of 3b with only
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9
AgOAc and AcOH did not yield compound 21 (entry 2, Scheme 5). Similarly, the reaction of 3b
with only AgOAc or AcOH also did not yield compound 21 (entries 3 and 4, Scheme 5). Next, we
performed a control experiment involving the CꢀH arylation reaction of 21 with PhI in the presence
of the Pd(OAc) catalyst and AgOAc, which resulted in the formation of 5b (Scheme 5, see the SI
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
for the crude NMR spectra for the reactions of compounds 3b and 21).
Scheme 5. Control Experiments Performed using Substrates 3b and 21 to Elucidate the
a
Proposed Mechanism.
a
b
See the SI for the crude NMR spectra of the reactions of compounds 3b and 21. 0.17 mmol of
c
3
b and 0.2 mL of AcOH were used. 0.08 mmol of 3b, 0.1 mL of AcOH and 2 mL of toluene
d
e
were used. 0.04 mmol of 3b were used. 0.125 mmol of 3b and 1 mL of AcOH were used.
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 6. Control Experiments Performed using Substrates 9, 13, 14 and 22 to Elucidate the
a
Proposed Mechanism.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
b
See the SI for the crude NMR spectra of the reactions of compounds 4a, 9, 13, 14 and 22. The
c
reaction time was 48 h. This reaction was performed using 4a (0.125 mmol) rather than 9 and 1
mL of AcOH.
Although
we
performed
the
control
reactions
using
unsubstituted
cyclopropanecarboxamide 1a and bisꢀarylated cyclopropanecarboxamide 3b, based on the results
shown in Scheme 2, we envisioned that the ring opening can also occur after the monoꢀarylation of
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8
9
1a (or before the bisꢀarylation of 1a). To validate this hypothesis, control experiments were
performed using monoꢀarylated cyclopropanecarboxamides 9 and 14 (Scheme 6). The reaction of
2
substrates 9 and 14 with only the Pd(OAc) catalyst, AgOAc and AcOH yielded the corresponding
openꢀchain compounds (i.e., 22 (33%) and 23a (43%)), which were isolated and characterized
(entries 1 and 2, Scheme 6). Then, a control experiment involving the CꢀH arylation reaction of 22
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
with PhI in the presence of the Pd(OAc) catalyst and AgOAc resulted in the formation of 5b,
which was obtained directly from 1a (entry 19, Table 2). Then, additional control experiments
were performed using substrates 9/14 by varying the control reagents (entries 3ꢀ7, Scheme 6).
However, none of these reactions afforded the corresponding compounds 22 and 23a. A control
experiment involving the reaction of 14 with only the Pd(OAc) catalyst and AcOH afforded openꢀ
2
chain compound 23a (entry 8, Scheme 6). In addition, the reaction of 13 with only the Pd(OAc)
catalyst and AcOH afforded openꢀchain compound 23b (Scheme 6). Then, the CꢀH arylation
reaction of 23b with 2c in the presence of the Pd(OAc) catalyst and AgOAc afforded compound
2
2
12e (47%, Scheme 6). It is important to note that the substituent present at the para position of 2c
and the substituent present at the para position of the aryl ring of 23b were not the same.
The formation of compounds 22/23a from the reactions of respective substrates 9/14 with
only the Pd(OAc)
cyclopropanecarboxamides 9/14 and ringꢀopened carboxamides 22/23a were possible
intermediates in the reaction of 1a/1b with PhI in the presence of the Pd(OAc) catalyst, AgOAc
2
catalyst, AgOAc and AcOH indicated that monoꢀarylated
2
2
and AcOH. This hypothesis was further validated from the Pd(OAc) ꢀcatalyzed double CꢀH
arylation reaction of the methyl group of 22 with PhI, which yielded compound 5b (see the SI for
the crude NMR spectra for the reactions of compounds 4a, 9, 13, 14, 22 and 23b).Based on the
results from the control reactions (Schemes 4ꢀ6) as well as observed products 5/6/10ꢀ12 (anti βꢀ
acyloxy amides), we propose a plausible mechanism for the diastereoselective Pd(II)ꢀcatalyzed Cꢀ
H arylation followed by ring opening of cyclopropanecarboxamides in Scheme 7. The mechanism
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
9
is proposed on the basis of the generally accepted Pd(II/IV) catalytic cycle mechanism involving
bidentate ligandꢀaided CꢀH arylation. Based on the control experiments (Schemes 4ꢀ6), we have
elucidated a possible mechanism for the formation of anti βꢀacyloxy amide 5b from the Pd(II)ꢀ
catalyzed reaction of 1a with PhI in the presence of AgOAc and AcOH. The CꢀC cleavage of the
cyclopropane ring is predicted to only occur after the formation of monoꢀarylation product 9 as
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
well as bisꢀarylation product 3b. For the CꢀC bond cleavage process, both the Pd(OAc)
and AcOH are essential. However, AgOAc is not essential for the CꢀC bond cleavage process, and
AgOAc simply helps to regenerate the Pd(OAc) catalyst in the CꢀH arylation process involved in
2
catalyst
2
1
9
the Pd(II/IV) catalytic cycle mechanism.
