Direct bis-arylation of cyclobutanecarboxamide via double C-H activation: An auxiliary-aided diastereoselective Pd-catalyzed access to trisubstituted cyclobutane scaffolds having three contiguous stereocenters and an all-cis stereochemistry

Article abstract of DOI:10.1021/jo4019733

An auxiliary-aided Pd-catalyzed highly diastereoselective double C-H activation and direct bis-arylation of methylene C(sp³)-H bonds of cyclobutanecarboxamides and the syntheses of several novel trisubstituted cyclobutanecarboxamide scaffolds h

Full text of DOI:10.1021/jo4019733

Article
pubs.acs.org/joc
Direct Bis-Arylation of Cyclobutanecarboxamide via Double C−H
Activation: An Auxiliary-Aided Diastereoselective Pd-Catalyzed
Access to Trisubstituted Cyclobutane Scaffolds Having Three
Contiguous Stereocenters and an All-cis Stereochemistry
Ramarao Parella, Bojan Gopalakrishnan, 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
S
* Supporting Information
ABSTRACT: An auxiliary-aided Pd-catalyzed highly diastereoselective double C−H activation and direct bis-arylation of
methylene C(sp3)−H bonds of cyclobutanecarboxamides and the syntheses of several novel trisubstituted cyclobutanecarbox-
amide scaffolds having an all-cis stereochemistry are reported. Extensive screening of various auxiliaries and reaction conditions
was performed to firmly establish the optimized reaction conditions required for effecting the mono- or double C−H arylation of
cyclobutanecarboxamides. The auxiliary-attached cyclobutanecarboxamides 15a, 15g, and 15h, prepared from the auxiliaries such
as, 8-aminoquinoline, 2-(methylthio)aniline, and N′,N′-dimethylethane-1,2-diamine were found to undergo an efficient direct
bis-arylation. The Pd-catalyzed arylation reaction of N-(quinolin-8-yl)cyclobutanecarboxamide 15a with one equivalent or more
of aryl iodides, afforded the corresponding bis-arylated cyclobutanecarboxamides 16a−y. Nevertheless, the Pd-catalyzed arylation
of 15a with just 0.5 equiv of the aryl iodides 13a, 13b, 13e, and 13m, selectively gave the corresponding monoarylated
cyclobutanecarboxamides 17a−17d. The Pd-catalyzed arylation of 15g or 15h with one equivalent or more of aryl iodides
afforded the bis-arylated cyclobutanecarboxamides 19a−19c and 21a−21m, respectively. However, the Pd-catalyzed arylations of
compounds 15g or 15h with just 0.5 equiv of aryl iodides were ineffective. The stereochemistry of compounds obtained in this
work was unambiguously assigned from the X-ray structures of representative products.
the other hand, in laboratories, the direct [2 + 2] photo-
cycloaddition reaction involving two similar olefins or hetero-
dimerizations of two distinct olefins has been one of the most
desirable routes for assembling cyclobutanes (Figure 2).18,19
However, the experimental synthetic method has limitations
such as the head-to-head or head-to-tail type additions,
homodimerization and E/Z isomerization of olefins, thereby
leading to the uncontrolled production of a complex mixture of
stereoisomers without the stereo- and regiocontrol.20 Fortu-
nately, the crystal engineering tactic and solid-state photo-
chemistry experiments lead to the assembly of a set of
stereochemically defined cyclobutanes.18,19 Apart from these
techniques, there exist only rare examples of direct hetero-
dimerizations of two different olefins leading to the formation of
cyclobutanes with a high regio- and stereocontrol.21,22 Hence,
the construction of substituted, especially the monoarylated or
bis-arylated, cyclobutanecarboxamides with a high degree of
regio- and stereocontrol is a demanding task in organic chemistry
INTRODUCTION
■
Cyclobutane is the second smallest, strained four-membered
carbocyclic ring in the family of smallest rings (as the first
member in the family is cyclopropane ring) and presents as a core
unit of natural products (Figure 1), pharmaceutical agents, and
synthetic compounds.1−3 Several cyclobutane natural products,
especially, monoarylated and bis-arylated cyclobutanecarbox-
amides exhibit a variety of biological activities and medicinal
properties.1−17 For example, incarvillateine has been traditionally
used in treating rheumatism and relieving pain as an ancient
Chinese crude medicine named as “Jiaohao”.4 Biyouyanagin5 is
exhibiting substantial activity against HIV and inhibiting cytokine
production. Littoralisone6 is an active agent for increased NGF-
induced neurite outgrowth in PC12D cells. Furthermore,
cyclobutanes isolated from Piper nigram and Piper chaba are
known to exhibit broad pharmacological activities.7,8 Various
research groups have elegantly completed the total synthesis of
several cyclobutane-based natural products by using different
routes.8−17
It is believed that in Nature the cyclobutane natural products
are constructed via the direct coupling of the parent monomeric
olefins with a very high degree of stereo- and regiocontrol. On
Received: September 5, 2013
© XXXX American Chemical Society
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Figure 1. Representative cyclobutane natural products.
due to the fact that many of the bioactive cyclobutane natural
products contain an aryl group as one of the substituents.
An efficient and commanding route for the construction of
stereodefined, arylated cyclobutanecarboxamides would be the
direct metal-catalyzed C−H arylation of the C(sp3)−H bond of
cyclobutanes. However, when compared to the field dealing with
the [2 + 2] photocycloaddition-based dimerization of olefins
leading to substituted cyclobutanes with an unpredictable
stereocontrol, the direct C−H functionalization of cyclobutanes
is an underexplored topic of research. To the best of our
knowledge there exist only two exceptional reports in this
regard,16,17 nevertheless the C−H activation reactions, espe-
cially, the Pd-catalyzed C−H activation/functionalization of
C(sp3)−H bond is one of the potential topics of the present and
future research since the direct C−H functionalization reactions
are considered to be the attractive methods in terms of simplicity
and atom economy.23−34
Employing the pioneering Pd-catalyzed C−H arylation
strategy developed by Daugulis et al., recently, Baran’s
group16,17 reported the synthesis of piperarborenines and
pipercyclobutanamide A. Baran’s group elegantly established
and optimized the reaction condition for an effective
monoarylation of 6a and 7a, which was a crucial step during
the synthesis of cyclobutane natural products (Scheme 1).16,17 In
this regard, Baran’ group reported that the Pd-catalyzed C−H
arylation of the substrates 6a and 7a gave the corresponding
monoarylated products 6c (52%) and 7c (54%).16,17 In contrast
to these results, during an attempt to synthesize pipercyclobu-
tanamide A via the mono C−H vinylation of 7a, Baran’s group
obtained the bis(olefinated)cyclobutane 8b (50%) instead of the
mono-olefinated product 8c.17 Notably, this is the only example
available on the “double C−H functionalization of cyclobutane”
using a vinyl iodide as the coupling partner. Baran’s group has
stated that “the reason for the direct bis(olefination) is unclear,
but it may be that the vinyl iodide 8a is smaller than the aryl
iodides, thereby leading to a more facile second reaction”.17
It is noteworthy to mention that Yu’s group has obtained the
bis-arylated product 11b along with the monoarylated product
11a from the Pd-catalyzed C−H arylation of the smallest
carbocyclic ring, cyclopropanecarboxamide 9.27c Daugulis’s
group has showed the occurrence of the bis-arylation of
cyclohexane ring and monoarylation of cyclopentane ring in
their groundbreaking report on an auxiliary-directed, palladium-
catalyzed arylation of C(sp3)−H bonds of various carboxylic
acids.26b
Recently, we reported35a an auxiliary-enabled and Pd-
catalyzed C−H arylation reaction of methylene C(sp3)−H
bond of the cyclopropanecarboxamide 12 using four equivalents
of 1-iodo-4-methoxybenzene (13a) in toluene, which exclusively
gave the monoarylated cyclopropanecarboxamide 1435b as the
single isomer via the C−H activation (Scheme 2). During our
previous work,35b by using the similar experimental conditions
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Figure 2. Methods for assembling substituted cyclobutane derivatives.
Scheme 1. Existing Examples Dealing with C−H Activation of Cyclobutane
adopted for the cyclopropanecarboxamide 12, curiously, we
attempted the Pd-catalyzed, C−H activation reaction of N-
(quinolin-8-yl)cyclobutanecarboxamide (15a) with 1-iodo-4-
methoxybenzene (13a) in toluene. Surprisingly, in contrast to
C
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Scheme 2. Theme of This Work: Double C−H Activation and Direct Bis-Arylation of Cyclobutanecarboxamides
Table 1. Optimization of the Reaction Conditions for the C−H Arylation of 15a
a
All the reactions were done using phenyl iodide (13b) and solvent (3 mL) under nitrogen atmosphere. The yields denoted here were calculated on
b
the basis of the starting compound 15a. In this case, bromobenzene (13c) or chlorobenzene (13d) was used instead of iodobenzene (13b).
the Baran’s substrate,16,17 we observed the formation of only the
bis-arylated product 16a as the single diastereomer in 99% yield.
Encouraged by this outcome and in continuation of our interest
on the construction of contiguous stereocenters of small
carbocyclic rings using C−H activation route,35 we envisaged
capitalizing on this result to accomplish the diastereoselective
direct bis-arylation of cyclobutanes. In this regard, to the best of
our knowledge there exist no reports dealing with the one-pot
bis-arylation of the cyclobutane ring by directly using aryl iodides
as the coupling partners.16,17,23−34
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a
Table 2. Ratio of Aryl Iodide Leading to the Formation of Monoarylated or Bis-Arylated Cyclobutanecarboxamide
a
All the reactions were done under nitrogen atmosphere. The yields denoted here were calculated based on the starting compound 15a.
Inspired by the latest developments on the Pd-catalyzed C−H
activation reactions, we envisaged examining a direct protocol for
the production of novel bis-arylated cyclobutanecarboxamide
scaffolds under the ‘auxiliary-aided and Pd(OAc)2-catalyzed C−
H activation method’.26b We herein, report an auxiliary-aided Pd-
catalyzed highly diastereoselective “double C−H activation and
direct bis-arylation of methylene C(sp3)−H bonds of cyclo-
butanecarboxamides” and an efficient access to novel 1,2-cis, 1,3-
cis, and 2,3-cis trisubstituted cyclobutane scaffolds having three
contiguous stereocenters with a high degree of stereo- and
regiocontrol.
(15a), obtained from cyclobutanecarbonyl chloride and an
auxiliary, 8-aminoquinoline, with iodobenzene (13b). The
reaction of N-(quinolin-8-yl)cyclobutanecarboxamide (15a)
with iodobenzene (13b) in the absence of a palladium catalyst
failed to afford any product (entry 1, Table 1). The C−H
arylation of N-(quinolin-8-yl)cyclobutanecarboxamide (15a) in
the presence of Pd(OAc)2 catalyst and AgOAc in 1,2-DCE gave
the bis-arylated product 16b in 68% yield (entry 2, Table 1).
Usage of other solvents such as 1,4-dioxane or MeCN did not
improve the yield of the product 16b (entries 3 and 4, Table 1).
The C−H arylation of cyclobutane 15a in the presence of
Pd(OAc)2 and AgOAc went smoothly in toluene at 110 °C and
afforded the bis-arylated product 16b in 94% yield as a single
diastereomer (entry 5, Table 1). Employing Pd(PPh3)4 as a
catalyst failed to furnish the product 16b (entry 6, Table 1), and
usage of other Pd catalysts instead of Pd(OAc)2 also gave the
product 16b in 69−73% yields (entries 7−10, Table 1). The Pd-
RESULTS AND DISCUSSION
■
We commenced our study to find the optimized reaction
conditions and solvents. Table 1 reveals the Pd- catalyzed
arylation reaction of N-(quinolin-8-yl)cyclobutanecarboxamide
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Scheme 3. Double C−H Activation Route to Trisubstituted Cyclobutane Scaffolds Having Contiguous Stereocenters with an All-
a,b,c
cis Stereochemistry
a
b
All the reaction were done under nitrogen atmosphere. The yields denoted here were calculated based on the starting compound 15a. The
c
reaction was performed using 1.7 mol % (1 mg) of Pd(OAc)2. The reaction was performed using 3 mol % (1.7 mg) of Pd(OAc)2.
catalyzed arylation reaction of 15a with 13b in the presence of
other oxidants/additives such as PhI(OAc)2, KOAc, and
Cu(OAc)2 furnished the product 16b in significantly low yields
or traces (entries 11−13, Table 1). The arylation of 15a with 13b
in the presence of Ag2CO3 instead of AgOAc gave the bis-
arylated product 16b in 68% yield (entry 14, Table 1).
Employing bromobenzene (13c) or chlorobenzene (13d)
instead of iodobenzene (13b) did not afford the product 16b
(entry 15, Table 1).
In order to obtain products with very good yields and to have
an efficient the C−H functionalization on the molecules,
typically, more than one equivalent of aryl iodide (1−4 equiv)
has been employed in the C(sp3)−H arylation strategy.23−35
However, though we have used the same experimental
conditions and reagent amounts which were used for the C−H
arylation of cyclopropanecarboxamides which gave only the
monoarylated products, in this work, the C−H arylation of the
cyclobutane 15a (1 equiv) with 1-iodo-4-methoxybenzene 13a
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Scheme 4. Double C−H Activation Route to Trisubstituted Cyclobutane Scaffolds Having Contiguous Stereocenters with an All-
a
cis Stereochemistry
a
All the reaction were done under nitrogen atmosphere. The yields denoted here were calculated based on the starting compound 15a.
(4 equiv) in the presence of Pd(OAc)2 and AgOAc afforded only
the bis-arylated product 16b as a single diastereomer (Scheme
2).
bond of cyclobutanecarboxamides were investigated (Scheme 3).
A variety of substituted aryl iodides having valuable functional
groups was used as the coupling partner in the Pd-catalyzed
double C−H activation and bis-arylation of methylene C(sp3)−
H bonds of cyclobutanecarboxamide 15a, thus offering an ample
opening and an efficient access to novel 1,2-cis, 1,3-cis, and 2,3-cis
trisubstituted cyclobutane scaffolds having three contiguous
stereocenters with a high degree of stereo- and regiocontrol
(Scheme 3).
Further, the Baran’s group also reported that the Pd-catalyzed
C−H arylation of 6a and 7a with excess of aryl iodides (6b and
7b, 2 equiv) gave only the corresponding monoarylated products
6c and 7c (Scheme 1).16,17 In order to have a clear insight
regarding equivalents of phenyl iodides required for producing
the monoarylated cyclobutane product 17 or the bis-arylated
cyclobutane product 16, we investigated the C−H arylation of
cyclobutane 15a by varying the amount of the aryl iodide 13b
(Table 2). Usage of one equivalent or more of iodobenzene
(13b) in the Pd-catalyzed C−H arylation of 15a gave only the
bis-arylated product 16b (entries 1−5, Table 2). The Pd-
catalyzed C−H arylation of 15a with 0.75 equiv of iodobenzene
(13b) gave both the bis-arylated cyclobutane 16b (11%) and the
monoarylated cyclobutane 17b (33%) (entry 6, Table 2).
Notably, the Pd-catalyzed C−H arylation reaction of 15a with
just 0.5 equiv of iodobenzene (13b) in toluene (refluxed for 15
h) selectively gave the monoarylated cyclobutane 17b in 20%
yield (entry 7, Table 2). Increasing the reaction period from 15 to
48 h did not improve the reaction yield (entry 8, Table 2).
Next, we attempted the Pd-catalyzed C−H arylation reaction
of 15a with 0.5 equiv of iodobenzene by increasing the catalyst
(Pd(OAc)2) loading to 15 mol %. However, this reaction also
afforded the monoarylated cyclobutane 17b in 35% yield (entry
9, Table 2). Furthermore, we performed the Pd-catalyzed C−H
arylation reaction of 15a by changing the reaction conditions and
however, our attempts to get the monoarylated cyclobutane 17b
in good yields were not fruitful (entries 10−13. Table 2). Using
the best reaction conditions (entries 7 and 9) described in the
Table 2, the other monoarylated cyclobutane derivatives 17a,
17c and 17d were synthesized (Table 2).
