Cyano-Sacrificial (Arylthio)arylamination of Quinoline and Isoquinoline N-Oxides Using N-(2-(Arylthio)aryl)cyanamides

Article abstract of DOI:10.1021/acs.joc.8b01797

A copper(I)-catalyzed regioselective arylthio-arylamination of quinoline and isoquinoline N-oxides has been achieved at the expense of a cyano (CN) group from N-(2-(arylthio)aryl)cyanamides. This reductive amination proceeds in one pot at 80 °C in the absence of any additives. This is a unique demonstration of aryl cyanamides serving as arylaminating agents on quinoline/isoquinoline N-oxides with concurrent autoreduction of N-oxide.

Full text of DOI:10.1021/acs.joc.8b01797

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Article
Cyano Sacrificial (Arylthio)-arylamination of Quinoline and
Isoquinoline N-Oxides using N-(2-(Arylthio)aryl)cyanamides.
Ahalya Behera, Prasenjit Sau, Ashish Kumar Sahoo, and Bhisma K. Patel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01797 • Publication Date (Web): 13 Aug 2018
Downloaded from http://pubs.acs.org on August 13, 2018
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Cyano Sacrificial (Arylthio)ꢀarylamination of Quinoline and Isoquinoline NꢀOxides using
Nꢀ(2ꢀ(Arylthio)aryl)cyanamides
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Ahalya Behera, Prasenjit Sau, Ashish Kumar Sahoo and Bhisma K. Patel*
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Department of Chemistry, Indian Institute of Technology Guwahati, Guwahatiꢀ781039, India
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Fax: (+91)361ꢀ26909762.
Eꢀmail: patel@iitg.ernet.in
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
ABSTRACT: A copper(I) catalyzed regioselective arylthioꢀarylamination of quinoline and
isoquinoline Nꢀoxides have been achieved at the expense of a cyano (ꢀCN) group from Nꢀ(2ꢀ
ο
(arylthio)aryl)cyanamides. This reductive amination proceeds in one pot at 80 C in the absence
of any additives. This is a unique illustration of aryl cyanamides serving as arylaminating agents
on quinoline/isoquinoline Nꢀoxides with concurrent autoꢀreduction of Nꢀoxide.
INTRODUCTION
Recent advances in transitionꢀmetal catalysis have led to the development of effective methods
for regioselective C−C and C−heteroatom bond formations.1,2 The construction of C−N bonds
has attracted considerable attention since nitrogen containing motifs have found significant
applications in biological and medicinal chemistry.1a,3 Among various nitrogen bearing scaffolds,
functionalized quinolines are reported to have antimalarial, antibacterial, antifungal and
antimicrobial activities (Figure 1).4 Representative examples of 2ꢀaminoquinoline moieties
exhibiting various biologically activities are shown in Figure 1. Compound (I) is a potent
antagonist that selectively modulates native TRPC4/C5 ion channels and has been used in
physiological and pathophysiological studies.4c Quinoline derivative (II) is an antagonist of the
MCHꢀ1R for the treatment of obesity.4d The potential activity of compound (II) demonstrated an
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IC50 value of 55 nM in a primary screening and exhibited antagonist properties in a functional
cellular assay measuring Ca2+ release. Compound (III) exhibits antibacterial activity against
gramꢀpositive bacteria.4e 2ꢀAminiquinoline (IV) display an IC50 value of 1.2 ꢁM against EZH2,
decreased global H3K27me3 level in cells and also showed good antiꢀviability activities against
tumor cell lines.4f
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Figure 1. Representative Biologically Active 2ꢀAminoquinolines.
Various transition metal catalyzed C2 selective functionalizations such as arylation,5
heteroarylation,6 alkylation,7 alkenylation8 and C−O or C−S bond formations9,10 on quinoline Nꢀ
oxide moiety have been successfully accomplished. Undoubtedly, the regioselective C−N bond
formation of these heterocyclic Nꢀoxides have emerged as powerful tools in organic synthesis.