Under the current experimental conditions, compound 3b or 9 is also expected to be present
as 24a. Then, due to the ring strain, the mono or bis CꢀH arylated cyclopropanecarboxamide
system 24a undergoes CꢀC cleavage through (a) a S
N
2 type internal attack by the OAc group of the
15a
Pd(II) species 24a or (b) an AcOHꢀinfluenced Pdꢀbased CꢀC activation/CꢀC bond cleavage
involving a S 2 type attack by the OAc group of AcOH (as shown in species 24b). Both of these
N
possibilities could form any one of the plausible intermediates 24c/24d/24e with a high degree of
stereocontrol. It is important to note that the stereochemistry of the OAc and CONH groups were
determined to be anti in the Xꢀray structures (e.g., 5b, 6c and 6d). Notably, the CꢀH arylation of
16g,19
cyclopropanecarboxamides has been reported to be a stereoselective process,
and in the
current study, the ring opening of the cyclopropanecarboxamides was determined to be a
stereoselective process.
The formation of compounds 21 (entry 1, Scheme 5) and 22 (entry 1, Scheme 6) from 3b or
9
confirmed the involvement of the plausible ringꢀopened intermediates 24c/24d/24e in the
proposed mechanism. If intermediates 24cꢀe were not quenched by AcOH, a further CꢀH arylation
1
9,20
of intermediates 24c/24d/24e (R = H/Ph) affords product 5b.
However, starting from 9 (R =
H), if compound 22 was formed after the ring opening and before any further CꢀH arylation due to
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9
the AcOHꢀmediated quenching of 24c/24d/24e (when R = H), the double CꢀH arylation of the
methyl group of 22 would afford compound 5b (based on the control reaction shown in Scheme 6).
Similarly, starting from 3b (R = Ph), if compound 21 was formed after the ring opening and before
any further CꢀH arylation due to the AcOHꢀmediated quenching of 24c/24d/24e (when R = Ph),
the CꢀH arylation of the methylene group of 21 would afford compound 5b (based on the control
reaction shown in Scheme 5). Moreover, the second arylation of 9 may be a slow reaction due to
the formation of the corresponding sterically crowded trisubstituted cyclopropanecarboxamide 3b.
Therefore, the ring opening of 9 may occur before the CꢀH arylation to afford 5b via 24aꢀe (based
on the control reaction shown in Scheme 6). Furthermore, starting from 1a, product 5b may have
been directly formed from 9 rather than 3b.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Finally, based on these discussions and the formation of ringꢀopened carboxamide 23b
from the reaction of 13 with only the Pd(OAc)
2
catalyst, AgOAc and AcOH (Scheme 6) as well as
ꢀcatalyzed double CꢀH arylation of the methyl
the subsequent formation of 12e from the Pd(OAc)
2
group of 23b with 2c indicated the following conclusions. First, the proposed structures of
compounds 10, 11, 12aꢀd (Scheme 2) have been confirmed. Second, the arylation of 8/4a/15b with
the respective aryl iodides 2aꢀc,l may involve the corresponding ringꢀopened product similar to
23b as the potential predominantly formed intermediates. In addition, because the second arylation
of 8/4a/15b may be a slow reaction due to the formation of the corresponding sterically crowded
trisubstituted cyclopropanecarboxamide (e.g., compound type 3b), we believe that the ring opening
of 8/4a/15b may occur prior to the CꢀH arylation of 8/4a/15b. Therefore, although the respective
reactions of 8/4a/15b with 2aꢀc and 2l are expected to afford more than one isomer, the respective
arylation reactions of 8/4a/15b with 2aꢀc and 2l yielded the respective compounds 10ꢀ12 (Scheme
2) as the predominant compounds.
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
9
Scheme 7. Plausible Mechanism for the Diastereoselective Pd(II)ꢀCatalyzed CꢀH Arylation
Followed by Ring Opening of Cyclopropanecarboxamides.