The arylation of methylene C−H bonds of 15a with para-
substituted aryl iodides having electron-withdrawing and
-donating groups went smoothly and gave the corresponding
cyclobutanes 16a, 16c−16i in 73−99% yields. The arylation of
15a with 1-iodonaphthalene, 1-iodo-3-methylbenzene, and 1-
iodo-3-(trifluoromethyl)benzene gave the corresponding cyclo-
butanes 16j−16l in 59−99% yields. The arylation of 15a with
meta-substituted aryl iodides having electron-withdrawing
groups furnished the respective products 16m−16p in 80−
97% yields. The bis-arylation of the cyclobutanecarboxamide 15a
with various disubstituted aryl iodides and 1-(4-iodophenyl)-
ethanone afforded the cyclobutane scaffolds 16q−16u in
moderate to very good yields (Scheme 3). In some cases, we
have performed the C−H arylation reaction of cyclobutane 15a
using 3 mol % of the catalyst Pd(OAc)2, which gave the
corresponding bis-arylated products 16c and 16g in 97 and 85%
yields, respectively (Scheme 3). Furthermore, we have attempted
to use only 1.7 mol % (1 mg) of the catalyst Pd(OAc)2 for the
double C−H arylation of the cyclobutane derivative 15a. The
C−H arylation of the cyclobutane 15a in the presence of just 1.7
mol % of Pd(OAc)2 gave the corresponding bis-arylated
products 16a (82%), 16c (81%), 16f (98%), 16k (68%), and
16q (72%) in good to moderate yields (Scheme 3).
Next, we aimed the auxiliary-aided Pd-catalyzed double C−H
activation and bis-arylation of the methylene C(sp3)−H bond of
cyclobutanecarboxamides with various heteroaryl iodides
(Scheme 4). The Pd-catalyzed double C−H functionalization
Having the optimized reaction conditions in hand, the
generality and scope of this auxiliary-aided Pd-catalyzed double
C−H activation and bis-arylation of the methylene C(sp3)−H
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Scheme 5. Screening of Various Auxiliaries for the C−H Activation of Cyclobutane
and heterocyclic substitution on the cyclobutanecarboxamide
15a commendably gave the trisubstituted cyclobutanecarbox-
amide scaffolds 16v−16y in good to excellent yields (66−96%)
(Scheme 4). It is noteworthy to mention that all these reactions
selectively gave the 1,2-cis, 1,3-cis, and 2,3-cis trisubstituted
cyclobutanes having three contiguous stereocenters with a high
degree of stereo- and regiocontrol, and the stereochemistries of
the products 16a−16y (Schemes 3 and 4) were assigned on the
basis of analysis of the X-ray structures of the representative
compounds 16c, 16f, 16g, and 16m.36
Table 3. C−H Arylation N-(2-
(Methylthio)phenyl)cyclobutanecarboxamide 15g
After the successful Pd-catalyzed bis-arylation reactions of N-
(quinolin-8-yl)cyclobutanecarboxamide (15a), we prepared a
variety of cyclobutanecarboxamides 15b−15h by linking cyclo-
butane carbonyl chloride with various auxiliaries, respectively
(Scheme 5). The Pd-catalyzed C−H arylation of cyclobutane-
carboxamides 15b−15f did not afford the expected bis-arylated
cyclobutanes 18a−18h. The reason for this may be that the
corresponding auxiliaries linked with the cyclobutane ring have
not aided the C−H functionalization of the cyclobutane ring.
Along this line, next we carried out the Pd-catalyzed arylation
of N-(2-(methylthio)phenyl)cyclobutanecarboxamide (15g,
prepared from an auxiliary, 2-(methylthio)aniline with different
aryl iodides. Initially, we investigated the C−H arylation of
cyclobutane 15g by varying the equivalents of 3-iodobenzalde-
hyde (13g, Table 3). Usage of one equivalent or more of 3-
iodobenzaldehyde (13g) in the Pd-catalyzed C−H arylation of
15g gave only the bis-arylated product 19a (entries 1−3, Table
3). Similarly, subsequent examples of the bis-arylated cyclo-
a
All the reactions were done under nitrogen atmosphere. The yields
denoted here were calculated based on the starting compound 15g.
The reaction was done using the reaction condition given for ’entry
b
1′.
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a16,17
Scheme 6. Trials Performed Aiming at the Monoarylation of 15a and 15g Using Baran’s Reaction Condition
a
The yields denoted here were calculated based on the starting compound 15a or 15g.
butanes 19b and 19c having the 1,2-cis, 1,3-cis, and 2,3-cis
stereochemistry were obtained in 45 and 29% yields, respectively
(Table 3).37 When compared to the starting material 15a, the C−
H arylation of 15g gave relatively low yields of the bis-arylated
cyclobutanes 19a−19c. However, unlike the substrate 15a, the
Pd-catalyzed C−H arylation of 15g with just 0.5 equiv of 3-
iodobenzaldehyde (13g) did not afford the monoarylated
cyclobutane 20 (entry 4, Table 3).
Baran’s group used the cyclobutanecarboxamides 6a and 7a
which were similar to the cyclobutanecarboxamides 15g and 15a,
respectively.16,17 When compared to this work, the Pd-catalyzed
C−H arylation reaction conditions were different in the Baran’s
work. Baran’s group performed the C−H arylation of 6c and 7c
with 2 equiv of 6b and 7b and revealed the formation of
monoarylated products 6c and 7c, respectively. Contrastingly,
under the experimental conditions of this work, the Pd-catalyzed
C−H arylation of the substrates 15g or 15a with even just one
equivalent of an aryl iodide gave only the bis-arylated
cyclobutanes as the major compounds. Consequently, we were
also interested to test the fate of our substrates 15g and 15a
under Baran’s reaction condition.16,17 Hence, we performed the
C−H arylation reactions of the substrate 15a and 15g under the
monoarylation reaction condition16,17 established by Baran’s
group for the C−H arylation of 7a (Baran’s substrate). However,
our attempts resulted in the formation of only the bis-arylated
cyclobutanes 16a, 16g, and 19b as the single isomers (Scheme 6)
and we did not obtain the monoarylated cyclobutanes 17a, 17g,
and 20b (Scheme 6). The reason for formation of only the
respective bis-arylated compounds 16a, 16g, and 19b from 15a
and 15g may be due to the substituent effect on the cyclobutane
ring. Baran’s substrates 6c and 7c have a substituent (carboxylic
acid ester group) at the third position of cyclobutane ring, and
hence the double arylation of 6c and 7c may not be a facile
reaction due to the steric hindrance of aryl groups (if two aryl
groups are introduced). However, the substrates investigated in
this work, such as 15a, 15g, and 15h, do not have any substituent
at the third position of the cycobutane ring when compared to
Baran’s substrate. Hence, the double arylations of cyclobutane-
carboxamides 15a, 15g, and 15h occur in a facile manner.
Then, we scrutinized the scope of the Pd-catalyzed C−H
activation and mono- or bis-arylation by using the N-(2-
(dimethylamino)ethyl)cyclobutanecarboxamide (15h, prepared
from an aliphatic auxiliary, N′,N′-dimethylethane-1,2-diamine
and cyclobutanecarbonyl chloride). At the outset, we examined
the Pd-catalyzed C−H arylation of N-(2-(dimethylamino)-
ethyl)-cyclobutanecarboxamide (15h) by varying the equivalents
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a
,b
Scheme 7. Investigation of the Pd-Catalyzed C−H Arylation of N-(2-(Dimethylamino)ethyl)-cyclobutanecarboxamide.
a
b
All the reactions were done under nitrogen atmosphere. The yields denoted here were calculated on the basis of the starting compound 15h. The
preparation of the compounds 21b−21m was carried out using the reaction condition given for ’entry 2′.
of 1-iodo-3-nitrobenzene (13f) (Scheme 7). The Pd-catalyzed
C−H arylation of N-(2-(dimethylamino)ethyl)-cyclobutane-
carboxamide (15h) by using either one equivalent or more of
1-iodo-3-nitrobenzene (13f) selectively afforded the bis-arylated
cyclobutanecarboxamide 21a (entries 1−5, Scheme 7). These
reactions did not afford any traces of the monoarylated
cyclobutanecarboxamide 22a (entries 1−5, Scheme 7). How-
ever, unlike the substrate 15a, the Pd-catalyzed C−H arylation of
15h with just 0.5 equiv of iodo-3-nitrobenzene (13f) did not
afford the monoarylated cyclobutane 22a (entry 6, Scheme 7).
Further, several substituted aryl iodides and hetereoaryl iodides
were used as the coupling partners in the Pd-catalyzed C−H
activation and bis-arylation of methylene C(sp3)−H bonds of
cyclobutanecarboxamide 15h, which led to the assembling of
various 1,2-cis, 1,3-cis, and 2,3-cis trisubstituted cyclobutane-
carboxamides 21a−21m (Scheme 7). Noticeably, all these
reactions selectively gave the 1,2-cis, 1,3-cis, and 2,3-cis
trisubstituted cyclobutanes having three contiguous stereo-
centers with a high degree of stereo- and regiocontrol and the
stereochemistry of the products 21a−21m (Scheme 7) was
assigned on the basis of the X-ray structure analysis of the
representative compounds 21a and 21f.36
Furthermore, we extended the scope this protocol by
producing a wide range of novel trisubstituted cyclobutane-
carboxamides 16z and 16aa−16ad having an all-cis stereo-
chemistry by performing a second C−H activation/arylation on
the corresponding monoarylated cyclobutanecarboxamides 17a
and 17c (Scheme 8). The C−H functionalization reaction of the
monoarylated cyclobutanecarboxamides 17a and 17c with a
variety of hetereoaryl iodides 13e, 13j, and 13k in the presence of
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a
Scheme 8. Scope and Investigation of Second Arylation of Mono-Arylated Cyclobutanes Using Heteroaryl Iodides.
a
The overall yields were calculated for the reaction of the starting material 15a converting in to the corresponding bis-arylated products.
Pd(OAc)2 catalyst and AgOAc gave the corresponding
trisubstituted cyclobutanecarboxamides 16z and 16aa−16ad in
30−82% yields, having two different aryl groups. The stereo-
chemistry of the products 16z and 16aa−16ad (Scheme 8) was
assigned on the basis of the X-ray structure analysis of the
representative compounds 16c, 16f, 16g, and 16m and the
similarity in the 1H NMR pattern.
Next, we planned to construct a variety of trisubstituted
cyclobutanecarboxamide frameworks analogous to the naturally
occurring cyclobutanecarboxamide molecules shown in the
Figure 1 (Scheme 9). In this line, initially, we performed the
Pd-catalyzed C−H arylation reaction of N-(quinolin-8-yl)cyclo-
butanecarboxamide (15a) by using more than one equivalent of
the aryl iodides 13l, 13m, 7b and 6b, which selectively afforded
the corresponding bis-arylated cyclobutanecarboxamide frame-
works 16ae, 16af, 16ag, and 16ah having an all cis-stereo-
chemistry (Scheme 9).37 Along this line, the C−H functionaliza-
tion reaction of the monoarylated cyclobutanecarboxamides 17a
and 17d with the aryl iodides 6b and 13m in the presence of the
catalyst Pd(OAc)2 and the AgOAc gave the corresponding
trisubstituted cyclobutanecarboxamide derivatives 16ai (40%)
and 16aj (75%), which are structurally equivalent to some of the
naturally occurring cyclobutanecarboxamide molecules with
respect to the arene units (Scheme 9 and Figure 1).
Consequently, to reveal the synthetic value of this protocol,
the Pd-catalyzed direct bis-arylation of the C−H bonds of the
cyclobutanecarboxamide 15a was carried out in a gram scale,
which afforded the product 16c in an excellent yield (95%)
(Scheme 10). Additionally, we also tried to elaborate the Pd-
catalyzed C−H activation of 15a by using different alkyl iodides
K
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a
Scheme 9. Scope and Synthesis of Cyclobutane Derivatives Analogous to Cyclobutane Natural Products.
a
The overall yields were calculated for the reaction of the starting material 15a converting in to the corresponding bis-arylated products.
give the expected mono- or bis-alkylated compounds, such as
16ak, 16al, 16am, and 16an (Scheme 11).
Scheme 10. Gram Scale Double C−H Arylation of 15a
In line with the pioneering studies carried out by Daugulis,26b
Chen28a and a recent work by Charette,24r a plausible mechanism
for the auxiliary-aided Pd(OAc)2-catalyzed, AgOAc-promoted
double C−H activation and direct bis-arylation of methylene
C(sp3)−H bonds of cyclobutanecarboxamides leading to the
formation of monoarylated and bis-arylated cyclobutanecarbox-
amide is shown in the Scheme 12.
Additionally, to explore the synthetic utility we carried out the
LiAlH4-mediated reduction of the amide group of a representa-
tive compound 16g, which furnished N-(((1S*,2R*,4S*)-2,4-
bis(4-bromophenyl)cyclobutyl)methyl)quinolin-8-amine (23).
Further, the base-mediated amide hydrolysis of the representa-
tive compounds 16c, 16f, and 16g successfully gave the
corresponding substituted bis-arylated cyclobutanecarboxylic
acids 24−26 in very good yields, respectively (Scheme 13).
The stereochemistry of the compounds 24−26 was unambigu-
ously established based on the X-ray structure analysis of a
representative compound 25,36,38 which revealed the occurrence
of complete epimerization at the carbonyl group containing
stereocenter of the cyclobutanes 16c, 16f and 16g during the
formation of the corresponding carboxylic acids 24−26 from the
as the coupling partners. We performed the Pd-catalyzed C−H
activation of 15a by using different alkyl iodides (13n−p) under
several reaction conditions, however, all our attempts failed to
L
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a,b,c
Scheme 11. Trials on the Alkylation of Cyclobutanecarboxamide 15a
a
b
c
All the reaction were done under nitrogen atmosphere. In this case, 1.5 mmol of 13r was used. The reaction was carried out in the open
atmosphere.
base-mediated hydrolysis of the amides 16c, 16f and 16g.
Treatment of the compound 16g with NaH followed by MeI
gave the N-methylated cyclobutanamide derivative 27, having a
cis-sterochemistry similar to the starting material 16g, and we did
not observe epimerization in this reaction (Scheme 13). The
stereochemistry of the product 27 was unambiguously assigned
on the basis of the single-crystal X-ray structure analysis.36
the regiocontrol and the exact reaction condition required for
effecting the mono- or double C−H arylation of cyclobutane-
carboxamides. The direct double C−H activation of cyclo-
butanecarboxamide led to the installation of two aryl groups on
cyclobutanecarboxamide and a facile synthesis of several novel
1,2-cis, 1,3-cis and 2,3-cis trisubstituted cyclobutanecarboxamide
frameworks having three contiguous stereocenters,39 which are
relatively difficult to prepare via the existing, popular direct [2 +
2] photocycloaddition method with a high degree of regio- and
stereocontrol.
CONCLUSION
■
In summary, we have reported an auxiliary-aided Pd-catalyzed
highly diastereoselective, double C−H activation and unprece-
dented direct bis-arylation of methylene C(sp3)−H bonds of
cyclobutanecarboxamides. Extensive screening of several auxil-
iaries and reaction conditions was performed to firmly establish
EXPERIMENTAL SECTION
■
General. Melting points are uncorrected. IR spectra were
recorded as thin films or KBr pellets. 1H and 13C NMR spectra
M
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Scheme 12. Plausible Mechanism for the Double C−H
Scheme 13. Synthetic Transformation and Observation of
Epimerization
Arylation of Cyclobutanecarboxamide24r,26b,28a
were recorded on 400 and 100 MHz spectrometers respectively
using CDCl3 or DMSO-d6 as solvent and TMS as an internal
standard. HRMS measurements reported in this work were
obtained from TOF and quadrupole mass analyzers. Column
chromatography was carried out on silica gel (100−200 mesh).
Reactions were carried out in anhydrous solvent under nitrogen
atmosphere. Solutions were dried using anhydrous Na2SO4. Thin
layer chromatography (TLC) was performed on silica gel plates
and components were visualized by observation under iodine.
Yields of products were not optimized. In all the reactions, the
column chromatographic purification of the reaction mixture
afforded only the bis-arylated cyclobutanecarboxamides as the
major diastereomer in pure form. However, in special cases,
monoarylated cyclobutanecarboxamides were obtained when the
experimental condition was changed.