Nevertheless few specialized synthetic methods are available to achieve this in a stepꢀeconomic
way (Scheme 1).11 A copper(II)ꢀcatalyzed C2 amination of quinoline Nꢀoxides using lactams,
cyclamines, or Oꢀbenzoyl hydroxylamines have been reported by Li et.al. [Scheme 1, (i) and
(ii)].11a,b Wu and Cui’s group have utilized aliphatic secondary amines as the aminyl sources for
the same in the presence of CuI [Scheme 1, (iii)].11c Bolm and coꢀworkers described a CuIꢀ
catalyzed sulfoximinations of quinoline Nꢀoxides at its C2 position [Scheme 1, (iv)].11d Recently,
Samanta group demonstrated a Cu(I) catalyzed regioselective arylamination using anthranils as
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the arylaminating source [Scheme 1, (v)].11e While the methods described in Scheme 1 (iꢀiii) are
applicable for secondary aliphatic aminations, the use of anthranil is the sole example of an
arylamination of quinoline Nꢀoxides. The last three methods in Scheme 1 use air as the oxidant
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but in the first two protocols, subꢀstoichiometric amounts of silver salt are essential. Very recently
Zhao group has reported a reductive amination of quinoline Nꢀoxides using ammonia, primary and
secondary amines. However, the method requires stoichiometric amount of reducing agent such as Hꢀ
phosphonate in the presence of potassium carbonate.11f
Scheme 1. Differential Reactivity of Quinoline Nꢀoxides
A Pd/xantphos catalyzed intramolecular regioselective aminocyanation of alkene has
been achieved via the cleavage of NꢀCN bond by Nakao group [Scheme 1, (vi)].12a Here,
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simultaneous installation of a cyano (ꢀCN) group and tetra or tri substituted carbon afforded
various indolines and pyrrolidines. An organic cyanamide possesses a nucleophilic NꢀH site, an
electrophilic cyanamide carbon12bꢀe and a fragile NꢀCN bond. On the other hand, because of the
nucleophilic nature of quinoline Nꢀoxide (1) and the presence of an electrophilic Cꢀ2 site, we
envisaged that the Nꢀ(2ꢀ(arylthio)aryl)cyanamide (a) might serve as an C2ꢀarylthioꢀ
arylaminating agent on (1). This may be accomplished by the initial nucleophilic attack of the
quinoline Nꢀoxide (1) onto the electrophilic carbon of cyanamide (a) followed by an
intramolecular nucleophilic attack at the Cꢀ2 position of (1). Here, the sulfur atom of Sꢀphenyl
ring may further facilitate the reactivity of the cyanamide via coꢀordination with a Cuꢀsalt. The
above anticipated reaction was initially executed using a Nꢀ(2ꢀ(phenylthio)phenyl)cyanamide (a)
(0.25 mmol), quinoline Nꢀoxide (1) (0.25 mmol) and CuI (20 mol%) in 1,4ꢀdioxane (2 mL) at
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110 C. Formation of a new product (1a) (43%) was observed along with the isolation of
quinoline (23%) and unreacted quinoline Nꢀoxide (15%). Spectroscopic analysis of the isolated
product revealed its structure to be Nꢀ(2ꢀ(phenylthio)phenyl)quinolinꢀ2ꢀamine (1a) (Scheme 1).
Here, formation of a C2 selective product (1a) using cyanamide (a) is associated with the
concurrent reduction of quinoline Nꢀoxide (1) and loss of a cyano (ꢀCN) group. To the best of
our knowledge, such arylamination of quinoline Nꢀoxide using arylcyanamide as the
arylaminating agent is unprecedented in the literature.
RESULTS AND DISCUSSION
Encouraged by this C2 selective cyano sacrificial arylthioꢀarylamination, various other reaction
parameters were further evaluated to achieve better yield of the product. The initial investigation
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was commenced by taking Nꢀ(2ꢀ(pꢀtolylthio)phenyl)cyanamide (b) and quinoline Nꢀoxide (1) as
the reacting partner (Table 1, entry 1). Since substantial amount of quinoline by product was
observed, this may be originating from the Nꢀoxide (1) via a reductive path, thereby decreasing
the net yield of (1a). Gratifyingly, an improved yield (65%) of the product (1b) was found when
a reaction was carried out using 2 equivalents of (1) (Table 1, entry 2). As solvent systems play a
pivotal role in any organic transformations, we screened few solvents for the present Cꢀ2
amination process. Among various solvents viz. chlorobenzene (39%), pꢀxylene (27%), CH3CN
(79%), DMSO (45%) and methanol (51%) surveyed (Table 1, entries 3−7), CH3CN turned out to
be the best (Table 1, entry5). The yield of the product remained unaltered (78%) even when the
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reaction was performed at 80 C (Table 1, entry 8). The reaction took longer time giving lower
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yield of the product when carried out below 80 C. Using CH3CN as the solvent at 80 C, the
efficacy of other copper I and II salts such as CuCl, CuBr and Cu(OAc)2 were screened (Table 1,
entries 9−11). All were turned out to be inferior to initially used CuI (Table 1, entry 8). The
superiority of CuI towards C2 selective amination of quinoline Nꢀoxides compared to other Cu
salts have been well established [Scheme 1 (iiiꢀiv)].11cꢀe The product (1b) yield (76%) remain
unchanged even by performing the reaction with 15 mol% of the catalyst loading (Table 1 and
entry 13). However, a 12% reduction in the yield (i.e. 68%) was noticed by further lowering the
catalyst loading to 10 mol% (Table 1 and entry 14). Interestingly, the same reaction in the
absence of any catalyst also gave a decent yield (22%) of the product (1b) (Table 1, entry 15).