SMe
NH
SMe
NH
Ar
I
Pd(OAc)2
AgOAc
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
Ar
1a
O
Ar
O
e.g.; Ar = Ph
Ar
9
3b
for C-H arylation mechanism
see refs. 15, 16f,g, 19
Ar
I
Me
S
Ar1
NH
O
c
R
Ar
a
b
AcO
SMe
5
2
b; R = Ar
1; R = H
NH
a
1
e.g.; Ar/Ar = Ph
b Ar
c
Me
O
OAc
Ar1
L
S
N
O
II
Pd
AcOH
R
3b; R = Ar
9; R = H
R
2
4g
Ar
II
Pd(OAc)
2
AcO
AgI
AgOAc
Me
Ar1
Me
S
II
Me
HOAc
S
L
L
IV
Pd
R
Pd
O
O
N
N
I
Ar
2
4f
24a
O
Ar
O
AcO
2
4a
Ar1
R
HOAc
I
2
4d
Me
S
L
S 2
N
Me
II
R
Pd
S
II
Pd
L
OH
N
O
HOAc
II OAc
Ar
N
Me
S
24d
O
R
AcO
24b
O
Pd
(OR)
H
H
Ar
N
O
L
R
O
S 2
O
2
4c/24d/24e
N
Ar
2
4e
Me
Me
AcO
OAc
S
II
Pd
AcOH
R
L
N
Ar
21; R = Ar
22; R = H
2
4c
O
AcO
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CONCLUSION
Our studies have demonstrated Pd(OAc)
3
2
ꢀcatalyzed, bidentate ligandꢀdirected sp CꢀH
activation/arylation followed by ring opening of cyclopropanecarboxamides. The treatment of
various cyclopropanecarboxamides with excess amounts of aryl iodides in the presence of the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Pd(OAc) catalyst, AgOAc and AcOH directly afforded the corresponding multiple βꢀCꢀH arylated
2
openꢀchain carboxamides (anti βꢀacyloxy amides). This method has led to the construction of
several anti βꢀacyloxy amides that possess vicinal stereocenters with a high degree of stereocontrol
with the formation of a new CꢀO bond and three new CꢀC bonds. Based on various control
experiments, a plausible mechanism has been proposed for the formation of multiple βꢀCꢀH
arylated openꢀchain carboxamides from the diastereoselective Pdꢀcatalyzed, bidentate ligandꢀ
directed βꢀCꢀH arylation and ring opening of cyclopropanecarboxamides. The observed
diastereoselectivity and anti stereochemistry of the obtained products were confirmed by Xꢀray
structure analysis of representative βꢀacyloxy amides.
EXPERIMENTAL SECTION
General. The melting points of the compounds were uncorrected, and the IR spectra of the
1
13
1
products were recorded as thin films or KBr pellets. The H and C{ H} NMR spectra of all of the
compounds were recorded on 400 MHz and 100 MHz spectrometers, respectively, using TMS as
an internal standard. The HRMS measurements of the samples were obtained from QTOF mass
analyzer using the electrospray ionization (ESI) method. Column chromatography was performed
using neutral alumina (in some cases, silica gel 100ꢀ200 mesh was used). The
cyclopropanecarboxamides that were employed in the Pd(II)ꢀcatalyzed CꢀH arylation reactions
were prepared from their corresponding acid chlorides and amines using standard literature
procedures. The reactions were performed in anhydrous solvents, which were prepared using
standard procedures, under a nitrogen atmosphere. The isolated yields of all of the compounds are
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2
2
2
2
2
2
2
3
3
3
3
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3
3
3
3
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4
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reported, and the yields were not optimized. In most cases, the purification of the crude reaction
mixtures yielded only the major diastereomer in pure form and did not afford any other
16g
16g
21a
15c
16g
16g
16g
16g
characterizable compounds. Compounds 1a, 1b, 1d, 1g, 3b, 15a/15b, 13, 14,
19b
21b
1
6d, and 17a have been previously reported in the literature.
0
1
2
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8
9
0
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2
3
4
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6
7
8
9
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2
3
4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General procedure for the preparation of 1a,b/1dꢀg/15a: To a dry round bottom (RB) flask, an
appropriate ligand/amine (1 mmol), triethyl amine (1.1 mmol) and DCM (6 mL) were added under
a nitrogen atmosphere. To this solution, the corresponding acid chloride (1 mmol) was added
dropwise at 0 °C. The resulting mixture was stirred at room temperature for 20 h. After the
reaction period, the mixture was diluted with DCM (2 x 10 mL) and transferred to a separatory
funnel, and the DCM solution was washed with water followed by an aq. NaHCO solution (2ꢀ5
3
mL). The organic layer was separated, dried over anhydrous Na
vacuum, and purification of the crude reaction mixture by column chromatography
EtOAc/hexane) furnished products 1a,b/1dꢀg/15a.
2 4
SO and concentrated under
(
General procedure for the Pd(II)ꢀcatalyzed CꢀH arylation/ring opening of 1a/1b and the
preparation of 5aꢀl/6aꢀe: To an oven dried RB flask, an appropriate cyclopropanecarboxamide
(
0.25 mmol, 1 equiv), the corresponding aryl iodide (2 mmol, 8 equiv), Pd(OAc)
mol%, 0.1 equiv), AgOAc (125 mg, 0.75 mmol, 3 equiv), AcOH (0.25 mL) and anhydrous toluene
2ꢀ3 mL) were added, and the reaction mixture was refluxed at 110 °C for 16ꢀ36 h under a nitrogen
2
(5.6 mg, 10
(
atmosphere. After the reaction period, the reaction mixture was diluted with EtOAc (15ꢀ20 mL),
transferred to a separatory funnel and washed with a dilute aq. NaHCO solution (2ꢀ5 mL). The
3
2 4
organic layer was separated, dried over Na SO and concentrated under vacuum, and purification
of the reaction crude mixture by column chromatography on neutral alumina furnished the
corresponding multiple CꢀH arylated aliphatic carboxamides 5aꢀl/6aꢀe (βꢀacyloxy amide
derivatives) (see the corresponding Tables/Schemes for specific examples).