General Procedure for the Synthesis of Cyclobutane-
carboxamides 15a−15c and 15e−15h. A dry flask
containing the corresponding amine (auxiliary) (1 mmol),
Et3N (1.1 mmol) was stirred for 5−10 min under a nitrogen
atmosphere. Then, to the reaction flask anhydrous DCM (4 mL)
was added followed by dropwise addition of cyclobutanecarbonyl
chloride (1 mmol). The resulting mixture was stirred for 10 min
at rt. Then, the reaction mixture was refluxed for 12 h. After this
period, the reaction mixture was diluted with dichloromethane
and washed with water and twice with saturated aqueous
NaHCO3 solution. The combined organic layers were dried over
anhydrous Na2SO4, concentrated in vacuum and purification of
the resulting reaction mixture by column chromatography (silica
gel, 100−200 mesh, EtOAc/hexanes =20:80) furnished the
corresponding cyclobutanecarboxamides 15a−15c and 15e−
15h.
After this period, the reaction mixture was concentrated in
vacuum and diluted with anhydrous DCM (3 mL) under
nitrogen atmosphere. Then, the DCM solution containing 2-
picolinoyl chloride was added to a separate flask containing
cyclobutanamine (1 mmol) and Et3N (1.1 mmol) in anhydrous
DCM (2 mL). Then, reaction mixture was stirred at rt for 10 min.
Next, the reaction mixture was refluxed for 12 h. Then, the
reaction mixture was further diluted with dichloromethane (5
mL) and washed with water followed by saturated aqueous
NaHCO3 solution. The combined organic layers were dried over
anhydrous Na2SO4, concentrated in vacuum and purification of
the resulting reaction mixture by column chromatography
(EtOAc/hexanes =20:80) furnished the cyclobutanecarbox-
amide 15d.
General Procedure for the Preparation of Bis-arylated
Cyclobutanecarboxamides 16a−16aj/19a−19c/21a−
21m. A solution of cyclobutanecarboxamide 15 (0.25 mmol),
Pd(OAc)2 (2.8 mg, 0.0125 mmol (5 mol %)), aryl iodide (1
mmol) AgOAc (91.8 mg, 0.55 mmol) in anhydrous toluene (2−3
mL) was heated at an appropriate temperature (73−110 °C, see
the corresponding Tables/Schemes for specific examples) for an
appropriate time (8−24 h, see the corresponding Tables/
Procedure for Synthesis of Cyclobutanecarboxamide
15d. 2-Picolinic acid (1.5 mmol) was dissolved in SOCl2 (4
mmol) and stirred for 24 h at rt under a nitrogen atmosphere.
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Schemes for specific examples) under a nitrogen atmosphere.
After the reaction period, the reaction mixture was diluted with
EtOAc and concentrated in vacuum and purification of the
resulting reaction mixture by column chromatography (silica gel,
100−200 mesh) furnished the corresponding bis-arylated
cyclobutanecarboxamides 16a-16aj/19a-19c/21a-21m (see the
corresponding Tables/Schemes for specific examples).
General Procedure for the Preparation of Monoary-
lated Cyclobutanecarboxamides 17a−17d. A solution of
N-(quinolin-8-yl)cyclobutanecarboxamide (15a, 56 mg, 0.25
mmol), Pd(OAc)2 (2.8 mg, 0.0125 mmol (5 mol %)), aryl iodide
(0.125 mmol) AgOAc (91.8 mg, 0.55 mmol) in anhydrous
toluene (2−3 mL) was heated at an appropriate temperature
(73−110 °C, see the corresponding Tables/Schemes for specific
examples) for an appropriate time (15−24 h, see the
corresponding Tables/Schemes for specific examples) under
nitrogen atmosphere. After the reaction period, the reaction
mixture was diluted with EtOAc and concentrated in vacuum and
purification of the resulting reaction mixture by column
chromatography (silica gel, 100−200 mesh) furnished the
corresponding monoarylated cyclobutanecarboxamides 17a−
17d (see the corresponding Tables/Schemes for specific
examples).
Procedure for the Preparation 23 from 16g. To dry flask
was added anhydrous THF (4 mL) and (1S*,2R*,4S*)-2,4-
bis(4-bromophenyl)-N-(quinolin-8-yl)cyclobutanecarboxamide
(16g, 0.25 mmol) and the reaction flask was cooled to 0 °C under
a nitrogen atmosphere. To this solution was added LiAlH4 (1
mmol) in portions and was refluxed overnight. Then EtOAc (3
mL) and water (1−2 mL) were added sequentially. The resulting
solution was extracted with EtOAc (2 × 15 mL) and dried over
anhydrous Na2SO4, and the solvent was removed by rotary
evaporation; product was purified by column chromatography
on silica gel (EtOAc/hexane, 10:90), which afforded the product
24.
Procedure for the Hydrolysis of the Bis-arylated
Cyclobutanecarboxamides 16c, 16f, and 16g. The
corresponding bis-arylated cyclobutanecarboxamides 16c or
16f or 16g (0.25 mmol) and NaOH (6 mmol) in ethanol (3
mL) were heated at 80 °C for overnight. After this period, the
reaction mixture was diluted with water and extracted with ether
(2 × 10 mL), and then acidified with 1 N HCl to get a pH ≈ 2.
Extraction with ether (2 × 10 mL) and drying of the combined
organic layers over Na2SO4 was followed by evaporation of the
solvent in vacuum and gave the corresponding carboxylic acids
24−26.
(400 MHz, CDCl3): δ 9.70 (br s, 1H), 8.79 (d, 1H, J = 8.0 Hz),
8.70 (d, 1H, J = 4.0 Hz), 8.02 (d, 1H, J = 8.0 Hz), 7.47−7.30 (m,
3H), 3.37−3.29 (m, 1H), 2.50−2.41 (m, 2H), 2.30−2.23 (m,
2H), 2.22−1.87 (m, 2H); 13C NMR (100 MHz, CDCl3): δ
173.6, 148.0, 138.2, 136.2, 134.4, 127.8, 127.2, 121.5, 121.3,
116.2, 41.3, 25.4, 18.1; FT-IR (KBr): 2988, 1698, 1598, 1351,
778 cm−1; HRMS (ESI): m/z [M + H]+ calcd for C14H15N2O:
227.1184; found 227.1189.
N-(Naphthalen-1-yl)cyclobutanecarboxamide (15b).
Analytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf =
0.70; red color liquid; 164 mg, 73%yield; 1H NMR (400 MHz,
CDCl3): δ 7.95−7.92 (m, 2H), 7.64 (br s, 1H), 7.56−7.51 (m,
3H), 7.29 (q, 1H, J = 8.0 Hz), 3.55−3.48 (m, 2H), 2.41−2.33 (m,
1H), 2.08 (q, 1H, J = 8.0 Hz), 1.89−1.80 (m, 3H); 13C NMR
(100 MHz, CDCl3): δ 177.6, 134.8, 134.4, 131.0, 129.4, 128.7,
127.5, 127.2, 126.6, 125.4, 121.8, 41.5, 26.2, 25.0, 17.6 ; FT-IR
(DCM): 2940, 1611, 1511, 1432, 810 cm−1; HRMS (ESI): m/z
[M + H]+ calcd for C15H16NO: 226.1231; found 226.1226.
N-(Pyridin-2-yl)cyclobutanecarboxamide (15c). Analyt-
ical TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.70; white
color liquid; 132 mg, 75% yield; 1H NMR (400 MHz, CDCl3): δ
9.67 (br s, 1H), 8.15−8.06 (m, 2H), 7.51 (q, 1H, J = 8.0 Hz),
6.85−6.82 (m, 1H), 3.07 (q, 1H, J = 8.0 Hz), 2.24−2.16 (m, 2H),
1.94 (t, 2H, J = 4.0 Hz), 1.74−1.67 (m, 2H); 13C NMR (100
MHz, CDCl3): δ 174.1, 152.0, 147.0, 138.4, 119.3, 114.6, 40.4,
24.9, 18.0; FT-IR (DCM): 2850, 1601, 1530, 1421, 801 cm−1;
HRMS (ESI): m/z [M + H]+ calcd for C10H13N2O: 177.1027;
found 177.1029.
N-Cyclobutylpicolinamide (15d). Analytical TLC on silica
gel, 1:4 ethyl acetate/hexane Rf = 0.60; red color liquid; 140 mg,
81% yield; 1H NMR (400 MHz, CDCl3): δ 8.66 (br s, 1H), 8.22
(d, 2H, J = 8.0 Hz),7.67 (t, 1H, J = 8.0 Hz), 7.44−7.41 (m, 1H),
4.62 (q, 1H, J = 8.0 Hz), 2.46−2.39 (m, 2H), 2.10−2.01 (m, 2H),
1.82−1.75 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 163.1,
149.8, 147.8, 137.5, 126.1, 122.3, 44.6, 31.2, 15.2; FT-IR (DCM):
2953, 1523, 1510, 1435, 798 cm−1; HRMS (ESI): m/z [M + H]+
calcd for C10H13N2O: 177.1027; found 177.1029.
N-(2-Methoxyphenyl)cyclobutanecarboxamide (15e).
Analytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.70;
1
brown color liquid; 164 mg, 80% yield; H NMR (400 MHz,
CDCl3): δ 8.38 (q, 1H, J = 8.0 Hz), 7.73 (br s, 1H), 6.95−6.84
(m, 2H), 6.83−6.75 (m, 1H), 3.74 (s, 3H), 3.14 (q, 1H, J = 8.0
Hz), 2.37−2.27 (m, 2H), 2.18−2.10 (m, 2H), 1.95−1.82 (m,
2H); 13C NMR (100 MHz, CDCl3): δ 173.1, 147.8, 127.7, 123.4,
120.8, 119.6, 109.8, 55.5, 41.0, 25.2, 18.0; FT-IR (DCM): 2990,
1672, 1588, 1393, 810 cm−1; HRMS (ESI): m/z [M + H]+ calcd
for C12H16NO2: 206.1181; found 206.1189.
Procedure for N-Methylation of 16g. To a dry flask was
added a suspension of NaH in oil (0.75 mmol) and washed with
hexane (2 × 2 mL). Then, to this reaction flask, anhydrous THF
(3 mL) and (1S*,2R*,4S*)-2,4-bis(4-bromophenyl)-N-(quino-
lin-8-yl)cyclobutanecarboxamide (16g, 0.25 mmol) were added,
and the reaction flask was cooled to 0 °C and allowed to stir for
15 min under a nitrogen atmosphere. To this solution was added
MeI (1.5 mmol) in dropwise and the reaction mixture was stirred
at rt for 12 h. Then, EtOAc (3 mL) and water (1−2 mL) were
added sequentially. The resulting solution was extracted with
EtOAc (2 × 10 mL) and dried over anhydrous Na2SO4, and the
solvent was removed by under vacuum, and the crude reaction
mixture was purified by column chromatography on silica gel
(EtOAc/hexane 15:85), which afforded the product 27.
N-(Quinolin-8-yl)cyclobutanecarboxamide (15a). Ana-
lytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.70;
brown color solid; 221 mg, 98% yield; mp 62−64 °C; 1H NMR
N-(2-(Phenylthio)phenyl)cyclobutanecarboxamide
(15f). Analytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf =
1
0.70; yellow color liquid; 240 mg, 85% yield; H NMR (400
MHz, CDCl3): δ 8.54 (d, 1H, J = 8.0 Hz), 8.20 (br s, 1H), 7.61 (q,
1H, J = 8.0 Hz), 7.46 (q, 1H, J = 8.0 Hz), 7.27−7.18 (m, 2H),
7.17−7.07 (m, 4H), 3.09−3.04 (m, 1H), 2.16−2.08 (m, 4H),
1.94−1.89 (m, 1H), 1.80−1.60 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 173.2, 139.9, 136.9, 135.6, 131.1, 129.3, 126.9, 126.2,
124.1, 120.7, 119.5, 41.0, 25.1, 17.8; FT-IR (DCM): 2965, 1578,
1559, 1401, 815 cm−1; HRMS (ESI): m/z [M + H]+ calcd for
C17H18NOS: 284.1109; found 284.1104.
N-(2-Methylthio)phenyl)cyclobutanecarboxamide
(15g). Analytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf =
0.70; White color solid; 194 mg, 88% yield; mp 66−68 °C; 1H
NMR (400 MHz, CDCl3): δ 8.36 (d, 1H, J = 8.0 Hz),8.27 (br s,
1H), 7.47−7.45 (d, 1H, J = 8.0 Hz), 7.29 (q, 1H, J = 4.0 Hz), 7.06
O
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(t, 1H, J = 8.0 Hz), 3.27 (q, 1H, J = 8.0 Hz), 2.45−2.36 (m, 2H),
2.35 (s, 3H), 2.35−2.26 (m, 2H), 2.06−1.91 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ 173.3, 138.4, 132.9, 128.9, 125.1, 124.1,
120.4, 41.1, 25.4, 18.8, 18.2; FT-IR (KBr): 3322, 1621, 1532,
1413, 807 cm−1; HRMS (ESI): m/z [M + H]+ calcd for
C12H16NOS: 222.0952; found 222.0943.
N-(2-(Dimethylamino)ethyl)cyclobutanecarboxamide
(15h). Analytical TLC on silica gel, 2.5:2.5 methanol/ethyl
acetate Rf = 0.50; light-yellow color liquid; 136 mg, 80% yield; 1H
NMR (400 MHz, CDCl3): δ 3.43 (q, 2H, J = 4.0 Hz), 3.01 (q,
1H, J = 4.0 Hz), 2.61 (t, 2H, J = 8.0 Hz), 2.36 (s, 6H), 2.30−2.25
(m, 2H), 2.14−2.12 (m, 2H), 2.03−1.93 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ 175.4, 57.7, 44.4, 39.8, 36.0, 25.3, 18.2;
FT-IR (DCM): 3290, 1603, 1557, 1485, 861 cm−1; HRMS
(ESI): m/z [M + H]+ calcd for C9H19N2O: 171.1497; found
171.1499.
(1S*,2R*,4S*)-2,4-Bis(4-methoxyphenyl)-N-(quinolin-
8-yl)cyclobutanecarboxamide (16a). Analytical TLC on
silica gel, 1.5:3.5 ethyl acetate/hexane Rf = 0.60; yellow color
solid; 108 mg, 99% yield; mp 146−149 °C; 1H NMR (400 MHz,
CDCl3): δ 9.43 (br s, 1H), 8.65 (q, 1H, J = 4.0 Hz), 8.30 (q, 1H, J
= 4.0 Hz), 7.95 (q, 1H, J1 = 8.0 Hz), 7.29−7.20 (m, 7H), 6.72−
6.69 (m, 4H), 4.02−3.97 (m, 1H), 3.95−3.90 (m, 2H), 3.61 (s,
6H), 3.44 (dd, 1H, J1 = 12.0 Hz, J2 = 8.0 Hz) 2.65−2.61 (m, 1H);
13C NMR (100 MHz, CDCl3): δ 169.2, 157.9, 147.8, 138.2,
136.1, 134.3, 132.7, 128.2, 127.7, 127.2, 121.3, 120.9, 116.4,
113.5, 55.1, 54.8, 38.5, 30.5; FT-IR (KBr): 2936, 1689, 1612,
1519, 825 cm−1; HRMS (ESI): m/z [M + H]+ calcd for
C28H27N2O3: 439.2021; found 439.2019.
169.2, 147.7, 141.8, 138.2, 137.8, 136.1, 134.3, 127.6, 127.5,
127.2, 127.0, 121.3, 120.8, 116.4, 54.7, 39.0, 30.2, 28.5, 15.5; FT-
IR (KBr): 3358, 1519, 1462, 1378, 825 cm−1; HRMS (ESI): m/z
[M + H]+ calcd for C30H31N2O: 435.2436; found 435.2436.