Nevertheless, CuI is found to be essential for obtaining better yield, as it enhances the
electrophilicity of the cyanamide and brings the quinolone Nꢀoxide (1) and cyanamide (b) to its
proximity via coordination. Thus, the ideal optimized condition for this arylamination is the use
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of Nꢀ(2ꢀ(pꢀtolylthio)phenyl)cyanamide (b) (0.25 mmol), quinoline Nꢀoxide (1) (0.5 mmol) and
CuI (15 mol%) in CH3CN (2 mL) at 80 oC for 18 h (Table 1, entry 13).
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Table 1. Optimization of the Arylthioꢀamination of Quinoline Nꢀoxidea
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Entry
1
Catalyst (mol %)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuCl (20)
CuBr (20)
Cu(OAc)2(20)
CuI (15)
CuI (10)
ꢀ
Solvent
Dioxane
Dioxane
PhCl
Temp oC Yield (%)
110
110
110
110
110
110
110
80
49c
65
39
27
79
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68
22
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pꢀXylene
CH3CN
DMSO
MeOH
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CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
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80
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80
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80
aReaction conditions: Nꢀ(2ꢀ(pꢀtolylthio)phenyl)cyanamide(b) (0.25 mmol), quinolineNꢀ
Oxide (1) (0.5 mmol), solvent (2 mL).bIsolated yield.c1 equiv. of quinoline Nꢀoxide (b).
After establishing the above cyanamide mediatory unprecedented arylamination, the feasibility
of the strategy was surveyed with a variety of substituted Nꢀ(2ꢀ(arylthio)aryl)cyanamides (aꢀf)
having electronꢀdonating and electronꢀwithdrawing groups (R1) on the Sꢀphenyl ring with
quinoline Nꢀoxide (1) (Scheme 2). The Nꢀ(2ꢀ(phenylthio)phenyl)cyanamide (a) reacted
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efficiently with (1) giving Cꢀ2 aminated product (1a) in 71% yield. Presence of moderately pꢀBr
(d), pꢀCl (e) and strongly mꢀCF3 (f) electroꢀwithdrawing groups (R1) on the Sꢀphenyl ring of aryl
cyanamides, underwent Cꢀ2 amination with quinoline Nꢀoxide (1) affording arylaminated
products (1d), (1e) and (1f) in 69%, 72% and 66% yields respectively (Scheme 2). The structure
of product (1e) has been reconfirmed by Xꢀray crystallographic analysis (Figure S1, see
Supporting Information). Subsequently, the variation of substituents (R1 and R2) on both the aryl
rings of arylcyanamides were explored (Scheme 1). When the substituent cyanamide possessing
an electronꢀdonating group such as 4ꢀMe (g) was treated with quinoline Nꢀoxide (1), a moderate
yield (64%) of the C2 aminated product (1g) was obtained. Further, the cyanamide bearing ring
is substituted with electronꢀwithdrawing (ꢀF/ꢀNO2) and the Sꢀphenyl ring with either electronꢀ
donating (ꢀMe/ꢀOMe) or electronꢀwithdrawing (ꢀCl) groups were tested. Various combinations
of substituents (R1 and R2) such as pꢀMe/4ꢀF (h), pꢀCl/4ꢀF (i), and pꢀOMe/4ꢀNO2 (j) all provided
their respective aryl aminated products (1h, 62%), (1i, 57%) and (1j, 43%) in modest yields
(Scheme 2). To demonstrate the scalability of the present methodology, a reaction of Nꢀ(2ꢀ(pꢀ
tolylthio)phenyl)cyanamide (b) (1 mmol) and quinoline Nꢀoxide (2 mmol), under the standard
optimized reaction condition give 70% yield of the product (1b) [Scheme 2, (1b)c].