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General procedure for the Pd(II)ꢀcatalyzed mono CꢀH arylation of 1a/1b and the preparation
1
6g
of 4a/8/9/13/14/15b: To an oven dried RB flask, an appropriate cyclopropanecarboxamide (1.0
mmol, 1 equiv), the corresponding aryl iodide (4 mmol, 4 equiv), Pd(OAc) (11.2 mg, 5 mol%,
.05 equiv), AgOAc (367 mg, 2.2 mmol, 2.2 equiv) and anhydrous toluene (6ꢀ8 mL) were added,
2
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
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47
48
49
50
51
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53
54
55
56
57
58
59
60
and the reaction mixture was refluxed at 110 °C for 15 h under a nitrogen atmosphere. After the
reaction period, the reaction mixture was concentrated under vacuum, and purification of the
resulting reaction mixture by column chromatography on neutral alumina furnished the
corresponding carboxamides 4a/8/9/13/14/15b.
General procedure for the Pd(II)ꢀcatalyzed bis CꢀH arylation of 1a and the preparation of
1
6g
3b: To an oven dried RB flask, cyclopropanecarboxamide 1a (1.0 mmol, 1 equiv), iodobenzene
10 mmol, 10 equiv), Pd(OAc) (22.4 mg, 10 mol%, 0.1 equiv), AgOAc (367 mg, 2.2 mmol, 2.2
equiv) and anhydrous toluene (6ꢀ8 mL) were added, and the reaction mixture was refluxed at 120
C for 20 h under a nitrogen atmosphere. After the reaction period, the reaction mixture was
(
2
°
concentrated under vacuum, and purification of the resulting reaction mixture by column
chromatography on neutral alumina furnished the corresponding carboxamide 3b (careful
repetitive purification was performed to obtain the pure compound 3b).
General procedure for the Pd(II)ꢀcatalyzed CꢀH arylation/ringꢀopening of 4a/8/9/13ꢀ15 and
the preparation of 5c,b/6a,d/10/11/12aꢀd: To an oven dried RB flask, an appropriate
cyclopropanecarboxamide (0.25 mmol, 1 equiv), the corresponding aryl iodide (1.5 mmol, 6
equiv), Pd(OAc) (5.6 mg, 10 mol%, 0.1 equiv), AgOAc (92 mg, 0.55 mmol, 2.2 equiv), AcOH
2
(0.25 mL) and anhydrous toluene (2ꢀ3 mL) were added, and the reaction mixture was refluxed at
110 °C for 24ꢀ48 h under a nitrogen atmosphere. After the reaction period, the reaction mixture
was diluted with EtOAc (15ꢀ20 mL), transferred to a separatory funnel and washed with a dilute
aq. NaHCO solution (2ꢀ5 mL). The organic layer was separated, dried over Na SO and
3
2
4
concentrated under vacuum, and purification of the reaction crude mixture by column
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2
2
2
2
2
2
2
3
3
3
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3
3
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4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
chromatography on neutral alumina furnished the corresponding multiple CꢀH arylated aliphatic
carboxamides 5c,b/6a,d/10/11/12aꢀd (βꢀacyloxy amide derivatives).
2 3
General procedure for the K CO –mediated hydrolysis carboxamide 5a and the preparation
of 18a/16c: To a RB flask (with a capacity of 25 mL) fitted with a condenser, a solution of
carboxamide 5a (0.25 mmol) dissolved in a mixture of methanol (2.5 mL), water (0.5 mL) and
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
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7
8
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5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2 3
K CO (69 mg, 2 equiv) were sequentially added. The reaction mixture was heated at 80 °C for 12
h in an open atmosphere. Then, the reaction mixture was transferred to a separatory funnel with the
aid of a syringe. The reaction mixture was diluted with ethyl acetate and washed with a dilute aq.
Na CO solution (5ꢀ10 mL). The combined organic layers were separated and concentrated under
2
3
vacuum, and purification of the reaction mixture on neutral alumina furnished products 18a/16c.
General procedure for the LiAlH –mediated reduction of carboxamide 5a and the
preparation of 16c: To a dry RB flask containing carboxamide 5a (0.125 mmol, 1 equiv) in THF
3 mL), LiAlH (10 mg, 0.25 mmol, 2 equiv) was added at 0 °C. Then, the reaction mixture was
4
(
4
warmed to room temperature and stirred for a total period of 15 h. After this period, the THF was
evaporated, and the reaction mixture was diluted with EtOAc and water. Then, the reaction
mixture was transferred to a separatory funnel, and the layers were separated. The organic layer
was concentrated under vacuum, and purification of the reaction mixture on neutral alumina
furnished products 16c.
General procedure for the NaOH–mediated hydrolysis of carboxamides 5a,l/6d/10/11/12b,c:
To a RB flask (with a capacity of 25 mL) fitted with a condenser, a solution of an appropriate
carboxamide (0.25 mmol) dissolved in ethanol (3 mL) and NaOH (6 or 12 equiv) were
sequentially added. The reaction mixture was heated at 80 °C for 12 h in an open atmosphere.