(1S*,2R*,4S*)-2,4-Bis(4-nitrophenyl)-N-(quinolin-8-yl)-
cyclobutanecarboxamide (16e). Analytical TLC on silica gel,
2:3 ethyl acetate/hexane Rf = 0.50; brown color solid; 86 mg,
1
74% yield; mp 182−184 °C; H NMR (400 MHz, CDCl3): δ
9.65 (br s, 1H), 8.73 (q, 1H, J = 4.0), 8.19 (q, 1H, J = 8.0), 8.08−
8.03 (m, 5H), 7.46−7.36 (m, 6H), 7.28 (q, 1H, J = 4.0 Hz),
4.35−4.30 (m, 1H), 4.20−4.13 (m, 2H), 3.60 (dd, 1H, J1 = 20.0
Hz, J2 = 12.0 Hz), 2.89−2.83 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 167.8, 148.2, 148.1, 146.4, 138.0, 136.5, 133.3, 127.8,
127.6, 127.1, 123.4, 121.9, 121.7, 116.4, 54.5, 38.6, 30.0; FT-IR
(KBr): 3344, 1682, 1596, 1391, 840 cm−1; HRMS (ESI): m/z [M
+ H]+ calcd for C26H21N4O5: 469.1511; found 469.1500.
(1S*,2R*,4S*)-2,4-Bis(4-chlorophenyl)-N-(quinolin-8-
yl)cyclobutanecarboxamide (16f). Analytical TLC on silica
gel, 1.5:3.5 ethyl acetate/hexane Rf = 0.60; light-yellow color
solid; 110 mg, 99% yield; mp 171−174 °C; 1H NMR (400 MHz,
CDCl3): δ 9.48 (br s, 1H), 8.69 (q, 1H, J = 4.0 Hz), 8.27 (q, 1H, J
= 4.0 Hz), 8.03 (q, 1H, J = 4.0 Hz), 7.36−7.27 (m, 3H), 7.25−
7.20 (m, 4H), 7.20−7.11 (m, 4H), 4.10−4.05 (m, 1H), 3.99−
3.97 (m, 2H), 3.42 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.70−
2.63 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 168.5, 147.9,
138.9, 138.1, 136.3, 133.8, 131.9, 128.4, 128.2, 127.7, 127.2,
121.5, 121.4, 116.5, 54.3, 38.4, 30.1; FT-IR (KBr): 2988, 1698,
1598, 1351, 778 cm−1; FT-IR (KBr): 3350, 1683, 1596, 1486,
790 cm−1; HRMS (ESI): m/z [M + H]+ calcd for
C26H21Cl2N2O: 447.1030; found 447.1010.
(1S*,2R*,4S*)-2,4-Diphenyl-N-(quinolin-8-yl)cyclo-
butanecarboxamide (16b).39 Analytical TLC on silica gel,
1.5:3.5 ethyl acetate/hexane Rf1= 0.70; brown color solid; 89 mg,
94% yield; mp 145−147 °C; H NMR (400 MHz, CDCl3): δ
9.47 (br s, 1H), 8.67 (q, 1H, J = 4.0 Hz), 8.25 (q, 1H, J = 4.0 Hz),
7.97 (q, 1H, J = 4.0 Hz), 7.32−7.15 (m, 11H), 7.06−7.02 (m,
2H), 4.13−4.10 (m, 1H), 4.06−3.99 (m, 2H), 3.53 (dd, 1H, J1 =
12.0 Hz, J2 = 8.0 Hz), 2.71−2.68 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 168.9, 147.8, 140.6, 138.2, 136.1, 134.2, 128.1, 127.7,
127.2, 127.0, 126.1, 121.3, 120.9, 116.4, 54.6, 39.1, 29.9; FT-IR
(KBr): 3342, 1669, 1521, 1484, 993 cm−1; HRMS (ESI): m/z [M
+ H]+ calcd for C26H23N2O: 379.1810; found 379.1824.
(1S*,2R*,4S*)-N-(Quinolin-8-yl)-2,4-di-p-tolylcyclo-
butanecarboxamide (16c). Analytical TLC on silica gel,
1.5:3.5 ethyl acetate/hexane Rf = 0.70; light-yellow color solid;
(1S*,2R*,4S*)-2,4-Bis(4-bromophenyl)-N-(quinolin-8-
yl)cyclobutanecarboxamide (16g). Analytical TLC on silica
gel, 2:3 ethyl acetate/hexane Rf = 0.60; light-yellow color solid;
1
131 mg, 99% yield; mp 158−160 °C; H NMR (400 MHz,
CDCl3): δ 9.49 (br s, 1H), 8.69 (q, 1H, J = 4.0 Hz), 8.27 (q, 1H, J
= 4.0 Hz), 8.03 (q, 1H, J = 4.0 Hz), 7.37−7.29 (m, 7H), 7.28−
7.15 (m, 4H) 4.10−4.05 (m, 1H), 3.96−3.90 (m, 2H), 3.42 (dd,
1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.70−2.64 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 168.5, 147.9, 139.5, 138.1, 136.3, 133.9,
131.1, 128.8, 127.7, 127.2, 121.5, 121.4, 120.1, 116.5, 54.2, 38.5,
30.1; FT-IR (KBr): 3349, 1687, 1524, 1323, 824 cm−1; HRMS
(ESI): m/z [M + H]+ calcd for C26H21Br2N2O: 535.0020; found
534.9999.
(1S*,2R*,4S*)-2,4-Bis(4-fluorophenyl)-N-(quinolin-8-
yl)cyclobutanecarboxamide (16h). Analytical TLC on silica
gel, 1:4 ethyl acetate/hexane Rf = 0.70; pale-yellow color solid;
1
100 mg, 99% yield; mp 156−160 °C; H NMR (400 MHz,
CDCl3): δ 9.45 (br s, 1H), 8.65 (q, 1H, J = 4.0 Hz), 8.32 (q, 1H, J
= 4.0 Hz), 7.94 (q, 1H, J = 8.0 Hz), 7.29−7.20 (m, 7H), 6.98 (d,
4H, J = 8.0 Hz), 4.09−4.04 (m, 1H), 4.0−3.93 (m, 2H), 3.51 (dd,
1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.67−2.64 (m, 1H), 2.15 (s, 6H);
13C NMR (100 MHz, CDCl3): δ 169.1, 147.5, 138.2, 137.5,
136.1, 135.4, 134.3, 128.9, 127.6, 127.3, 126.9, 121.2, 120.8,
116.4, 54.6, 38.9, 30.2, 21.0; FT-IR (KBr): 3359, 1689, 1595,
1484, 791 cm−1; HRMS (ESI): m/z [M + H]+ calcd for
C28H27N2O: 407.2123; found 407.2117.
1
100 mg, 97% yield; mp 137−139 °C; H NMR (400 MHz,
CDCl3): δ 9.48 (br s, 1H), 8.69 (q, 1H, J = 4.0 Hz), 8.28 (q, 1H, J
= 4.0 Hz), 8.02 (q, 1H, J = 8.0 Hz), 7.36−7.23 (m, 7H), 6.90−
6.89 (m, 4H), 4.10−4.05 (m, 1H), 4.00 (dd, 2H, J1 = 20.0 Hz, J2 =
12.0 Hz), 3.48 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.71−2.67
(m, 1H); 13C NMR (100 MHz, CDCl3): δ 168.7, 161.5 (d, JC−F
=
242 Hz), 147.9, 138.2, 136.3, 136.2 (d, JC−F = 3 Hz), 134.0, 128.5
(d, JC−F = 8.0 Hz), 127.7, 127.2, 121.4, 121.3, 116.4, 115.1 (d,
JC−F = 21.1 Hz), 54.5, 38.3, 30.3; FT-IR (KBr): 3349, 1605, 1599,
1392, 737 cm−1; HRMS (ESI): m/z [M + H]+ calcd for
C26H21F2N2O: 415.1621; found 415.1611.
(1S*,2R*,4S*)-2,4-Bis(4-iodophenyl)-N-(quinolin-8-yl)-
cyclobutanecarboxamide (16i). Analytical TLC on silica gel,
2:3 ethyl acetate/hexane Rf = 0.60; brown color solid; 114
mg,73% yield; mp 169−171 °C; 1H NMR (400 MHz, CDCl3): δ
9.48 (br s, 1H), 8.70 (q, 1H, J = 4.0 Hz), 8.28 (q, 1H, J = 4.0 Hz),
8.06 (q, 1H, J = 4.0 Hz), 7.50−7.46 (m, 4H), 7.39−7.24 (m, 3H),
(1S*,2R*,4S*)-2,4-Bis(4-ethylphenyl)-N-(quinolin-8-
yl)cyclobutanecarboxamide (16d). Analytical TLC on silica
gel, 1.5:3.5 ethyl acetate/hexane Rf = 0.70; white color solid; 106
mg, 98% yield; mp 136−138 °C; 1H NMR (400 MHz, CDCl3): δ
9.43 (br s, 1H), 8.68 (q, 1H, J = 4.0 Hz), 8.30 (q, 1H, J = 4.0 Hz),
7.98 (q, 1H, J = 4.0 Hz), 7.32−7.22 (m, 7H), 7.02 (d, 4H, J = 8.0
Hz), 4.11−4.08 (m, 1H), 4.04−3.97 (m, 2H), 3.53 (dd, 1H, J1 =
20.0 Hz, J2 = 12.0 Hz) 2.70−2.66 (m, 1H), 2.50 (q, 4H, J = 8.0
Hz), 1.08 (t, 6H, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3): δ
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7.04 (d, 4H, J = 8.0 Hz), 4.11−4.06 (m, 1H), 3.97−3.90 (m, 2H),
3.42 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.70−2.63 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ 168.4, 147.9, 140.2, 138.1, 137.1,
136.3, 133.9, 129.0, 127.7, 127.2, 121.5, 121.4, 116.5, 91.6, 54.2,
38.6, 29.9; FT-IR (KBr): 3346, 1681, 1520, 1485, 808 cm−1;
HRMS (ESI): m/z [M + H]+ calcd for C26H21I2N2O: 630.9743;
found 630.9737.
(1S*,2R*,4S*)-2,4-Di(naphthalen-1-yl)-N-(quinolin-8-
yl)cyclobutanecarboxamide (16j). Analytical TLC on silica
gel, 2:3 ethyl acetate/hexane Rf = 0.60; brown color solid; 112
mg, 94% yield; mp 225−227 °C; 1H NMR (400 MHz, CDCl3): δ
9.03 (br s, 1H), 8.43 (dd, 1H, J1 = 8.0 Hz, J2 = 4.0 Hz), 8.23 (d,
2H, J = 8.0 Hz), 7.85 (dd, 1H, J1 = 8.0 Hz, J2 = 4.0 Hz), 7.77 (dd,
1H, J1 = 8.0 Hz, J2 = 4.0 Hz), 7.70−7.64 (m, 4H), 7.58−7.50 (m,
4H), 7.48−7.38 (m, 2H), 7.35−7.31 (m, 2H), 7.16 (q, 1H, J = 4.0
Hz), 7.03−6.94 (m, 2H), 4.77−4.72 (m, 3H), 4.08 (dd, 1H, J1 =
12.0 Hz, J2 = 8.0 Hz), 2.91−2.84 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 168.1, 147.2, 137.7, 135.8, 135.7, 133.7, 133.5, 131.8,
128.8, 127.1, 126.9, 126.7, 126.0, 125.4, 125.2, 125.0, 123.5,
120.8, 120.4, 115.7, 56.6, 37.9, 28.1; FT-IR (KBr): 3351, 1683,
1523, 1485, 780 cm−1; HRMS (ESI): m/z [M + H]+ calcd for
C34H27N2O: 479.2123; found 479.2115.
(1S*,2R*,4S*)-N-(Quinolin-8-yl)-2,4-di-m-tolylcyclo-
butanecarboxamide (16k). Analytical TLC on silica gel, 1:4
ethyl acetate/hexane Rf = 0.70; light-yellow color solid; 100 mg,
99% yield; mp 98−100 °C; 1H NMR (400 MHz, CDCl3): δ 9.46
(br s, 1H), 8.70 (q, 1H, J = 4.0 Hz), 8.28 (q, 1H, J = 8.0 Hz), 8.0
(q, 1H, J1 = 8.0 Hz), 7.35−7.23 (m, 3H), 7.23−7.04 (m, 6H),
6.85 (d, 2H, J = 8.0 Hz), 4.14−4.10 (m, 1H), 4.04−3.97 (m, 2H),
3.52 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.71−2.67 (m, 6H),
2.13 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 169.1, 147.8,
140.6, 138.2, 137.5, 136.2, 134.3, 127.9, 127.7, 127.5, 127.2,
126.8, 124.0, 121.3, 120.9, 116.4, 54.6, 39.1, 30.0, 21.4; FT-IR
(KBr): 3400, 1596, 1389, 1360, 1047 cm−1; HRMS (ESI): m/z
[M + H]+ calcd for C28H27N2O: 407.2123; found 407.2123.
(1S*,2R*, 4S*)-N-(Quinolin-8-yl)-2,4-bis(3-
(trifluoromethyl)phenyl)cyclobutanecarboxamide (16l).
Analytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.70;
brown color solid; 75 mg, 59% yield; mp 114−116 °C; 1H NMR
(400 MHz, CDCl3): δ 9.46 (br s, 1H), 8.65 (q, 1H, J = 4.0), 8.14
(q, 1H, J = 4.0 Hz), 7.99 (q, 1H, J = 4.0 Hz), 7.50 (s, 2H), 7.44 (q,
2H, J = 8.0 Hz), 7.32−7.18 (m, 7H), 4.17−4.12 (m, 1H), 4.06−
3.99 (m, 2H), 3.51 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.77−
2.69 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 168.2, 148.0,
141.3, 138.0, 136.2, 133.6, 130.3 (q, JC−F = 32 Hz), 130.3, 128.5,
127.6, 127.1, 126.8 (q, JC−F = 271 Hz), 123.7 (q, JC−F = 4 Hz),
123.1 (q, JC−F = 4 Hz), 121.4, 121.4, 116.3, 54.2, 38.7, 29.9; FT-
IR (KBr): 3445, 1519, 1321, 1313, 989 cm−1; HRMS (ESI): m/z
[M + H]+ calcd for C28H21F6N2O: 515.1558; found 515.1536.
(1S*,2R*,4S*)-2,4-Bis(3-nitrophenyl)-N-(quinolin-8-yl)-
cyclobutanecarboxamide (16m). Analytical TLC on silica
gel, 2.5:2.5 ethyl acetate/hexane Rf = 0.50; brown color solid; 100
mg, 86% yield; mp 183−185 °C; 1H NMR (400 MHz, CDCl3): δ
9.57 (br s, 1H), 8.67 (q, 1H, J = 4.0 Hz), 8.16 (s, 2H), 8.16 (dd,
1H, J1 = 8.0 Hz, J2 = 4.0 Hz), 8.01 (dd, 1H, J1 = 8.0 Hz, J2 = 4.0
Hz), 7.88 (q, 2H, J = 4.0 Hz), 7.63 (d, 2H, J = 8.0 Hz), 7.36−7.28
(m, 4H) 7.23 (q, 1H, J = 4.0 Hz), 4.29−4.24 (m, 1H), 4.17−4.10
(m, 2H), 3.60 (q, 1H, J = 12.0 Hz), 2.84−2.81 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ 167.9, 148.2, 148.1, 142.4, 138.0,
136.3, 133.4, 133.1, 129.0, 127.7, 127.0, 122.0, 121.7, 121.6,
121.4, 116.3, 54.2, 38.3, 29.7; FT-IR (KBr): 3344, 1682, 1579,
1485, 792 cm−1; HRMS (ESI): m/z [M + H]+ calcd for
C26H21N4O5: 469.1511; found 469.1512.
(1S*,2R*,4S*)-2,4-Bis(3-fluorophenyl)-N-(quinolin-8-
yl)cyclobutanecarboxamide (16n). Analytical TLC on silica
gel, 1:4 ethyl acetate/hexane Rf = 0.70; pale-yellow color solid;
1
100 mg, 97% yield; mp 132−134 °C; H NMR (400 MHz,
CDCl3): δ 9.49 (br s, 1H), 8.68 (q, 1H, J = 4.0 Hz), 8.25 (q, 1H, J
= 4.0 Hz), 7.99 (q, 1H, J = 8.0 Hz), 7.33−7.20 (m, 3H), 7.12−
6.98 (m, 6H), 6.73−6.69 (m, 2H), 4.12−4.07 (m, 1H), 4.01−
3.93 (m, 2H), 3.45 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.70−
2.63 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 168.4, 164.0 (d,
JC−F = 244 Hz) 147.9, 143.1 (d, JC−F = 8.0 Hz), 138.1, 136.2,
133.9, 129.5 (d, JC−F = 9.0 Hz), 127.7, 127.2, 122.5 (d, JC−F = 3
Hz), 121.4, 121.3, 116.4, 114.1 (d, JC−F = 21.5 Hz), 113.1 (d, JC−F
= 20.9 Hz); FT-IR (KBr): 3435, 1655, 1528, 1481, 793 cm−1;
HRMS (ESI): m/z [M + H]+ calcd for C26H21F2N2O: 415.1621;
found 415.1609.