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Scheme 2. Demonstration of C2 Arylamination using Arylthiophenyl Cyanamidesa,b
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aReaction conditions: Nꢀ(2ꢀ(phenylthio)phenyl)cyanamide (aꢀj) (0.25 mmol), quinoline Nꢀoxide (0.5 mmol) (1), CuI (15 mol%),
CH3CN (2 mL), time (20 h) at 80 oC. bYields of isolated pure products. c1 mmol scale
After successfully demonstrating the C2 selective arylthioꢀarylamination of quinoline Nꢀoxide
(1), the scope and versatility of the process was assessed with other substituted (R3) quinoline Nꢀ
oxides (Scheme 3). We were delighted to observe that the developed protocol displayed a broad
scope across various sterically and electronically distinct quinoline Nꢀoxides (2ꢀ9). Both electron
donating 3ꢀMe (2) and electronꢀwithdrawing 3ꢀBr (3) groups on the quinoline Nꢀoxide at its C3ꢀ
position did not suffer any significant steric effect. 3ꢀMethyl quinoline Nꢀoxide (2) reacted
smoothly with cyanamides having a variety of substituents (R1). The electronꢀneutral (a),
electronꢀdonating pꢀOMe (b) and electroꢀwithdrawing pꢀCl (c) and mꢀCF3 (d) all afforded their
corresponding products (2a, 75%), (2c, 73%), (2e, 71%) and (2f, 85%) respectively (Scheme 3).
The presence of a C3ꢀBr group (3) in lieu of a C3ꢀMe (2) at the Cꢀ3 position of quinoline Nꢀ
oxide was equally successful with a similar set of substituted arylcyanamides (aꢀf) providing
their arylaminated products (3a, 59%), (3b, 78%), (3e, 94%) and (3f, 81%) respectively (Scheme
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3). The cyano sacrificial Cꢀ2 amination strategy was equally effective with quinoline Nꢀoxides
substituted with electronꢀdonating groups such as 6ꢀMe (4) and 6ꢀOMe (5) when reacted with a
set of cyanamides (aꢀf) as shown in Scheme 3. Their Cꢀ2 aminated products (4aꢀ5f) were
isolated in the range of 60ꢀ89% and product yields are summarized in Scheme 3. It was not
possible to correlate the actual yield of product obtained with the electronic and steric effects of
the substituents present in quinoline Nꢀoxides or cynamides. This strategy was feasible when
electronꢀdonating 8ꢀMe (6) and electronꢀwithdrawing 8ꢀNO2 (7) substituents (R2) are present at
the Cꢀ8 position of quinoline Nꢀoxide. Inspite of the anticipated steric crowding due to (R3) when
Nꢀoxide (6) was reacted with cyanamide (a) and Nꢀoxide (8) with cyanamide (c) decent yields of
the Cꢀ2 aminated products (6a, 56%) and (7c, 47%) were obtained. In addition to this, mono
substituted quinoline Nꢀoxides (1ꢀ7), 4,7ꢀdichloroꢀquinoline Nꢀoxide (8) underwent Cꢀ2
amination with Nꢀ(2ꢀ(phenylthio)phenyl)cyanamides bearing pꢀMe (b), pꢀCl (e) and mꢀCF3 (f)
substituents on the Sꢀphenyl ring, providing their corresponding products (8b, 67%), (8e, 82%)
and (8f, 52%) respectively. Besides quinoline Nꢀoxides (Schemes 2 and 3), a benzoꢀfused
analogue, benzo[h]quinoline Nꢀoxide (9) (Scheme 3) underwent effective C2ꢀamination with a
variety of cyanamides such as H (a), pꢀMe (b) and pꢀCl (e), all providing their respective Cꢀ2
arylaminated products (9a), (9b) and (9e) in 57%, 76% and 52% yields. Surprisingly, this
arylamination strategy, using pyridine Nꢀoxide and quinoxaline Nꢀoxides as the Cꢀ2 aminating
sites failed to react with Nꢀ(2ꢀ(phenylthio)phenyl)cyanamide (a).