Then, EtOH was removed under vacuum, and the reaction mixture was diluted with ethyl acetate
(10ꢀ15 mL) and washed with aq. 1 N NaOH (5 mL x 2). The organic layer was concentrated under
vacuum, and purification of the reaction mixture on a neutral alumina column furnished the
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corresponding products 16aꢀe. Then, the combined aqueous layers were acidified with 1 N HCl
(
15 mL x 2) to achieve a pH of ~2. The aqueous layers were extracted using ethyl acetate (10 mL x
), and the combined organic layers were dried over anhydrous Na SO and evaporation under
vacuum to afford the corresponding carboxylic acids 17a,b.
2
2
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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34
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38
39
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43
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45
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57
58
59
60
1
6g
Nꢀ(2ꢀ(Methylthio)phenyl)cyclopropanecarboxamide (1a): Following the general procedure,
a was obtained after purification by column chromatography on neutral alumina (EtOAc:Hexanes
5:95) as a colourless solid; mp 69ꢀ71 °C; Yield: 45% (93 mg); IR (KBr): 3264, 3005, 2916,
1
=
ꢀ
1 1
1
651, 1578 cm ; H NMR (400 MHz, CDCl
3
): δ 8.53 (br. s,1H), 8.27 (d, 1H, J = 6.0 Hz), 7.44 (d,
1
H, J = 7.7 Hz), 7.26ꢀ7.21 (m, 1H), 7.03 (t, 1H, J = 7.4 Hz), 2.36 (s, 3H), 1.63ꢀ1.58 (m, 1H), 1.10ꢀ
13
1
1.06 (m, 2H), 0.87ꢀ0.82 (m, 2H); C{ H} NMR (100 MHz, CDCl ): δ 172.0, 138.5, 132.7, 128.7,
3
+
1
25.2, 125.2, 124.2, 120.8, 18.9, 16.0, 8.2; HRMS (ESI): m/z [M + H] calcd for C11
H
14NOS:
208.0796; found 208.0793.
16g
Nꢀ(Quinolinꢀ8ꢀyl)cyclopropanecarboxamide (1b): Following the general procedure, 1b was
obtained after purification by column chromatography on neutral alumina (EtOAc:Hexanes =
15:85) as a colourless solid; mp 81ꢀ83 °C; Yield: 83% (176 mg); IR (KBr): 3242, 3351, 1676,
ꢀ
1 1
1
525, 1487 cm ; H NMR (400 MHz, CDCl
.6 Hz), 8.76 (dd, 1H, J = 7.3 Hz, J = 1.6 Hz), 8.18 (dd, 1H, J
= 8.2 Hz, J = 4.2 Hz), 1.87ꢀ1.81 (m, 1H), 1.20ꢀ1.16 (m, 2H), 0.96ꢀ0.91
3
): δ 10.05 (br. s,1H), 8.83 (dd, 1H, J
1 2
= 4.2 Hz, J =
1
1
2
1
= 8.2 Hz, J = 1.6 Hz), 7.56ꢀ7.49
2
(m, 2H), 7.48 (dd, 1H, J
1
2
13
1
(
m, 2H); C{ H} NMR (100 MHz, CDCl ): δ 172.3, 148.1, 138.2, 136.4, 134.7, 128.0, 127.5,
3
+
121.6, 121.2, 116.4, 16.3, 8.2; HRMS (ESI): m/z [M + H] calcd for C13
H
13
N
2
O: 213.1028; found
2
13.1035.
16g
(
1S*,2S*)ꢀNꢀ(2ꢀ(Methylthio)phenyl)ꢀ2ꢀphenylcyclopropanecarboxamide (15a):
Following
the general procedure, 15a (trans isomer) was obtained after purification by column
chromatography on neutral alumina (EtOAc:Hexanes = 10:90) as a colourless solid; mp 119ꢀ121
ꢀ1 1
°C; Yield: 78% (220 mg); IR (KBr): 3434, 3242, 3098, 1649, 1593 cm ; H NMR (400 MHz,
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CDCl
3
): δ 8.61 (br. s, 1H), 8.41 (d, 1H, J = 7.8 Hz), 7.51 (d, 1H, J = 7.6 Hz), 7.36ꢀ7.24 (m, 4H),
7
1
1
.19 (d, 2H, J = 7.3 Hz), 7.10 (t, 1H, J = 7.3 Hz), 2.69ꢀ2.64 (m, 1H), 2.41 (s, 3H), 1.90ꢀ1.86 (m,
13
1
3
H), 1.80ꢀ1.76 (m, 1H), 1.46ꢀ1.41 (m, 1H); C{ H} NMR (100 MHz, CDCl ): δ 170.3, 140.5,
38.6, 133.2, 129.1, 128.6, 126.5, 126.2, 124.7, 124.2, 120.4, 28.0, 26.1, 19.2, 16.7; HRMS (ESI):
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
m/z [M + H] calcd for C H NOS: 284.1109; found 284.1090.