(1S*,2R*,4S*)-2,4-Bis(3-chlorophenyl)-N-(quinolin-8-
yl)cyclobutanecarboxamide (16o). Analytical TLC on silica
gel, 1:4 ethyl acetate/hexane Rf = 0.70; white color solid; 89 mg,
80% yield; mp 130−132 °C;1H NMR (400 MHz, CDCl3): δ 9.52
(br s, 1H), 8.79 (q, 1H, J = 4.0 Hz), 8.30 (q, 1H, J = 4.0 Hz,), 8.10
(q, 1H, J = 4.0 Hz,), 7.44−7.11 (m, 5H), 7.07−7.04 (m, 6H),
4.19−4.14 (m, 1H), 4.06−4.0 (m, 2H), 3.50 (dd, 1H, J1 = 20.0
Hz, J2 = 12.0 Hz), 2.77−2.70 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 168.3, 148.0, 142.5, 138.2, 136.2, 134.0, 133.8, 129.3,
127.7, 127.3, 127.2, 126.4, 125.1, 121.4, 121.3, 116.5, 54.3, 38.6,
29.8; FT-IR (KBr): 3434, 1601, 1525, 1323, 890 cm−1; HRMS
(ESI): m/z [M + H]+ calcd for C26H21NCl2O: 447.1030; found
447.1018.
(1S*,2R*,4S*)-2,4-Bis(3-bromophenyl)-N-(quinolin-8-
yl)cyclobutanecarboxamide (16p). Analytical TLC on silica
gel, 2:3 ethyl acetate/hexane Rf = 0.60; yellow color liquid; 106
mg, 80% yield; 1H NMR (400 MHz, CDCl3): δ 9.55 (br s, 1H),
8.78 (q, 1H, J = 4.0 Hz), 8.33 (q, 1H, J = 4.0 Hz), 8.06 (q, 1H, J =
4.0 Hz), 8.50 (s, 2H), 7.40−7.21 (m, 7H), 7.08 (t, 2H, J = 8.0
Hz), 4.17−4.12 (m, 2H), 4.05−4.0 (m, 2H), 3.50 (dd, 1H, J1 =
20.0 Hz, J2 = 12.0 Hz), 2.74−2.71 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 168.3, 148.0, 142.8, 138.1, 136.2, 133.8, 130.1, 129.7,
129.3, 127.7, 127.2, 126.4, 125.6, 122.4, 121.4, 121.3, 116.5, 54.3,
38.5, 29.9; FT-IR (DCM): 3332, 1592, 1423, 1361, 889 cm−1;
HRMS (ESI): m/z [M + H]+ calcd for C26H21Br2N2O:
535.0020; found 535.0024.
(1S*,2R*,4S*)-2,4-Bis(3,4-dimethylphenyl)-N-(quino-
lin-8-yl)cyclobutanecarboxamide (16q). Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.70; light-yellow color
solid; 107 mg, 99% yield; mp 99−102 °C; 1H NMR (400 MHz,
CDCl3): δ 9.42 (br s, 1H), 8.64 (q, 1H, J = 4.0 Hz), 8.32−8.30
(m, 1H), 7.92 (d, 1H, J = 8.0 Hz), 7.28−7.17 (m, 3H), 7.08 (t,
4H, J = 8.0 Hz), 6.92 (d, 2H, J = 8.0 Hz) 4.07−4.03 (m, 1H), 3.92
(q, 2H, J = 8.0 Hz), 3.48 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz),
2.66−2.63 (m, 1H), 2.05 (s, 12H); 13C NMR (100 MHz,
CDCl3): δ 169.4, 147.7, 138.2, 138.1, 136.1, 136.0, 134.4, 134.1,
129.4, 128.4, 127.6, 127.2, 124.5, 121.2, 120.8, 116.4, 54.7, 39.0,
30.3, 19.8, 19.4; FT-IR (KBr): 3435, 1575, 1365, 1291, 1047
cm−1; HRMS (ESI): m/z [M + H]+ calcd for C30H31N2O:
435.2423; found 435.2419.
(1S*,2R*,4S*)-2,4-Bis(3,5-dimethylphenyl)-N-(quino-
lin-8-yl)cyclobutanecarboxamide (16r). Analytical TLC on
silica gel, 1:4 ethyl acetate/hexane Rf = 0.70; pale-yellow color
liquid; 100 mg, 93% yield; 1H NMR (400 MHz, CDCl3): δ 9.40
(br s, 1H), 8.69 (q, 1H, J = 4.0 Hz), 8.28 (q, 1H, J = 4.0 Hz), 7.98
(q, 1H, J = 4.0 Hz), 7.32−7.19 (m, 3H), 6.90 (s, 4H), 6.62 (s,
2H), 4.09−4.04 (m, 1H), 3.96−3.90 (m, 2H), 3.45 (dd, 1H, J1 =
20.0 Hz, J2 = 12.0 Hz), 2.67−2.62 (m, 1H), 2.09 (s, 12H); 13
C
Q
dx.doi.org/10.1021/jo4019733 | J. Org. Chem. XXXX, XXX, XXX−XXX

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NMR (100 MHz, CDCl3): δ 169.3, 147.7, 140.5, 138.3, 137.3,
136.1, 134.4, 127.8, 127.7, 127.2, 124.8, 121.2, 120.7, 116.4, 54.6,
39.0, 30.0, 21.3; FT-IR (DCM): 3358, 1690, 1520, 1387, 791
cm−1; HRMS (ESI): m/z [M + H]+ calcd for C30H31N2O:
435.2436; found 435.2423.
1H, J = 4.0 Hz), 7.40−7.37 (m, 3H), 7.10−7.06 (m, 4H), 6.92 (q,
2H, J = 4.0 Hz), 4.22−4.16 (m, 2H), 4.06−4.01 (m, 1H), 3.57
(dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.95−2.88 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ 168.1, 147.9, 143.4, 138.2, 136.2,
134.3, 127.7, 127.3, 126.7, 125.2, 123.9, 121.4, 121.2, 116.6, 55.9,
35.7, 35.5; FT-IR (DCM): 3313, 1612, 1554, 1302, 801 cm−1;
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2OS2: 391.0938;
found 391.0936.
(1S*,2R*,4S*)-2,4-Bis(3,4-dichlorophenyl)-N-(quinolin-
8-yl)cyclobutanecarboxamide (16s). Analytical TLC on
silica gel, 1.5:3.5 ethyl acetate/hexane Rf = 0.60; white color
solid; 51 mg, 40% yield; mp 140−145 °C; 1H NMR (400 MHz,
CDCl3): δ 9.64 (br s, 1H), 8.81 (q, 1H, J = 4.0 Hz), 8.19 (q, 1H, J
= 8.0 Hz), 8.09 (q, 1H, J = 4.0 Hz), 7.44−7.30 (m, 4H), 7.29−
7.18 (m, 5H), 4.58−4.53 (m, 1H), 4.19−4.12 (m, 2H), 3.60 (dd,
1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.66−2.60 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 168.3, 148.0, 138.2, 136.3, 136.1, 134.0,
133.9, 132.6, 129.7, 128.8, 127.7, 127.1, 126.8, 121.4, 121.3,
116.2, 53.6, 37.4, 27.5; FT-IR (KBr): 3341, 1631, 1587, 1332,
804 cm−1; HRMS (ESI): m/z [M + H]+ calcd for
C26H19Cl4N2O: 515.0251; found 515.0249.
(1S*,2R*,4S*)-2,4-Bis(4-acetylphenyl)-N-(quinolin-8-
yl)cyclobutanecarboxamide (16t). Analytical TLC on silica
gel, 2:3 ethyl acetate/hexane Rf = 0.30; yellow color solid; 99 mg,
86% yield; mp181−183 °C; 1H NMR (400 MHz, CDCl3): δ 9.60
(br s, 1H), 8.75 (q, 1H, J = 4.0 Hz), 8.25 (q, 1H, J = 4.0 Hz), 8.06
(q, 1H, J = 8.0 Hz), 7.81−7.79 (m, 4H), 7.42−7.24 (m, 7H), 4.28
(q, 1H, J = 4.0 Hz), 4.16−4.09 (m, 2H), 3.59 (dd, 1H, J1 = 20.0
Hz, J2 = 12.0 Hz), 2.83 (t, 1H, J = 4.0 Hz), 2.47 (s, 6H); 13C NMR
(100 MHz, CDCl3): δ 197.9, 168.4, 148.0, 146.3, 138.1, 136.3,
135.1, 133.8, 128.3, 127.7, 127.1, 127.0, 121.5, 121.4, 116.4, 54.4,
38.9, 29.8, 26.5; FT-IR (KBr): 3345, 1605, 1524, 1391, 793 cm−1;
HRMS (ESI): m/z [M + H]+ calcd for C30H27N2O3: 463.2021;
found 463.2012.
(1S*,2R*,4S*)-2,4-Bis(4-methoxy-2-nitrophenyl)-N-
(quinolin-8-yl)cyclobutanecarboxamide (16u). Analytical
TLC on silica gel, 2:3 ethyl acetate/hexane Rf = 0.30; yellow color
solid; 75 mg, 57% yield; mp145−147 °C; 1H NMR (400 MHz,
CDCl3): δ 9.53 (br s, 1H), 8.74 (q, 1H, J = 4.0 Hz), 8.12 (q, 1H, J
= 8.0 Hz), 8.01 (q, 1H, J = 8.0 Hz), 7.57 (d, 2H, J = 8.0 Hz),
7.37−7.34 (m, 1H), 7.30−7.29 (m, 3H), 7.28−7.29 (m, 1H),
7.09−7.07 (m, 2H), 4.65 (q, 1H, J = 4.0 Hz), 4.34−4.27 (m, 2H),
3.70 (s, 6H), 3.52 (dd, 1H, J1 = 12.0 Hz, J2 = 8.0 Hz), 2.61 (q, 1H,
J = 8.0 Hz); 13C NMR (100 MHz, CDCl3): δ 168.9, 158.2, 148.9,
148.2, 138.2, 135.8, 133.9, 130.8, 127.5, 126.7, 121.4, 121.2,
119.5, 116.1, 109.3, 55.6, 55.2, 35.9, 28.1; FT-IR (KBr): 3430,
1555, 1521, 1493, 819 cm−1; HRMS (ESI): m/z [M + H]+ calcd
for C28H25N4O7: 529.1723; found 529.1728.
(1S*,2R*,4S*)-2,4-Di(1H-indol-5-yl)-N-(quinolin-8-yl)-
cyclobutanecarboxamide (16v). Analytical TLC on silica gel,
2:3 ethyl acetate/hexane Rf = 0.30; yellow color semisolid; 75 mg,
66% yield; 1H NMR (400 MHz, CDCl3): δ 9.53 (br s, 1H), 8.95
(br s, 2H), 8.45 (d, 1H, J = 4.0 Hz), 8.13 (d, 1H, J = 8.0 Hz),
7.90−7.78 (m, 1H), 7.66−7.39 (m, 2H), 7.22 (q, 1H, J = 4.0 Hz),
7.20−6.75 (m, 8H), 6.32 (s, 2H), 4.16 (t, 3H, J = 8.0 Hz), 3.58
(dd, 1H, J1 = 12.0 Hz, J2 = 8.0 Hz), 2.79 (t, 1H, J = 8.0 Hz); 13C
NMR (100 MHz, CDCl3): δ 169.9, 147.8, 138.1, 135.9, 134.6,
134.2, 131.5, 127.8, 127.5, 126.9, 124.3, 121.2, 120.7, 118.7,
116.2, 110.8, 101.8, 55.2, 39.7, 30.9; FT-IR (KBr): 3440, 1616,
1528, 1412, 710 cm−1; HRMS (ESI): m/z [M + H]+ calcd for
C30H25N4O: 457.2028; found 457.2035.
(1S*,2R*,4S*)-2,4-Bis(6-fluoropyridin-3-yl)-N-(quino-
lin-8-yl)cyclobutanecarboxamide (16x). Analytical TLC on
silica gel, 2:3 ethyl acetate/hexane Rf = 0.30; yellow color solid;
1
83 mg, 80% yield; mp187−189 °C; H NMR (400 MHz,
CDCl3): δ 9.70 (br s, 1H), 8.76 (q, 1H, J = 4.0 Hz), 8.23−8.17
(m, 4H), 7.86−7.81 (m, 2H), 7.48 (t, 2H, J = 4.0 Hz), 7.46−7.28
(m, 1H), 6.80 (q, 2H, J = 8.0 Hz), 4.20−4.05 (m, 3H), 3.56 (dd,
1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.79 (q, 1H, J = 4.0 Hz); 13C
NMR (100 MHz, CDCl3): δ 168.3, 162.4 (d, JC−F = 236 Hz),
147.6, 146.2 (d, JC−F = 14.5 Hz), 140.1 (d, JC−F = 8 Hz), 137.8,
137.2, 133.1, 132.8, 128.0, 127.5, 122.3, 121.5, 118.2, 108.9 (d,
J
C−F = 37.1 Hz), 54.1, 36.1, 30.0; FT-IR (KBr): 3430, 1624, 1554,
1341, 798 cm−1; HRMS (ESI): m/z [M + H]+ calcd for
C24H19F2N4O: 417.1526; found 417.1526.
(1S*,2R*,4S*)-2,4-Bis(2-chloropyridin-4-yl)-N-(quino-
lin-8-yl)cyclobutanecarboxamide (16y). Analytical TLC on
silica gel, 2:3 ethyl acetate/hexane Rf = 0.30; yellow color liquid;
107 mg, 96% yield; 1H NMR (400 MHz, CDCl3): δ 9.70 (br s,
1H), 8.75 (q, 1H, J = 4.0 Hz), 8.22−8.15 (m, 3H), 8.10 (q, 1H, J
= 8.0 Hz), 7.43−7.39 (m, 2H), 7.34−7.26 (m, 3H), 7.13−7.11
(m, 2H), 4.28−4.23 (m, 1H), 4.03−3.96 (m, 2H), 3.45 (dd, 1H,
J1 = 20.0 Hz, J2 = 12.0 Hz), 2.78−2.73 (m, 1H); 13C NMR (100
MHz, CDCl3): δ 167.3, 152.7, 151.5, 149.8, 148.3, 138.1, 136.5,
133.6, 127.8, 127.1, 122.7, 122.1, 121.7, 120.9, 116.7, 53.6, 37.7,
28.9; FT-IR (DCM): 3350, 1624, 1510, 1491, 810 cm−1; HRMS
(ESI): m/z [M + H]+ calcd for C24H19Cl2N4O: 449.0935; found
449.0936.
(1S*,2S*,4R*)-2-(4-Methoxyphenyl)-N-(quinolin-8-yl)-
4-(thiophen-2-yl)cyclobutanecarboxamide (16z). Analyt-
ical TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.70; yellow
color liquid; 69 mg, 67% yield; 1H NMR (400 MHz, CDCl3): δ
9.55 (br s, 1H), 8.75 (q, 1H, J = 4.0 Hz), 8.46 (q, 1H, J = 4.0 Hz),
8.09 (q, 1H, J = 4.0 Hz), 7.41−7.27 (m, 5H), 7.07−7.03 (m, 2H),
6.88−6.81 (m, 1H), 6.80−6.78 (m, 2H), 4.22−4.17 (m, 1H),
4.09−4.0 (m, 2H), 3.98 (s, 3H), 3.55 (dd, 1H, J1 = 12.0 Hz, J2 =
8.0 Hz), 2.83−2.71 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
168.6, 157.9, 147.8, 143.8, 138.2, 136.2, 134.3, 132.4, 128.1,
127.7, 127.3, 126.6, 125.0, 123.8, 121.3, 121.0, 116.5, 113.5, 55.3,
55.1, 38.7, 35.2, 33.2; FT-IR (KBr): 3439, 1602, 1534, 1423, 990
cm−1; HRMS(ESI): m/z [M + H]+ calcd for C25H23N2O2S:
415.1480; found 415.1488.