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Scheme 3. Demonstration of C2 Arylamination using Various QuinolineNꢀoxidesa,b
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aReaction conditions: Nꢀ(2ꢀ(phenylthio)phenyl)cyanamide (a−f) (0.25 mmol), quinoline Nꢀoxides (2ꢀ9) (0.5 mmol), CuI (15
mol%), CH3CN (2 mL), time (20 h) at 80 oC. bYields of isolated pure products.
We are inquisitive to see whether the present Cꢀ2 arylamination strategy of quinoline Nꢀoxide
(1) will be applicable to isoquinoline Nꢀoxide (10) as well to provide analogous Cꢀ1
arylamination? To our delight, the reaction of isoquinoline Nꢀoxide (10) with Nꢀ(2ꢀ
(phenylthio)phenyl)cyanamide (a), resulted in the formation of an exclusive C1 arylaminated
product (10a) in 73% yield (Scheme 4). This result is significant, because 1ꢀaminoisoquinolines
are found to have interesting biological activities (Figure 1). The amino isoquinoline core in
compound (V) is reported to have potent antitumor activity in xenograft models.13a The
compound (VI) possess antimalarial activity and found to be submicromolar inhibitors in vitro
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towards drugꢀresistant plasmodium falciparum and the best possessing activity comparable to
chloroquine.13b
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Encouraged by this positive outcome, the scope of this protocol was then extended to other
substituted cyanamides (cꢀf) and isoquinoline Nꢀoxides (10ꢀ13). Initially, the electronic effect of
the substituent R1 present on the Nꢀ(2ꢀ(phenylthio)phenyl)cyanamides (cꢀf) was investigated
(Scheme 4). Nꢀ(2ꢀ(Phenylthio)phenyl)cyanamides containing electronꢀdonating [pꢀOMe (c)] or
electroꢀwithdrawing [pꢀCl (e) and mꢀCF3 (f)] substituents, all underwent effective C1ꢀamination
with isoquinoline Nꢀoxides (10) giving products [(10b, 64%), (10e, 69%) and (10f, 57%)] as
shown in Scheme 4. Next, the effect of the substituents (R3) present on the isoquinoline Nꢀoxides
(11ꢀ13) were examined with (R1)ꢀsubstituted cyanamides (bꢀf). Isoquinoline Nꢀoxides bearing an
electronꢀdonating group such as 3ꢀMe (11) reacted smoothly with (R1) substituted cyanamides pꢀ
Me (b) and pꢀCl (e), furnishing their corresponding C1 arylaminated products (11b, 86%) and
(11e, 83%). Similarly, 4ꢀbromo isoquinoline Nꢀoxide (12) reacted with differentially (R1)
substituted Nꢀ(2ꢀ(arylthio)phenyl)cyanamides (aꢀf) and yielded their C1 aminated products (12aꢀ
12e) in a range of 84ꢀ93% (Scheme 4). Moderate to lower yields of C1 aminated products (13aꢀ
13f) were obtained via the coupling of 5–NO2 isoquinoline Nꢀoxide (13) with (R1) substituted
cyanamides (aꢀf) (Scheme 4).
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Scheme 4. Demonstration of C1 Arylamination with Isoquinoline Nꢀoxidea,b
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aReaction conditions: Nꢀ(2ꢀ(phenylthio)phenyl)cyanamide (aꢀf) (0.25 mmol), isoquinolineNꢀoxides (10ꢀ13) (0.5 mmol), CuI (15
mol%), CH3CN (2 mL), time (20 h) at 80 oC. bYields of isolated pure products.