1
7
18
2
1a
Nꢀ(4ꢀMethoxyphenyl)cyclopropanecarboxamide (1d): Following the general procedure, 1d
was obtained after purification by column chromatography on neutral alumina (EtOAc:Hexanes =
3
2
6
0:70) as a pink coloured solid; mp 134ꢀ136 °C; Yield: 68% (130 mg); IR (KBr): 3283, 3095,
ꢀ1 1
822, 1648, 1555 cm ; H NMR (400 MHz, CDCl ): δ 7.88 (br. s, 1H), 7.41 (d, 2H, J = 8.9 Hz),
3
.83 (d, 2H, J = 8.9 Hz), 3.79 (s, 3H), 1.53ꢀ1.49 (m, 1H), 1.07ꢀ1.03 (m, 2H), 0.82ꢀ0.77 (m, 2H);
1
3
1
C{ H} NMR (100 MHz, CDCl
3
): δ 172.1, 156.2, 131.4, 121.8, 114.0, 55.5, 15.4, 7.7; HRMS
: 192.1025; found 192.1020.
+
(ESI): m/z [M + H] calcd for C11
H
14NO
2
Nꢀ(4ꢀPhenylbutanꢀ2ꢀyl)cyclopropanecarboxamide (1e): Following the general procedure, 1e
was obtained after purification by column chromatography on neutral alumina (EtOAc:Hexanes =
15:85) as a colourless solid; mp 109ꢀ111 °C; Yield: 92% (199 mg); IR (KBr): 3270, 3094, 2967,
ꢀ1 1
1638, 1550 cm ; H NMR (400 MHz, CDCl
3
): δ 7.31ꢀ7.28 (m, 2H), 7.21ꢀ7.18 (m, 3H), 6.01 (br. s,
1
3
1
H), 4.13ꢀ 4.05 (m, 1H), 2.67 (t, 2H, J = 8.4 Hz), 1.84ꢀ1.73 (m, 2H), 1.38ꢀ1.34 (m, 1H), 1.19 (d,
13
1
H, J = 6.6 Hz), 0.99ꢀ0.94 (m, 2H), 0.74ꢀ0.69 (m, 2H); C{ H} NMR (100 MHz, CDCl
3
): δ
+
73.0, 141.9, 128.4, 128.4, 125.9, 45.2, 38.8, 32.6, 21.1, 14.8, 7.0, 6.9; HRMS (ESI): m/z [M + H]
calcd for C H NO: 218.1545; found 218.1538.
14
20
Nꢀ(2ꢀ(Dimethylamino)ethyl)cyclopropanecarboxamide (1f): Following the general procedure,
1f was obtained after purification by column chromatography on neutral alumina (EtOAc:Hexanes
ꢀ1
=
30:70) as a colourless liquid ; Yield: 8% (13 mg); IR (KBr): 3241, 3189, 3096, 1592, 1561 cm ;
1
H NMR (400 MHz, CDCl ): δ 3.34 (dd, 1H, J = 11.5 Hz, J = 5.6 Hz), 2.85 (br. s, 1H), 2.41 (t,
3
1
2
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1H, J = 6.0), 2.23 (s, 6H), 1.42ꢀ1.35 (m, 1H), 0.96ꢀ0.91 (m, 2H), 0.73ꢀ0.68 (m, 2H); C NMR (100
+
MHz, CDCl
3
): δ 173.7, 58.0, 45.1, 36.9, 14.6, 7.0; HRMS (ESI): m/z [M + H] calcd for
8 17 2
C H N
O: 157.1341; found 157.1338.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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42
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47
48
49
50
51
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54
55
56
57
58
59
60
15c
Nꢀ(Cyclopropylmethyl)picolinamide (1g): Following the general procedure, 1g was obtained
after purification by column chromatography on neutral alumina (EtOAc:Hexanes = 20:80) as a
ꢀ1 1
colourless liquid ; Yield: 63% (111 mg); IR (KBr): 3241, 3186, 3092, 1667, 1526 cm ; H NMR
400 MHz, CDCl ): δ 8.57ꢀ8.56 (m, 1H), 8.21 (dd, 1H, J = 7.8 Hz, J = 0.9 Hz), 8.16 (br. s, 1H),
= 7.8 Hz, J = 1.6 Hz), 7.44ꢀ7.41 (m, 1H,), 3.34 (dd, 2H, J = 7.0 Hz, J = 6.0 Hz),
(
3
1
2
7
1
1
.85 (dt, 1H, J
1
2
1
2
13
.13ꢀ1.08 (m, 1H), 0.58ꢀ0.54 (m, 2H), 0.32ꢀ0.28 (m, 2H); C NMR (100 MHz, CDCl ): δ 164.1,
3
+
50.1, 148.0, 137.3, 126.1, 122.2, 44.2, 10.8, 3.5; HRMS (ESI): m/z [M + H] calcd for
10 13 2
C H N O: 177.1028; found 177.1024.