(1S*,2R*,4S*)-2-(1H-Indol-5-yl)-4-(4-methoxyphenyl)-
N-(quinolin-8-yl)cyclobutanecarboxamide (16aa). Analyt-
ical TLC on silica gel, 2.5:2.5 ethyl acetate/hexane Rf = 0.30;
1
yellow color liquid; 91 mg, 82% yield; H NMR (400 MHz,
CDCl3): δ 9.60 (br s, 1H), 8.60 (q, 1H, J = 4.0 Hz), 8.32 (q, 1H, J
= 4.0 Hz), 8.21 (br s, 1H), 7.96−7.94 (m, 1H), 7.67 (d, 1H, J =
4.0 Hz), 7.32−7.05 (m, 8H), 6.98−6.75 (m, 2H), 6.42−6.41 (m,
1H), 4.20−4.15 (m, 2H), 4.06 (t, 1H, J = 4.0 Hz), 3.68 (s, 3H),
3.59 (dd, 1H, J1 = 12.0 Hz, J2 = 8.0 Hz), 2.80−2.72 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ 169.7, 157.8, 147.7, 138.2, 136.0,
134.6, 134.2, 132.9, 131.6, 128.2, 127.8, 127.6, 127.1, 124.2,
121.3, 121.2, 120.9, 118.8, 116.4, 113.5, 110.8, 102.1, 55.1, 55.0,
39.3, 38.7, 30.7; FT-IR (KBr): 3430, 1623, 1515, 1421, 890 cm−1;
(1S*,2R*,4S*)-N-(Quinolin-8-yl)-2-(thiophen-2-yl)-4-
(thiophen-3-yl)cyclobutanecarboxamide (16w). Analytical
TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.70; yellow color
solid; 81 mg, 83% yield; 1H NMR (400 MHz, CDCl3): δ 9.61 (br
s, 1H), 8.75 (q, 1H, J = 4.0 Hz), 8.56 (t, 1H, J = 4.0 Hz), 8.08 (q,
R
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HRMS(ESI): m/z [M + H]+ calcd for C29H26N3O2: 448.2025;
found 448.2034.
MHz, CDCl3): δ 9.56 (br s, 1H), 8.72 (q, 1H, J = 4.0 Hz), 8.43 (q,
1H, J = 4.0 Hz), 8.10 (q, 1H, J = 4.0 Hz), 7.42−7.28 (m, 3H),
6.90−6.87 (m, 4H), 6.76 (t, 1H, J = 8.0 Hz), 4.17−4.10 (m, 1H),
4.04−3.98 (m, 2H), 3.73 (s, 6H), 3.73 (s, 6H), 3.72 (dd, 1H, J1 =
20.0 Hz, J2 = 12.0 Hz), 2.75−2.74 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 169.3, 148.5, 147.7, 147.2, 138.2, 136.3, 134.2, 133.3,
127.7, 127.3, 121.3, 121.1, 119.1, 116.4, 110.8, 110.1, 50.7, 55.6,
54.6, 38.8, 31.1; FT-IR (KBr): 2922, 1601, 1545, 1434, 821 cm−1;
HRMS (ESI): m/z [M + H]+ calcd for C30H31N2O5: 499.2233;
found 499.2245.
(1S*,2R*,4S*)-2,4-Bis(benzo-[d][1,3]-dioxol-5-yl)-N-
(quinolin-8-yl)cyclobutanecarboxamide (16ag). Analytical
TLC on silica gel, 4:1 ethyl acetate/hexanes Rf = 0.70 yellow
color liquid; 58 mg, 50% yield; 1H NMR (400 MHz, CDCl3): δ
9.51(br s, 1H), 8.76 (q, 1H, J = 4.0 Hz), 8.41 (q, 1H, J = 4.0 Hz),
8.09 (q, 1H, J = 4.0 Hz), 7.44−7.33 (m, 3H), 6.85−6.79 (m, 4H),
6.68 (q, 2H, J = 4.0 Hz), 5.82 (d, 4H, J = 4.0 Hz),4.09−4.04 (m,
1H), 3.98−3.91 (m, 2H), 3.42 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0
Hz), 2.70−2.63 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 168.9,
147.8, 147.4, 145.8, 138.2, 136.2, 134.4, 134.2, 127.7, 127.7,
127.3, 121.3, 121.0, 120.0, 116.4, 107.9, 107.7, 100.7, 54.7, 38.8,
30.6; FT-IR (DCM): 3041, 1723, 1487, 1421, 991 cm−1; HRMS
(ESI): m/z [M + H]+ calcd for C28H23N2O5: 467.1607; found
467.1608.
(1S*,2R*,4S*)-2-(2-Chloropyridin-4-yl)-4-(4-methoxy-
phenyl)-N-(quinolin-8-yl)cyclobutanecarboxamide
(16ab). Analytical TLC on silica gel, 2.5:2.5 ethyl acetate/hexane
Rf = 0.30; light-yellow color liquid; 33 mg, 30% yield; 1H NMR
(400 MHz, CDCl3): δ 9.47 (br s, 1H), 8.70 (m, 1H), 8.22−8.04
(q, 1H, J = 4.0 Hz), 7.40−7.09 (m, 8H), 6.65 (q, 2H, J = 8.0 Hz),
4.24−3.87 (m, 3H), 3.59 (s, 3H), 3.40 (dd, 1H, J1 = 20.0 Hz, J2 =
12.0 Hz), 2.68−2.65 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
168.2, 158.1, 154.2, 151.4, 149.0, 148.0, 147.9, 144.3, 138.1,
136.3, 133.7, 131.3, 128.2, 127.7, 127.1, 122.6, 121.5, 120.9,
116.5, 113.5, 55.1, 54.2, 39.0, 37.3, 31.9; FT-IR (KBr): 3423,
1566, 1513, 1448, 810 cm−1; HRMS (ESI): m/z [M + H]+ calcd
for C26H23ClN3O2: 444.1478; found 444.1483.
(1S*,2S*,4R*)-2-(2-Chloropyridin-4-yl)-N-(quinolin-8-
yl)-4-(thiophen-2-yl)cyclobutanecarboxamide (16ac).
Analytical TLC on silica gel, 2.5:2.5 ethyl acetate/hexane Rf =
0.30; yellow color solid; 54 mg, 52% yield; mp 182−184 °C; 1H
NMR (400 MHz, CDCl3): δ 9.59 (br s, 1H), 8.77 (q, 1H, J = 4.0
Hz), 8.40 (q, 1H, J = 4.0 Hz), 8.24 (q, 1H, J = 4.0 Hz), 8.10 (q,
1H, J = 8.0 Hz), 7.44−7.35 (m, 3H), 7.28 (d, 1H, J = 8.0 Hz),
7.14 (q, 1H, J = 4.0 Hz), 7.03−7.02 (m, 2H), 6.82 (q, 1H, J = 8.0
Hz), 4.31−4.24 (m, 1H), 4.18−4.13 (m, 1H), 3.94−3.80 (m,
1H), 3.50 (dd, 1H, J1 = 12.0 Hz, J2 = 8.0 Hz), 2.89−2.82 (m, 1H);
13C NMR (100 MHz, CDCl3): δ 167.7, 153.9, 151.5, 149.2,
148.0, 142.3, 138.2, 136.3, 133.8, 127.8, 127.3, 126.7, 125.4,
124.3, 122.5, 121.6, 121.5, 120.8, 116.6, 54.9, 37.5, 35.5, 32.5;
FT-IR (KBr): 3530, 1654, 1529, 1409, 990 cm−1; HRMS(ESI):
m/z [M + H]+ calcd for C23H19ClN3OS: 420.0937; found
420.0943.
(1S*,2S*,4R*)-2-(1H-Indol-5-yl)-N-(quinolin-8-yl)-4-
(thiophen-2-yl)cyclobutanecarboxamide (16ad). Analyti-
cal TLC on silica gel, 2.5:2.5 ethyl acetate/hexane Rf = 0.30; red
color liquid; 54 mg, 51% yield; 1H NMR (400 MHz, CDCl3): δ
9.60 (br s, 1H), 8.60 (q, 1H, J = 4.0 Hz), 8.40 (q, 1H, J = 4.0 Hz),
8.16 (br s, 1H), 8.01 (q, 1H, J = 8.0 Hz), 7.99 (d, 1H, J = 4.0 Hz),
7.65−7.23 (m, 3H), 7.13−7.04 (m, 5H), 6.88 (q, 1H, J = 4.0 Hz),
6.45 (q, 1H, J = 8.0 Hz), 4.29−4.10 (m, 3H), 3.62 (dd, 1H, J1 =
12.0 Hz, J2 = 8.0 Hz), 2.92−2.88 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 169.1, 147.8, 144.0, 138.2, 136.0, 134.6, 134.3, 131.3,
127.9, 127.6, 127.2, 126.6, 125.0, 124.2, 123.8, 121.3, 121.2,
121.0, 118.7, 116.5, 110.8, 102.3, 55.6, 39.4, 35.5, 33.4; FT-IR
(KBr): 3400, 1613, 1531, 1454, 910 cm−1; HRMS(ESI): m/z [M
+ H]+ calcd for C26H22N3OS: 424.1483; found 424.1492.
(1S*,2R*,4S*)-2,4-Bis(2,4-dimethoxyphenyl)-N-(quino-
lin-8-yl)cyclobutanecarboxamide (16ae). Analytical TLC
on silica gel, 4:1 ethyl acetate/hexanes Rf = 0.60 red color liquid;
100 mg, 80% yield; 1H NMR (400 MHz, CDCl3): δ 9.52 (br s,
1H), 8.80 (q, 1H, J = 4.0 Hz), 8.36 (q, 1H, J = 4.0 Hz), 8.07 (q,
1H, J = 4.0 Hz), 7.40 (q, 1H, J = 4.0 Hz), 7.31−7.24 (m, 4H),
6.48 (q, 2H, J = 4.0 Hz), 6.25 (d, 2H, J = 4.0 Hz), 4.27−4.24 (m,
1H), 4.09−4.02 (m, 2H), 3.75 (s, 6H), 3.71 (s, 6H), 3.40 (dd,
1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.64−2.60 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 170.3, 159.1, 158.0, 147.6, 138.2, 136.2,
134.8, 128.1, 127.7, 127.4, 122.1, 121.2, 120.2, 115.9, 103.5, 97.5,
55.3, 55.2, 53.8, 35.4; FT-IR (DCM): 2881, 1643, 1511, 1423,
811 cm−1; HRMS (ESI): m/z [M + H]+ calcd for C30H31N2O5:
499.2333; found 499.2227.
(1S*,2R*,4S*)-N-(Quinolin-8-yl)-2,4-bis(3,4,5-trimeth-
oxyphenyl)cyclobutanecarboxamide (16ah). Analytical
TLC on silica gel, 2.5:2.5 ethyl acetate/hexanes Rf = 0.30 light-
1
yellow color liquid; 70 mg, 50% yield; H NMR (400 MHz,
CDCl3): δ 9.58 (br s, 1H), 8.73 (q, 1H, J = 4.0 Hz), 8.46 (q, 1H, J
= 4.0 Hz), 8.12 (q, 1H, J = 4.0 Hz), 7.44−7.34 (m, 3H), 6.53 (s,
4H), 4.16 (q, 1H, J = 4.0 Hz), 4.03−3.91 (m, 2H), 3.73 (s, 12H),
3.67 (s, 6H), 3.40 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.80−2.77
(m, 1H); 13C NMR (100 MHz, CDCl3): δ 169.1, 152.9, 147.8,
138.1, 136.5, 136.3, 136.2, 134.2, 127.8, 127.3, 121.5, 121.3,
116.4, 103.7, 60.7, 55.9, 54.4, 39.2, 31.2; FT-IR (DCM): 3120,
1611, 1436, 1346, 771 cm−1; HRMS (ESI): m/z [M + H]+ calcd
for C32H35N2O7: 559.2444; found 559.2455.
(1S*,2S*,4R*)-2-(4-Methoxyphenyl)-N-(quinolin-8-yl)-
4-(3,4,5-trimethoxyphenyl)cyclobutanecarboxamide
(16ai). Analytical TLC on silica gel, 2.5:2.5 ethyl acetate/hexanes
Rf = 0.40 red color liquid; 50 mg, 40% yield; 1H NMR (400 MHz,
CDCl3): δ 9.52 (br s, 1H), 8.73 (q, 1H, J = 4.0 Hz), 8.42 (q, 1H, J
= 8.0 Hz), 8.10 (q, 1H, J = 4.0 Hz), 7.42−7.26 (m, 5H), 6.82 (q,
2H, J = 4.0 Hz), 6.50 (d, 2H, J = 8.0 Hz), 6.55 (t, 2H, J = 4.0 Hz),
4.15−4.10 (m, 1H), 4.02−3.97 (m, 2H), 3.73 (s, 3H), 3.71 (s,
6H), 3.61 (s, 3H), 3.44 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz),
2.25−2.72 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 169.2,
157.8, 152.8, 147.8, 138.1, 136.4, 136.3, 136.2, 134.2, 132.7,
127.8, 127.7, 127.3, 121.4, 121.1116.4, 113.6, 103.8, 60.6, 55.8,
55.2, 54.6, 30.7, 38.1, 30.8; FT-IR (DCM): 2921, 1523, 1476,
1444, 749 cm−1;HRMS (ESI): m/z [M + H]+ calcd for
C30H31N2O5: 499.2233; found 499.2234.
(1R*,2R*,4S*)-2-(3,4-Dimethoxyphenyl)-N-(quinolin-
8-yl)-4-(3,4,5-trimethoxyphenyl)cyclobutanecarbox-
amide (16aj). Analytical TLC on silica gel, 2.5:2.5 ethyl acetate/
hexanes Rf = 0.30 light-brown color liquid; 99 mg, 75% yield; 1H
NMR (400 MHz, CDCl3): δ 9.57 (br s, 1H), 8.72 (q, 1H, J = 4.0
Hz), 8.44 (dd, 1H, J1 = 8.0 Hz, J2 = 4.0 Hz), 8.10 (q, 1H, J = 4.0
Hz), 7.41−7.32 (m, 3H), 6.90 (q, 1H, J = 4.0 Hz), 6.77 (t, 1H, J =
8.0 Hz), 6.55 (t, 2H, J = 4.0 Hz), 4.14−4.11 (m, 1H), 4.02−3.98
(m, 2H), 3.78 (s, 6H), 3.74 (s, 3H), 3.72 (s, 6H), 3.65 (s, 3H),
3.43 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.77−2.76 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ 169.2, 152.9, 148.6, 147.8, 147.3,
(1S*,2R*,4S*)-2,4-Bis(3,4-dimethoxyphenyl)-N-(quino-
lin-8-yl)cyclobutanecarboxamide (16af). Analytical TLC
on silica gel, 2.5:2.5 ethyl acetate/hexanes Rf = 0.30; pale-yellow
color solid; 40 mg, 32% yield; mp 175−177 °C; 1H NMR (400
S
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138.1, 136.6, 136.3, 136.1, 134.2, 133.3, 127.7, 127.3, 121.4,
121.2, 119.0, 116.4, 110.8, 110.4, 103.8, 60.7, 55.9, 55.6, 54.5,
39.4, 38.6, 31.3; FT-IR (DCM): 2811, 1535, 1476, 1423, 981
cm−1; HRMS (ESI): m/z [M + H]+ calcd for C31H33N2O6:
529.2338; found 529.2343.
(m, 2H), 4.17−4.04 (m, 3H), 3.64 (dd, 1H, J1 = 20.0 Hz, J2 = 8.0
Hz), 2.82−2.79 (m, 1H), 2.11 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 192.5, 168.0, 141.4, 137.1, 136.3, 133.1, 132.1, 128.9,
128.3, 125.6, 124.5, 121.0, 54.1, 38.5, 29.5, 18.5; FT- IR (KBr):
3351, 1668, 1582, 1398, 810 cm−1; HRMS (ESI): m/z [M + H]+
calcd for C26H24NO3S: 430.1476; found 430.1482.