To demonstrate the applicability of our protocol, biologically active indoloquinoline moiety
(14a) was synthesized in good yield (65%) utilizing product (3a) (in Scheme 3) via an
intramolecular Heck coupling (Scheme 5).14
Scheme 5. Post Synthetic Modifications
To understand the mechanistic aspect for this cyano sacrificial regioselective arylthioꢀ
arylamination of quinoline and isoquinoline Nꢀoxides, some experiments were carried out
(Scheme 6). Most of the Cꢀ2 amination protocols of quinoline Nꢀoxides uses secondary amines
directly or indirectly as the aminating source. In this strategy as well arylamine might be
generating from arylcyanamide which could be the actual aminating source. To ascertain this,
when a reaction was executed using pꢀanisidine in lieu of (a) under otherwise identical condition,
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failed to give any product which rules out arylamine to be the possible aminating source
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[Scheme 6, (i)]
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Scheme 6. Control Experiments
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Now a query arises whether S atom of the (arylthio)aryl)cyanamides play any specific role in
achieving the C2ꢀamination, or other simple arylcyanamides may also serve as the possible
aminating source towards quinoline/isoquinoline Nꢀoxides? When phenyl cyanamide (k) was
employed for the C2 amination of quinoline Nꢀoxide (1) under the present reaction condition, a
trace amount of Cꢀ2 aminated product (<10%) was observed. However, after further optimization
o
an acceptable yield (59%) could be achieved using 25 mol% of catalyst (CuI), at 120 C for 32 h
[Scheme 6, (ii)]. This observation suggests that the S atom in (arylthio)aryl)cyanamides is
playing an active role via chelating with the metal. However, other aryl cyanamides can serve as
the alternative amine source only at high temperature, high catalyst loading at longer reaction
time.
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Scheme 7. Plausible Mechanism
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Based on the control experiments and the literature reports11c,12 a possible mechanism for this
regioselective arylthioꢀarylamination is depicted in Scheme 7. The imidic form (a) of cyanamide
́
coꢀordinates with Cu(I) forming a reactive intermediate (A). The quinoline Nꢀoxide (1) attacks at
the electrophilic carbon of (A) to form a new Cu intermediate (B) by bringing both the reacting
partners to the proximity which is facilitated by the S atom of cyanamide (a). An intramolecular
nucleophilic attack of the amine on to the metal bound Cꢀ2 site of quinoline Nꢀoxide generates
intermediate (C). Rearomatization of quinoline part of the (C) with transfer of Nꢀoxide oxygen
forms species (D). The unstable NꢀC=O bound Cu moiety is hydrolyzed to amine carbonate
(which is decomposed to CO2 and ammonia) releasing the metallated product (E). Finally, the
C2 aminated product (1a) is released from intermediate (E) with regeneration of the CuI for the
subsequent catalytic cycle. An unfavourable reversible cleavage of NꢀC bond (C2 carbon of
quinoline Nꢀoxide) of intermediate (C) leads to the formation of by product quinoline. A similar
mechanism can be proposed for the Cꢀ1 amination of isoquinoline Nꢀoxide.
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In conclusion, for the first time we have utilized arylcyanamides as an aminating agent towards
regioselective C2ꢀarylamination and Cꢀ1ꢀarylamination of quinoline and isoquinoline
respectively. In many amination of quinoline and isoquinoline Nꢀoxides, the Nꢀoxide moiety
remained intact there by requiring additional reduction step, however here it is removed in situ
via an autoꢀreduction process. The present arylthioꢀarylamination of quinoline and isoquinoline
using Nꢀ(2ꢀ(phenylthio)phenyl)cyanamide as an aminating agent works best. Nevertheless, there
is avenues to develop other aryl and alkyl cyanamides as aminating agents for various
heterocyclic Nꢀoxides.
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EXPERIMENTAL SECTION
General information:
All the reagents were of commercial grade and purified according to the established procedures.
Organic extracts were dried over anhydrous sodium sulphate. Solvents were removed in a rotary
evaporator under reduced pressure. Silica gel (60–120 mesh size) was used for the column
chromatography. Reactions were monitored by TLC on silica gel 60 F254 (0.25 mm). NMR
spectra were recorded in CDCl3 with tetramethylsilane as the internal standard for 1H NMR (400
13
MHz and 600 MHz) CDCl3 solvent as the internal standard for C NMR (100 MHz and 150
MHz). Mass spectra were recorded using ESI mode and APCI mode (QꢀTOF MS analyzer). IR
spectra were recorded in KBr or neat.
General Procedure for the Formation of Nꢀ(2ꢀ(Phenylthio)phenyl)quinolinꢀ2ꢀamine (1a).
An ovenꢀdried round bottom flask was charged with Nꢀ(2ꢀ(phenylthio)phenyl)cyanamide (a)
(56.5 mg, 0.25 mmol), quinoline Nꢀoxide (1) (72.5 mg, 0.5 mmol), CuI (15 mol%, 7 mg),
CH3CN (2 mL). The flask was fitted with a condenser and the resultant reaction mixture was
ο
stirred in a preꢀheated oil bath maintained at 80 C. The reaction progress was monitored by
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TLC. After 18 h, the reaction mixture was cooled to room temperature. The reaction mixture was
evaporated under reduced pressure to remove CH3CN. Then it was admixed with ethyl acetate
(25 mL) and washed with saturated brine solution (5 mL). The ethyl acetate layer was dried over
anhydrous Na2SO4. The solvent was then evaporated under reduced pressure and the residue was
purified by column chromatography with an eluent hexane / ethylacetate (98 / 02) to afford the
desired product (1a) in an isolated yield of 71% (58 mg).