(1S*,2R*,3S*)ꢀNꢀ(2ꢀ(Methylthio)phenyl)ꢀ2,3ꢀdiꢀpꢀtolylcyclopropanecarboxamide
(3a):
Following the general procedure, 3a was obtained after purification by column chromatography on
alumina (EtOAc:Hexanes = 2:98) as a colourless semiꢀsolid; Yield: 35% (28 mg); IR (KBr): 3241,
ꢀ1 1
3
094, 1692, 1578, 1508 cm ; H NMR (400 MHz, CDCl
Hz), 7.40 (dd, 1H, J = 7.7 Hz, J = 1.4 Hz), 7.23ꢀ7.19 (m, 1H), 7.14 (d, 4H, J = 8.1 Hz), 7.02 (d,
H, J = 8.1 Hz), 7.03ꢀ6.98 (m, 1H), 2.96 (d, 2H, J = 9.4 Hz), 2.60 (t, 1H, J = 9.4 Hz), 2.30 (s, 6H),
3
): δ 8.32 (br. s, 1H), 8.26 (d, 1H, J = 8.0
1
2
4
2
1
13
.11 (s, 3H); C NMR (100 MHz, CDCl
3
): δ 167.0, 138.6, 135.9, 133.1, 131.2, 130.9, 128.8,
+
28.8, 123.9, 120.6, 29.7, 29.2, 28.2, 21.1, 18.9; HRMS (ESI): m/z [M + H] calcd for
C H NNaOS: 410.1555; found 410.1540.
25
25
(1R*,2S*)ꢀNꢀ(2ꢀ(Methylthio)phenyl)ꢀ2ꢀ(pꢀtolyl)cyclopropanecarboxamide (4a): Following the
general procedure, 4a was obtained after purification by column chromatography on alumina
(
EtOAc:Hexanes = 10:90) as a colorless solid; mp 77ꢀ79 °C; Yield: 56% (166 mg); IR (KBr):
ꢀ1 1
3
234, 3014, 2919, 1681, 1652 cm ; H NMR (400 MHz, CDCl ): δ 8.40 (br. s,1H), 8.10 (d, 1H, J
3
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
= 7.4 Hz), 7.45 (dd, 1H, J
1
= 7.7 Hz, J
2
= 1.2 Hz), 7.23ꢀ7.21 (m, 3H), 7.08 (d, 2H, J = 7.9 Hz), 7.01
(
(
t, 1H, J = 7.4 Hz), 2.60 (dd, 1H, J = 16.7 Hz, J
1
2
= 8.6 Hz), 2.31 (s, 3H), 2.30 (s, 3H), 2.18ꢀ2.13
13
m, 1H), 1.87ꢀ1.83 (m, 1H), 1.43ꢀ1.38 (m, 1H); C NMR (100 MHz, CDCl
3
): δ 167.9, 138.6,
138.6, 136.1, 133.4, 133.1, 133.0, 128.9, 124.6, 123.9, 120.6, 25.4, 25.1, 21.1, 18.9, 10.8; HRMS
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
(ESI): m/z [M + Na] calcd for C H NNaOS: 320.1085; found 320.1105.
18
19
1
6g
(1S*,2R*,3S*)ꢀNꢀ(2ꢀ(Methylthio)phenyl)ꢀ2,3ꢀdiphenylcyclopropanecarboxamide
(3b):
Following the general procedure, 3b was obtained after purification by column chromatography on
neutral alumina (EtOAc:Hexanes = 2:98) as a colourless solid; mp 92ꢀ94 °C; Yield: 40% (144
ꢀ1 1
mg); IR (KBr): 3337, 3091, 1692, 1578, 1509 cm ; H NMR (400 MHz, CDCl ): δ 8.31 (br. s,1H),
3
8.23 (d, 1H, J = 8.0 Hz), 7.40 (dd, 1H, J
1 2
= 7.7 Hz, J = 1.3 Hz), 7.25ꢀ7.16 (m, 11H), 7.0 (t, 1H, J =
13
1
7.5 Hz), 3.02 (d, 2H, J = 9.4 Hz), 2.67 (t, 1H, J = 9.4 Hz), 2.08 (s, 3H); C{ H} NMR (100 MHz,
CDCl
3
): δ 166.7, 138.5, 134.3, 133.1, 131.0, 128.8, 127.6, 126.4, 124.9, 124.0, 120.5, 29.4, 28.5,
+
19.0; HRMS (ESI): m/z [M + H] calcd for C23
H
22NOS: 360.1422; found 360.1404.
(1S*,2S*)ꢀ2ꢀ(Diꢀpꢀtolylmethyl)ꢀ3ꢀ((2ꢀ(methylthio)phenyl)amino)ꢀ3ꢀoxoꢀ1ꢀ(pꢀtolyl)propyl
acetate (5a): Following the general procedure, 5a (anti isomer) was obtained after purification by
column chromatography on neutral alumina (EtOAc:Hexanes = 15:85) as a colourless solid; mp
ꢀ1 1
1
23ꢀ125 °C; Yield: 86% (115 mg); IR (KBr): 3241, 3264, 2921, 1739, 1512 cm ; H NMR (400
MHz, CDCl ): δ 8.15 (br. s, 1H), 7.95 (dd, 1H, J = 8.2 Hz, J = 1.0 Hz), 7.43ꢀ7.39 (m, 3H), 7.27
d, 2H, J = 8.1 Hz), 7.22ꢀ7.15 (m, 5H), 7.09 (d, 2H, J = 8.1 Hz), 7.04ꢀ6.98 (m, 3H), 6.12 (d, 1H, J
= 6.3 Hz), 4.29 (d, 1H, J = 11.6 Hz), 3.94 (dd, 1H, J = 11.6 Hz, J = 6.3 Hz), 2.36 (s, 3H), 2.31 (s,
3
1
2
(
1
2
1
3
1
3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.87 (s, 3H); C{ H} NMR (100 MHz, CDCl
3
): δ 169.8, 168.3,
140.0, 139.1, 138.1, 138.0, 136.2, 135.9, 134.0, 132.7, 129.6, 129.3, 128.8, 128.7, 128.1, 127.5,
+
125.0, 124.2, 120.6, 76.0, 57.4, 51.3, 21.3, 21.1, 21.0, 20.9, 19.0; HRMS (ESI): m/z [M + Na]
3
calcd for C34H35NNaO S: 560.2235; found 560.2249.