(1S*,2R*,4S*)-N-(2-(Methylthio)phenyl)-2,4-di-p-tolyl-
cyclobutanecarboxamide (19b). Analytical TLC on silica gel,
1:4 ethyl acetate/hexane Rf = 0.70; white color solid; 45 mg, 45%
yield; mp 98−100 °C; 1H NMR (400 MHz, CDCl3): δ 7.95 (br s,
1H),7.74 (d, 1H, J = 8.0 Hz), 7.34 (q, 1H, J = 8.0 Hz), 7.29−7.21
(m, 4H), 7.09−7.05 (m, 5H), 6.94−6.91 (m, 1H), 4.01−3.94 (m,
3H), 3.48 (dd, 1H, J1 = 12.0 Hz, J2 = 8.0 Hz), 2.70−2.67 (m, 1H),
2.28 (s, 6H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
168.8, 138.2, 137.3, 135.6, 132.8, 129.0, 128.9, 128.6, 126.8,
123.8, 121.0, 54.5, 38.7, 30.0, 21.1, 18.8; FT-IR (KBr): 3324,
1622, 1534, 1491, 810 cm−1; HRMS (ESI): m/z [M + H]+ calcd
for C26H28NOS: 402.1891; found 402.1896.
(1R*,2S*)-2-(4-Methoxyphenyl)-N-(quinolin-8-yl)-
cyclobutanecarboxamide (17a). Analytical TLC on silica gel,
1:4 ethyl acetate/hexane Rf = 0.70; brown color liquid; 25 mg,
30% yield; 1H NMR (400 MHz, CDCl3): δ 9.36 (br s, 1H), 8.73
(q, 1H, J = 8.0 Hz), 8.54 (q, 1H, J = 8.0 Hz), 8.11 (q, 1H, J = 8.0
Hz), 7.47−7.39 (m, 3H), 7.25−7.23 (m, 2H), 6.65 (q, 2H, J = 4.0
Hz), 4.08 (dd, 1H, J1 = 20.0 Hz, J2 = 8.0 Hz), 3.75 (q, 1H, J = 4.0
Hz), 3.57 (s, 3H), 2.69−2.63 (m, 2H), 2.12−2.33 (m, 2H); 13
C
NMR (100 MHz, CDCl3): δ 171.4, 158.0, 147.8, 138.2, 136.1,
134.4, 132.8, 128.4, 127.7, 127.3, 121.3, 120.9, 116.1, 113.5, 55.0,
47.8, 42.8, 25.4, 20.4, ; FT-IR (DCM): 3231, 1610, 1494, 1321,
710 cm−1; HRMS (ESI): m/z [M + H]+ calcd for C21H21N2O2:
333.1603; found 333.1599.
(1R*,2S*)-2-Phenyl-N-(quinolin-8-yl)cyclobutane-
carboxamide (17b). Analytical TLC on silica gel, 1:4 ethyl
acetate/hexane Rf = 0.70; brown color liquid; 15 mg, 20% yield;
1H NMR (400 MHz, CDCl3): δ 9.40 (br s, 1H), 8.73 (t, 1H, J =
8.0 Hz), 8.54 (q, 1H, J = 8.0 Hz), 8.10 (q, 1H, J = 8.0 Hz), 7.46−
7.36 (m, 2H), 7.34−7.32 (m, 2H), 7.32−7.28 (m, 1H), 7.24−
7.09 (m, 2H), 6.98−6.94 (m, 1H), 4.12 (dd, 1H, J1 = 20.0 Hz, J2 =
8.0 Hz), 3.80 (q, 1H, J = 4.0 Hz), 2.75−2.64 (m, 2H), 2.45−2.36
(m, 2H); 13C NMR (100 MHz, CDCl3): δ 171.3, 147.8, 140.7,
138.2, 136.1, 134.3, 128.0, 127.4, 127.3, 126.9, 126.3, 121.3,
121.1, 116.1, 47.7, 43.4, 25.1, 20.6; FT-IR (DCM): 3355, 1650,
1534, 1475, 890 cm−1; HRMS (ESI): m/z [M + H]+ calcd for
C20H19N2O: 303.1497; found 303.1504.
(1R*,2S*)-N-(Quinolin-8-yl)-2-(thiophen-2-yl)cyclo-
butanecarboxamide (17c). Analytical TLC on silica gel, 1:4
ethyl acetate/hexane Rf = 0.70; yellow color liquid; 32 mg, 42%
yield; 1H NMR (400 MHz, CDCl3): δ 9.51 (br s, 1H), 8.76 (q,
1H, J = 8.0 Hz), 8.65 (q, 1H, J = 4.0 Hz), 8.12 (q, 1H, J = 8.0 Hz),
7.49−7.40 (m, 3H), 6.98−6.93 (m, 2H), 6.76 (q, 1H, J = 4.0 Hz),
4.35−4.35 (dd, 1H, J1 = 20.0 Hz, J2 = 8.0 Hz), 3.79 (q, 1H, J2 =
4.0 Hz), 2.71−2.53 (m, 3H), 2.36−2.30 (m, 1H); 13C NMR (100
MHz, CDCl3): δ 170.8, 147.9, 144.2, 138.3, 136.2, 134.4, 127.8,
127.4, 126.7, 124.7, 123.7, 121.4, 121.1, 116.2, 48.2, 38.7, 27.8,
20.6; FT-IR (KBr): 3335, 1641, 1510, 1431, 790 cm−1; HRMS
(ESI): m/z [M + H]+ calcd for C18H17N2OS: 309.1061; found
309.1071.
(1R*,2S*)-N-(Quinolin-8-yl)-2-(3,4,5-trimethoxy-
phenyl)cyclobutanecarboxamide (17d). Analytical TLC on
silica gel, 2.5:2.5 ethyl acetate/hexanes Rf = 0.40; white solid 31
mg, 32% yield; mp 125−127 °C; 1H NMR (400 MHz, CDCl3): δ
9.26 (br s, 1H), 8.67−8.62 (m, 2H), 8.08 (q, 1H, J = 8.0 Hz),
7.46−7.39 (m, 3H), 6.50 (s, 2H), 4.08−4.05 (m, 1H), 4.04−3.71
(m, 1H), 3.67 (s, 6H), 3.67 (s, 6H), 3.30 (s, 3H), 2.70−2.60 (m,
2H), 2.38−2.28 (m, 2H); 13C NMR (100 MHz, CDCl3): δ
171.4, 152.8, 147.7, 138.1, 136.4, 136.3, 136.2, 134.5, 127.8,
127.2, 121.4, 121.1, 115.8, 104.3, 60.3, 55.8, 48.2, 43.9, 25.5, 19.9;
FT-IR (KBr): 2830, 1599, 1502, 1391, 881 cm−1; HRMS (ESI):
m/z [M + H]+ calcd for C23H25N2O4: 393.1814; found 393.1808.
(1S*,2R*,4S*)-2,4-Bis(3-formylphenyl)-N-(2-(methyl-
thio)phenyl)cyclobutanecarboxamide (19a). Analytical
TLC on silica gel, 1.5:3.5 ethyl acetate/hexane Rf = 0.30;
brown color solid; 56 mg, 52% yield; mp 100−102 °C; 1H NMR
(400 MHz, CDCl3): δ 10.1 (s, 2H), 7.95 (br s, 1H), 7.84 (s, 2H),
7.69 (d, 2H, J = 8.0 Hz), 7.61 (d, 2H, J = 8.0 Hz), 7.50−7.44 (m,
1H), 7.29 (q, 2H, J = 4.0 Hz), 7.02 (q, 1H, J = 8.0 Hz), 6.98−6.90
(1S*,2R*,4S*)-2,4-Bis(4-acetylphenyl)-N-(2-(methyl-
thio)phenyl)cyclobutanecarboxamide (19c). Analytical
TLC on silica gel, 2:3 ethyl acetate/hexane Rf = 0.60; white
color solid; 33 mg, 29% yield; mp 189−191 °C; 1H NMR (400
MHz, CDCl3): δ 7.99 (br s, 1H),7.94 (q, 4H, J = 8.0 Hz), 7.61 (q,
1H, J = 8.0 Hz), 7.39 (q, 4H, J = 8.0 Hz), 7.33−7.28 (m, 1H),
7.05−7.03 (m, 1H), 7.01−6.93 (m, 1H), 4.11−4.06 (m, 3H),
3.57 (dd, 1H, J1 = 12.0 Hz, J2 = 8.0 Hz), 2.77−2.67 (m, 1H), 2.56
(s, 6H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 197.9,
168.0, 146.0, 137.3, 135.3, 134.9, 132.3, 128.5, 128.4, 128.3,
127.0, 125.3, 124.4, 120.9, 54.3, 38.9, 29.7, 26.6, 18.3; FT-IR
(KBr): 3350, 1620, 1551, 1441, 710 cm−1; HRMS (ESI): m/z [M
+ Na]+ calcd for C28H27NO3SNa: 480.1609; found 480.1604.
(1S*,2R*,4S*)-N-(2-(Dimethylamino)ethyl)-2,4-bis(3-
nitrophenyl)cyclobutanecarboxamide (21a). Analytical
TLC on silica gel, 2:3.methanol/ethyl acetate Rf = 0.40; black
color solid; 46 mg, 45% yield; mp 130−132 °C; 1H NMR (400
MHz, CDCl3): δ 8.07−8.01 (m, 4H), 7.60 (d, 2H, J = 12.0 Hz),
7.46 (t, 2H, J = 8.0 Hz), 6.34 (br s, 1H), 4.03−3.89 (m, 2H), 3.87
(q, 1H, J = 4.0 Hz), 3.51 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz),
2.83−2.72 (m, 3H), 2.01 (s, 6H), 1.96 (t, 2H, J = 4.0 Hz); 13
C
NMR (100 MHz, CDCl3): δ 169.0, 148.0, 143.0, 133.2, 129.0,
121.9, 121.3, 57.4, 52.5, 44.7, 37.9, 36.0, 29.7; FT-IR (KBr):
2876, 2325, 1618, 1532, 817 cm−1; HRMS (ESI): m/z [M + H]+
calcd for C21H25N4O5: 413.1824; found 413.1813.
(1S*,2R*,4S*)-N-(2-(Dimethylamino)ethyl)-2,4-di-
phenylcyclobutanecarboxamide (21b). Analytical TLC on
silica gel, 2:3. methanol/ethyl acetate Rf = 0.40; red color liquid;
24 mg, 30% yield; 1H NMR (400 MHz, CDCl3): δ 7.33−7.17 (m,
10H), 5.78 (br s, 1H), 3.96−3.89 (m, 2H), 3.78 (q, 1H, J = 4.0
Hz), 3.41 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.83−2.78 (q, 2H,
J = 4.0 Hz), 2.65−2.61(q, 1H, J = 4.0 Hz), 2.0 (s, 6H), 1.86 (t,
2H, J = 4.0 Hz); 13C NMR (100 MHz, CDCl3): δ 169.9, 140.9,
127.9, 127.1, 126.1, 57.4, 53.3, 44.8, 38.6, 35.9, 29.5; FT-IR
(DCM): 2912, 2324, 1612, 1543, 809 cm−1; HRMS (ESI): m/z
[M + H]+ calcd for C21H27N2O: 323.2123; found 323.2113.
(1S*,2R*,4S*)-N-(2-(Dimethylamino)ethyl)-2,4-bis(4-
methoxyphenyl)cyclobutanecarboxamide (21c). Analyt-
ical TLC on silica gel, 2:3. methanol/ethyl acetate Rf = 0.40; pale-
1
yellow color liquid; 51 mg, 53% yield; H NMR (400 MHz,
CDCl3): δ 7.26−7.17 (m, 4H), 6.84−6.80 (m, 4H), 5.67 (br s,
1H), 3.84−3.79 (m, 2H), 3.75 (s, 6H), 3.66−3.63 (m, 1H),3.26
(dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.84−2.79 (m, 2H), 2.56−
2.52 (m, 1H), 1.98 (s, 6H), 1.85 (t, 2H, J = 4.0 Hz); 13C NMR
(100 MHz, CDCl3): δ 170.2, 157.9, 132.9, 128.2, 113.4, 57.6,
T
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55.2, 53.5, 44.8, 38.0, 36.0, 30.1; FT-IR (DCM,): 2948, 2213,
1623, 1534, 812 cm−1; HRMS (ESI): m/z [M + H]+ calcd for
C23H31N2O3: 383.2335; found 383.2352.
TLC on silica gel, 2.5:2.5. methanol/ethyl acetate Rf = 0.40;
black color solid; 45 mg, 48% yield; mp 159−161 °C; 1H NMR
(400 MHz, CDCl3): δ 7.58−7.55 (m, 4H), 7.35−7.28 (m, 2H),
6.13 (br s, 1H), 3.97−3.90 (m, 2H), 3.82 (q, 1H, J = 4.0 Hz), 3.45
(dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.83 (q, 2H, J = 4.0 Hz),
2.66−2.63 (m, 1H), 2.03 (s, 6H), 1.94 (t, 2H, J = 8.0 Hz); 13C
NMR (100 MHz, CDCl3): δ 168.9, 146.4, 131.8, 127.8, 119.1,
109.8, 57.5, 53.0, 45.1, 44.8, 38.4, 35.9, 29.2; FT- IR (KBr): 2945,
2226, 1607, 1506, 827 cm−1; HRMS (ESI): m/z [M + H]+ calcd
for C23H25N4O: 373.2028; found 373.2026.
(1S*,2R*,4S*)-2,4-Bis(4-bromo-3-fluorophenyl)-N-(2-
(dimethylamino)ethyl)cyclobutanecarboxamide (21j).
Analytical TLC on silica gel, 2.5:2.5. methanol/ethyl acetate Rf
= 0.40; red color liquid; 68 mg, 53% yield; 1H NMR (400 MHz,
CDCl3): δ 7.46−7.42 (m, 2H), 7.03 (q, 2H, J = 4.0 Hz), 6.92 (q,
2H, J = 8.0 Hz), 6.45 (br s, 1H), 3.82−3.71 (m, 2H), 3.70 (q, 1H,
J = 4.0 Hz), 3.23 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.94−2.90
(m, 2H), 2.61−2.58 (m, 1H), 2.10 (s, 6H), 2.03 (t, 2H, J = 4.0
Hz); 13C NMR (100 MHz, CDCl3): δ 169.0, 160.1, 157.5 (d,
(1S*,2R*,4S*)-N-(2-(Dimethylamino)ethyl)-2,4-di-p-
tolylcyclobutanecarboxamide (21d). Analytical TLC on
silica gel, 2:3. methanol/ethyl acetate Rf = 0.40; brown color
liquid; 35 mg, 40% yield; 1H NMR (400 MHz, CDCl3): δ 7.19−
7.11 (m, 8H), 5.70 (br s, 1H), 3.89−3.84 (m, 2H), 3.72 (q, 1H, J
= 4.0 Hz), 3.32 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.86−2.82
(m, 2H), 2.61 (q, 1H, J = 4.0 Hz), 2.33 (s, 6H), 2.01 (s, 6H), 1.85
(t, 2H, J = 4.0 Hz); 13C NMR (100 MHz, CDCl3): δ 170.1, 137.8,
135.4, 128.6, 127.2, 57.5, 53.4, 44.8, 38.4, 36.0, 29.7, 21.1; FT-IR
(DCM): 2900, 2316, 1627, 1553, 737 cm−1; HRMS (ESI): m/z
[M + H]+ calcd for C23H31N2O: 351.2436; found 351.2429.
(1S*,2R*,4S*)-N-(2-(Dimethylamino)ethyl)-2,4-bis(4-
ethylphenyl)cyclobutanecarboxamide (21e). Analytical
TLC on silica gel, 2:3. methanol/ethyl acetate Rf = 0.40;
brown color solid; 37 mg, 39% yield; mp 185−188 °C; 1H NMR
(400 MHz, CDCl3): δ 7.21−7.12 (m, 8H), 6.50 (br s, 1H), 3.88
(q, 2H, J = 4.0 Hz), 3.73 (q, 1H, J = 4.0 Hz), 3.33 (dd, 1H, J1 =
20.0 Hz, J2 = 12.0 Hz), 2.91−2.87 (m, 3H), 2.61 (q, 4H, J = 4.0
Hz), 2.05 (s, 6H), 1.94 (t, 2H, J = 4.0 Hz), 1.24 (t, 6H, J = 4.0
Hz); 13C NMR (100 MHz, CDCl3): δ 170.4, 141.8, 138.1, 127.4,
127.1, 57.4, 53.2, 44.1, 38.4, 35.6, 29.7, 28.5, 15.7; FT-IR
(DCM): 3240, 1634, 1494, 1344, 710 cm−1; HRMS (ESI): m/z
[M + H]+ calcd for C25H35N2O: 379.2749; found 3792746.