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General Procedure for the Synthesis of 7ꢀ(Phenylthio)ꢀ6Hꢀindolo[2,3ꢀb]quinoline (14a): A 5
mL microwave vial was charged with bis(ꢀtriphenylphosphine)palladium(II) dichloride (14 mg,
0.02 mmol), 3ꢀbromoꢀNꢀ(2ꢀ(phenylthio)phenyl)quinolinꢀ2ꢀamine (3a) (0.2 mmol, 81 mg) and
sodium acetate (65 mg, 0.8 mmol) followed by N,Nꢀdimethylacetamide (3 mL) and flushed with
ο
argon. The reaction was irradiated at 150 C for 120 min. After completion of the reaction the
reaction was cooled to room temperature. Then it was admixed with ethyl acetate (25 mL) and
washed with iceꢀcooled water (3 x 5 mL). The ethyl acetate layer was dried over anhydrous
Na2SO4. The solvent was then evaporated under reduced pressure and the residue was purified
by column chromatography with an eluent hexane / ethylacetate (93 / 07) to afford 7ꢀ
(Phenylthio)ꢀ6Hꢀindolo[2,3ꢀb]quinoline (14a) in an isolated yield of 65% (42 mg).
General Procedure for Control Experiments:
General Procedure for the Synthesis of NꢀPhenylquinolinꢀ2ꢀamine (1k).
NꢀPhenylcyanamide (k) (29 mg, 0.25 mmol), quinoline Nꢀoxide (1) (72.5 mg, 0.5 mmol), CuI
(25 mol%, 11 mg), CH3CN (2 mL) were taken in a round bottom flask. Then it was fitted with a
condenser and the resultant reaction mixture was stirred in a preꢀheated oil bath maintained at
o
120 C. The reaction progress was monitored by TLC. After 32 h, the reaction mixture was
cooled to room temperature. The reaction mixture was evaporated under reduced pressure to
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remove CH3CN. Then it was admixed with ethyl acetate (25 mL) and washed with brine solution
(2 x 5 mL). The ethyl acetate layer was dried over anhydrous Na2SO4. The solvent was then
evaporated under reduced pressure and the residue was purified by column chromatography with
an eluent hexane / ethylacetate (97 / 03) to afford the desired product (1k) in an isolated yield of
59% (32 mg).
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Nꢀ(2ꢀ(Phenylthio)phenyl)quinolinꢀ2ꢀamine (1a):
N
N
H
S
o
1
Yield 71% (58 mg) as a brownish solid; mp 97−99 C; H NMR (400 MHz, CDCl3):
δ (ppm)
6.79 (d, 1H, J = 8.8 Hz), 7.03−7.17 (m, 4H), 7.17−7.24 (m, 3H), 7.32 (t, 1H, J = 7.6 Hz),
13
7.45−7.53 (m, 1H), 7.59−7.64 (m, 3H), 7.87 (t, 2H, J = 8.4 Hz), 8.94 (d, 1H, J = 8.4 Hz); C
NMR (150 MHz, CDCl3):
δ (ppm) 113.6, 115.5, 118.9, 119.5, 122.5, 123.7, 124.4, 126.2, 126.6,
127.2, 127.4, 127.5, 129.2, 129.4, 130.0, 131.1, 136.3, 136.9, 137.8, 142.4, 147.3, 153.5; IR
(KBr): 3449, 2927, 2856, 1625, 1587, 1523, 1437, 1317, 810, 754cmꢀ1; HRMS (ESI): calcd. for
C21H17N2S [M+H]+ 329.1107; found 329.1117.