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Page 29 of 53
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(1S*,2S*)ꢀ2ꢀBenzhydrylꢀ3ꢀ((2ꢀ(methylthio)phenyl)amino)ꢀ3ꢀoxoꢀ1ꢀphenylpropyl acetate (5b):
Following the general procedure, 5b (anti isomer) was obtained after purification by column
chromatography on neutral alumina (EtOAc:Hexanes = 20:80) as a colourless solid; mp 170ꢀ172
ꢀ1
1
°
C; Yield: 57% (71 mg); IR (KBr): 3228, 3025, 2920, 1735, 1657 cm ; H NMR (400 MHz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CDCl ): δ 8.01 (br. s, 1H), 7.80 (dd, 1H, J = 8.2 Hz, J = 1.0 Hz), 7.51 (d, 2H, J = 7.3 Hz), 7.40ꢀ
3
1
2
7
.35 (m, 5H), 7.26ꢀ7.11 (m, 9H), 7.05 (t, 1H, J = 7.4 Hz), 6.98 (td, 1H, J
.16 (d, 1H, J = 7.0 Hz), 4.40 (d, 1H, J = 11.5 Hz), 3.93 (dd, 1H, J = 11.5 Hz, J
): δ 169.8, 168.2, 142.6, 141.9, 137.6,
37.3, 132.5, 128.9, 128.6, 128.6, 128.5, 128.3, 128.2, 127.8, 127.5, 126.8, 126.6, 125.1, 124.4,
1
= 7.6 Hz, J
2
= 1.3 Hz),
6
1
2
= 7.0 Hz), 2.19
13
1
(s, 3H), 1.75 (s, 3H); C{ H} NMR (100 MHz, CDCl
3
1
+
120.6, 76.1, 57.6, 52.6, 20.8, 19.0; HRMS (ESI): m/z [M + Na] calcd for C H NNaO S:
31
29
3
518.1766; found 518.1779.
(1S*,2S*)ꢀ2ꢀ(Bis(4ꢀethylphenyl)methyl)ꢀ1ꢀ(4ꢀethylphenyl)ꢀ3ꢀ((2ꢀ(methylthio)phenyl)amino)ꢀ3ꢀ
oxopropyl acetate (5c): Following the general procedure, 5c (anti isomer) was obtained after
purification by column chromatography on neutral alumina (EtOAc:Hexanes = 20:80) as a pale
yellow solid; mp 68ꢀ70 °C; Yield: 60% (87 mg); IR (DCM): 3542, 3427, 3024, 2918, 1708, 1665
ꢀ
1 1
cm ; H NMR (400 MHz, CDCl
3
): δ 7.99 (br. s, 1H), 7.80 (dd, 1H, J
= 7.7 Hz, J = 1.4 Hz), 7.28 (d, 2H, J = 8.2 Hz), 7.22ꢀ7.18 (m,
= 1.5 Hz), 7.09 (d, 2H, J = 8.2 Hz), 7.01ꢀ6.96 (m, 3H), 6.12 (d,
H, J = 6.9 Hz), 4.33 (d, 1H, J = 11.5 Hz), 3.90 (dd, 1H, J = 6.9 Hz, J = 11.5 Hz), 2.64 (q, 2H, J
1 2
= 8.2 Hz, J = 1.1 Hz), 7.41
(
d, 2H, J = 8.1 Hz), 7.36 (dd, 1H, J
1
2
4
1 2
H), 7.14 (dt, 1H, J = 7.6 Hz, J
1
1
2
= 7.6 Hz), 2.58 (q, 2H, J = 7.6 Hz), 2.47 (q, 2H, J = 7.6 Hz), 2.17 (s, 3H), 1.75 (s, 3H), 1.24 (t, 3H,
1
3
1
J = 7.6 Hz), 1.16 (t, 3H, J = 7.6 Hz), 1.07 (t, 3H, J = 7.6 Hz); C{ H} NMR (100 MHz, CDCl
3
): δ
1
1
69.8, 168.5, 144.3, 142.4, 142.2, 140.2, 139.4, 137.9, 134.6, 132.6, 128.6, 128.3, 128.2, 128.1,
27.6, 127.5, 125.1, 124.2, 120.6, 76.1, 57.8, 51.8, 28.5, 28.4, 28.3, 20.8, 18.9, 15.5, 15.3, 15.3;
+
HRMS (ESI): m/z [M + Na] calcd for C37
H
41NNaO
3
S: 602.2705; found 602.2721.
29
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