(1S*,2R*,4S*)-2,4-Bis(4-chlorophenyl)-N-(2-(dimethyl-
amino)ethyl)cyclobutanecarboxamide (21f). Analytical
TLC on silica gel, 2:3. methanol/ethyl acetate Rf = 0.40; white
color solid; 40 mg, 41% yield; mp 155−157 °C; 1H NMR (400
MHz, CDCl3): δ 7.28−7.18 (m, 8H), 5.71 (br s, 1H), 3.88−3.81
(m, 2H), 3.70−3.65 (m, 1H), 3.36 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0
Hz), 2.86−2.82 (m, 2H), 2.62−2.55 (m, 1H), 1.90 (s, 6H), 1.89
(t, 2H, J = 4.0 Hz); 13C NMR (100 MHz, CDCl3): δ 169.4, 139.1,
131.9, 128.5, 128.1, 57.5, 53.2, 44.9, 38.1, 36.0, 29.7; FT-IR
(KBr): 2912, 2323, 1618, 1512, 812 cm−1; HRMS (ESI): m/z [M
+ H]+ calcd for C21H25Cl2N2O: 391.1343; found 391.1340.
(1S*,2R*,4S*)-2,4-Bis(4-bromophenyl)-N-(2-(dimethyl-
amino)ethyl)cyclobutanecarboxamide (21g). Analytical
TLC on silica gel, 2:3. methanol/ethyl acetate Rf = 0.40;
JC−F = 246 Hz), 142.6 (d, JC−F = 7.0 Hz), 132.9, 123.9 (d, JC−F
=
3.0 Hz), 115.2 (d, JC−F = 22.0 Hz), 106.3 (d, JC−F = 20.0 Hz),
57.6, 52.8, 44.8, 37.8, 36.0, 29.7; FT-IR (DCM): 3252, 1601,
1511, 1468, 710 cm−1; HRMS (ESI): m/z [M + H]+ calcd for
C21H23Br2F2N2O: 515.0145; found 515.0101.
(1S*,2R*,4S*)-N-(2-(Dimethylamino)ethyl)-2,4-bis(3,4-
dimethylphenyl)cyclobutanecarboxamide (21k). Analyt-
ical TLC on silica gel, 2:3. methanol/ethyl acetate Rf = 0.40 black
color solid; 40 mg, 42% yield; mp 220−222 °C; 1H NMR (400
MHz, CDCl3): δ 7.08−7.01 (m, 6H), 6.08 (br s, 1H), 3.85−3.81
(m, 2H), 3.71 (t, 1H, J = 4.0 Hz), 3.32 (dd, 1H, J1 = 20.0 Hz, J2 =
12.0 Hz), 2.92−2.88 (m, 2H), 2.58−2.56 (m, 1H), 2.27 (s, 6H),
2.24 (s, 6H), 2.04 (s, 6H), 1.91 (t, 2H, J = 4.0 Hz); 13C NMR
(100 MHz, CDCl3): δ 170.4, 138.3, 135.9, 134.0, 129.3, 128.4,
124.5, 57.5, 53.2, 44.5, 38.4, 35.8, 29.7, 19.9, 19.4; FT-IR (KBr):
2937, 2316, 1567, 1516, 918 cm−1; HRMS (ESI): m/z [M + H]+
calcd for C25H35N2O: 379.2749; found 379.2748.
(1S*,2R*,4S*)-2,4-Bis(2,3-dihydrobenzo[b][1,4]dioxin-
5-yl)-N-(2-(dimethylamino)ethyl)cyclobutanecarbox-
amide (21l). Analytical TLC on silica gel, 2:3. methanol/ethyl
acetate Rf = 0.40 brown color solid; 45 mg, 41% yield; 1H NMR
(400 MHz, CDCl3): δ 6.77−6.70 (m, 6H), 6.11 (br s, 1H), 4.21
(q, 8H, J = 4.0 Hz), 3.77−3.70 (m, 2H), 3.64 (q, 1H, J = 4.0 Hz),
3.15 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.94 (q, 2H, J = 4.0 Hz),
2.52−2.49 (m, 1H), 2.09 (s, 6H), 2.10 (t, 2H, J = 4.0 Hz); 13C
NMR (100 MHz, CDCl3): δ 170.2, 143.0, 141.8, 134.3, 120.0,
116.7, 115.9, 64.3, 57.6, 52.9, 44.8, 44.7, 37.8, 35.9, 30.0; FT-IR
(DCM): 3303, 1651, 1588, 1425, 890 cm−1; HRMS (ESI): m/z
[M + H]+ calcd for C25H31N2O5: 439.2223; found 439.2233.
(1S*,2R*,4S*)-N-(2-(Dimethylamino)ethyl)-2,4-di-
(thiophen-2-yl)cyclobutanecarboxamide (21m). Analyti-
cal TLC on silica gel, 2:3. methanol/ethyl acetate Rf = 0.40 black
color liquid; 25 mg, 30% yield; 1H NMR (400 MHz, CDCl3): δ
7.17 (q, 2H, J = 4.0 Hz), 6.99−6.94 (m, 4H), 6.05 (br s, 1H),
4.03−3.98 (m, 2H), 3.61(q, 1H, J = 4.0 Hz), 3.35 (dd, 1H, J1 =
20.0 Hz, J2 = 12.0 Hz), 3.02 (q, 2H, J = 4.0 Hz), 2.80 (q, 1H, J =
4.0 Hz), 2.07 (s, 6H), 2.03 (t, 2H, J = 4.0 Hz); 13C NMR (100
MHz, CDCl3): δ 169.3, 143.7, 126.7, 125.1, 123.8, 57.6, 54.7,
48.1, 36.1, 35.4, 35.0; FT-IR (DCM): 2800, 2312, 1621, 1512,
800 cm−1; HRMS (ESI): m/z [M + H]+ calcd for C17H23N2OS2:
335.1251; found 335.1245.
1
brown color liquid; 54 mg, 45% yield; H NMR (400 MHz,
CDCl3): δ 7.41−7.38 (m, 4H), 7.14 (d, 4H, J = 8.0 Hz), 6.50 (br
s, 1H), 3.82−3.77 (m, 2H), 3.70 (q, 1H, J = 4.0 Hz), 3.33 (dd,
1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.92−2.82 (m, 2H), 2.57 (t, 1H, J
= 4.0 Hz), 2.09 (s, 6H), 2.0 (t, 2H, J = 4.0 Hz); 13C NMR (100
MHz, CDCl3): δ 169.6, 139.8, 130.9, 129.1, 119.9, 57.5, 52.9,
44.4, 38.1, 35.5, 29.5; FT-IR (KBr): 2912, 2316, 1637, 1544, 917
cm−1 HRMS (ESI): m/z [M + H]+ calcd for C21H25Br2N2O:
479.0333; found 479.0316.
(1S*,2R*,4S*)-N-(2-(Dimethylamino)ethyl)-2,4-bis(4-
nitrophenyl)cyclobutanecarboxamide (21h). Analytical
TLC on silica gel, 2.5:2.5. methanol/ethyl acetate Rf = 0.40;
1
yellow color liquid; 44 mg, 43% yield; H NMR (400 MHz,
CDCl3 and DMSO-d6): δ 8.08 (d, 4H, J = 8.0 Hz), 7.36−7.28 (m,
4H), 6.56 (br s, 1H), 3.96−3.91 (m, 2H), 3.86 (q, 1H, J = 4.0
Hz), 3.42 (dd, 1H, J1 = 20.0 Hz, J2 = 12.0 Hz), 2.81−2.77 (m,
2H), 2.68 (q, 2H, J = 4.0 Hz), 2.0 (s, 6H), 1.92 (t, 2H, J = 8.0 Hz);
13C NMR (100 MHz, CDCl3 and DMSO-d6): δ 169.0, 148.8,
146.3, 127.7, 123.2, 57.6, 53.0, 44.7, 38.2, 35.9, 29.5; FT-IR
(KBr): 3243, 1632, 1521, 1494, 810 cm−1; HRMS (ESI): m/z [M
+ H]+ calcd for C21H25N4O5: 413.1824; found 413.1823.
(1S*,2R*,4S*)-2,4-Bis(4-cyanophenyl)-N-(2-(dimethyl-
amino)ethyl)cyclobutanecarboxamide (21i). Analytical
N-(((1S*,2R*,4S*)-2,4-Bis(4-bromophenyl)cyclobutyl)-
methyl)quinolin-8-amine (23). Analytical TLC on silica gel,
1:4 ethyl acetate/hexanes Rf . = 0.70 brown color liquid; 51 mg,
U
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40% yield; 1H NMR (400 MHz, CDCl3): δ 8.65 (q, 1H, J = 4.0
Hz), 8.07 (q, 1H, J = 4.0 Hz), 7.50−7.17 (m, 10H), 7.07−7.04
(m, 1H), 6.62−6.59 (m, 1H), 3.59 (q, 2H, J = 4.0 Hz), 3.38−3.26
(m, 2H), 2.77−2.74 (m, 2H), 2.22−2.13 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 146.8, 142.6, 138.1, 135.9, 131.5, 131.4,
128.5, 127.6, 127.5, 126.9, 120.1, 114.0, 104.7, 51.0, 46.8, 40.3,
34.0; FT-IR (DCM): 3234, 1644, 1412, 1382, 819 cm−1; HRMS
(ESI): m/z [M + H]+ calcd for C26H23Br2N2: 521.0228; found
521.0229.
(1R*,2R*,4S*)-2,4-Di-p-tolylcyclobutanecarboxylic
acid (24). Following the general procedure described above, 24
was obtained as a brown color liquid (crude material was almost
pure); 67 mg, 96% yield; 1H NMR (400 MHz, CDCl3): δ 7.36−
7.17 (m, 8H), 3.79 (q, 2H, J = 8.0 Hz), 3.30 (t, 1H, J = 12.0 Hz),
2.79−2.76 (m, 1H), 2.38 (s, 6H), 2.37−2.27 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 179.7, 139.7, 136.3, 129.2, 126.5, 52.6,
39.2, 32.9, 21.1; FT-IR (DCM): 2833, 1515, 1485, 1354, 806
cm−1; HRMS (ESI): m/z [M - H]¯ calcd for C19H19O2: 279.1385;
found 279.1389.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sababu@iisermohali.ac.in
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was funded by IISER-Mohali. We thank the NMR,
HRMS, and X-ray facilities of IISER-Mohali. R.P. and B.G. are
thankful to CSIR and DST, New Delhi, for JRF and INSPIRE
fellowships, respectively. We thank NIPER-Mohali, CDRI-
Lucknow, and IICT-Hyderabad for providing the mass spectral
data.
REFERENCES
■
(1) (a) Dembisky, V. M. J. Nat. Med. 2008, 62, 1 and references cited
therein. (b) For selected reviews on the chemistry of cyclobutanes, see
the following: Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103,
1485. (c) Demuth, M.; Mikhail, G. Synthesis 1989, 145. (d) Bach, T.
Synthesis 1998, 683. (e) Lee-Ruff, E.; Madenova, G. Chem. Rev. 2003,
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(1R*,2R*,4S*)-2,4-Bis(4-chlorophenyl)cyclobutane-
carboxylic acid (25). Following the general procedure
described above, 25 was obtained as a white color liquid
1
(crude material was almost pure); 78 mg, 98% yield; H NMR
(400 MHz, CDCl3): δ 7.35−7.32 (m, 8H), 3.80 (q, 2H, J = 8.0
Hz), 3.27 (t, 1H, J = 12.0 Hz), 2.84−2.78 (m, 1H), 2.31 (q, 1H, J
= 8.0 Hz); 13C NMR (100 MHz, CDCl3): δ 179.6, 140.8, 132.6,
128.6, 128.0, 52.3, 38.8, 32.5; FT-IR (DCM): 2966, 1565, 1432,
1331, 800 cm−1; HRMS (ESI): m/z [M - H]¯ calcd for
C17H13Cl2O2: 319.0292; found 319.0298.
(1R*,2R*,4S*)-2,4-Bis(4-bromophenyl)cyclobutane-
carboxylic acid (26). Following the general procedure
described above, 26 was obtained as a brown color solid
(crude material was almost pure); 97 mg, 95% yield; mp131−
1
133 °C; H NMR (400 MHz, CDCl3): δ 7.50−7.46 (m, 4H),
7.21−7.19 (m, 4H), 3.79(q, 2H, J = 8.0 Hz), 3.27 (t, 1H, J = 12.0
Hz), 2.84−2.77 (m, 1H), 2.30−2.15 (m, 1H); 13C NMR (100
MHz, CDCl3): δ 179.5, 141.3, 131.6, 128.3, 120.6, 52.2, 38.8,
32.3; FT-IR (KBr): 2922, 1698, 1516, 1425, 806 cm−1; HRMS
(ESI): m/z [M + Na]+ calcd for C17H14Br2O2Na: 430.9258;
found 430.9281.
(1S*,2R*,4S*)-2,4-Bis(4-bromophenyl)-N-methyl-N-
(quinolin-8-yl)cyclobutanecarboxamide (27). Analytical
TLC on silica gel, 1:4 ethyl acetate/hexanes Rf = 0.70 light-
1
yellow color liquid; 130 mg, 95% yield; H NMR (400 MHz,
CDCl3): δ 8.98 (q, 1H, J = 4.0 Hz), 8.26 (q, 1H, J = 4.0 Hz), 7.85
(q, 1H, J = 8.0 Hz), 7.54−7.46 (m, 6H), 7.26−7.23 (m, 4H), 6.72
(q, 1H, J = 4.0 Hz), 3.54−3.36 (m, 4H), 2.98 (s, 3H), 2.48 (q, 1H,
J = 4.0 Hz); 13C NMR (100 MHz, CDCl3): δ 170.2, 151.0, 144.2,
141.4, 141.3, 139.2, 136.3, 131.0, 130.8, 130.4, 129.4, 128.8,
128.9, 128.1, 126.4, 122.1, 120.8, 119.2, 50.0, 39.7, 37.7, 37.1;
FT-IR (DCM): 2941, 1613, 1523, 1468, 791 cm−1; HRMS
(ESI): m/z [M + H]+ calcd for C27H23Br2N2O: 549.0177; found
549.0175.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of NMR spectra of all compounds and X-ray structures
(ORTEP diagrams of the compounds 16c, 16f, 16g, 16m, 21a,
21f, 25 and 27) and crystal data. This material is available free of
charge via the Internet at http://pubs.acs.org.
V
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auxiliary-attached cyclopropanecarboxamide (1 equiv) was carried out
by using an aryl iodide in excess amount (8 equiv), see ref 35a.
(36) See SI for the X-ray structures.
(37) The stereochemistry of the products was assigned on the basis of
the X-ray structures of 16c, 16f, 16g, and 16m as well as the similarity in
the NMR pattern of the cyclobutane ring.
(38) The stereochemistry of the products 24 and 26 was assigned on
the basis of the X-ray structure of 25 as well as the similarity in the NMR
pattern of the cyclobutane ring.
(39) A day before the submission of this article, an article containing an
example of the formation of the 2,4-diphenyl-N-(quinolin-8-yl)
cyclobutanecarboxamide (16b, the compound number refers to the
numbering with respect to our work) using a diarylhyperiodonium salt
as the arylating agent was reported by Shi Z.-J. et al., see: Pan, F.; Shen,
P.-X.; Zhang, L.-S.; Wang, X.; Shi, Z.-J. Org. Lett. 2013, 15, 4758. Shi Z.-
J. et al., it is mentioned that the stereochemistry of 2,4-diphenyl-N-
(quinolin-8-yl)cyclobutanecarboxamide was assigned based on the
report by the Daugulis’s group.26b To the best of our knowledge, the
compound 2,4-diphenyl-N-(quinolin-8-yl)cyclobutanecarboxamide was
not reported by Daugulis’s group (ref 26b).
X
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