Nꢀ(2ꢀ(pꢀTolylthio)phenyl)quinolinꢀ2ꢀamine (1b):
o
1
Yield 76% (65 mg) as a light yellowish solid; mp 84−86 C; H NMR (600 MHz, CDCl3):
δ
(ppm); 2.25 (s, 3H), 6.79 (d, 1H, J = 9.0 Hz), 7.03 (d, 3H, J = 8.4 Hz), 7.10 (d, 2H, J = 7.8 Hz),
7.30−7.33 (m, 1H), 7.45−7.48 (m, 1H), 7.55 (d, 1H, J = 7.2 Hz), 7.59−7.61 (m, 1H), 7.63 (d, 1H,
J = 7.8 Hz), 7.85 (d, 1H, J = 8.4 Hz), 7.89 (d, 1H, J = 8.4 Hz), 8.86 (d, 1H, J = 8.4 Hz);13C NMR
(150 MHz, CDCl3):
δ (ppm) 21.1, 113.6, 119.7, 122.6, 123.7, 124.4, 127.2, 127.5, 128.3, 129.9,
130.2, 130.6, 132.5, 136.3, 136.5, 137.7, 142.0, 147.4, 153.6; IR (KBr): 3448, 2925, 2855, 1623,
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1586, 1524, 1438, 1316, 806, 753 cmꢀ1; HRMS (ESI): calcd. for C22H19N2S [M+H]+ 343.1263;
found 343.1269.
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Nꢀ(2ꢀ((4ꢀBromophenyl)thio)phenyl)quinolinꢀ2ꢀamine (1d):
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Yield 69% (70 mg) as a brownish solid; mp 101−103 oC; 1H NMR (400 MHz, CDCl3):
δ (ppm)
6.80 (d, 1H, J = 8.8 Hz), 7.0 (d, 2H, J = 8.4 Hz), 7.05 (t, 1H, J = 7.2 Hz), 7.33 (t, 3H, J = 8.0
Hz), 7.52 (t, 1H, J = 8.0 Hz), 7.57−7.66 (m, 3H), 7.76 (s, 1H), 7.88 (dd, 2H, J = 17.6, 8.8 Hz),
13
8.94 (d, 1H, J = 8.0 Hz); C NMR (150 MHz, CDCl3):
δ (ppm) 113.5, 118.8, 119.6, 119.9,
122.6, 123.8, 124.5, 127.3, 127.6, 128.8, 130.0, 131.4, 132.4, 135.8, 136.9, 137.8, 142.6, 147.4,
153.4; IR (KBr): 3367, 2964, 2928, 2854, 1630, 1582, 1524, 1438, 1260, 1091, 1012, 814, 750,
630 cmꢀ1; HRMS (ESI): calcd. for C21H16BrN2S [M+H]+ 407.0212; found 407.0233.
Nꢀ(2ꢀ((4ꢀChlorophenyl)thio)phenyl)quinolinꢀ2ꢀamine (1e):
Yield 72% (65 mg) as a brownish solid; mp 102−104 oC; 1H NMR (400 MHz, CDCl3):
δ (ppm)
6.80 (d, 1H, J = 8.8 Hz), 7.03−7.09 (m, 3H), 7.18 (d, 2H, J = 7.4 Hz), 7.33 (t, 1H, J = 7.2 Hz),
7.50−7.54 (m, 1H), 7.57−7.65 (m, 3H), 7.76 (s, 1H), 7.88 (dd, 2H, J = 17.2, 8.8 Hz), 8.93 (d, 1H,
13
J = 8.4 Hz); C NMR (150 MHz, CDCl3):
δ (ppm) 113.5, 119.0, 119.6, 122.6, 123.8, 124.5,
127.3, 127.6, 128.6, 129.5, 130.0, 131.4, 132.1, 135.0, 136.9, 137.8, 142.6, 147.4, 153.4; IR
(KBr): 3369, 2963, 2929, 2853, 1631, 1585, 1525, 1439, 1262, 1092, 1010, 813, 752, 576 cmꢀ1;
HRMS (ESI): calcd. for C21H16ClN2S [M+H]+ 363.0717; found 363.0718.
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Nꢀ(2ꢀ((3ꢀ(Trifluoromethyl)phenyl)thio)phenyl)quinolinꢀ2ꢀamine (1f):
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1
Yield 66% (65 mg) as a light brownish gummy; H NMR (400 MHz, CDCl3):
δ
(ppm) 6.82 (d, J
= 8.8 Hz, 1H), 7.08 (t, 1H, J = 7.6 Hz), 7.20 (d, 1H, J = 8.0 Hz), 7.28–7.35 (m, 3H), 7.45 (s, 1H),
7.55 (t, 1H, J = 7.6 Hz), 7.59–7.65 (m, 3H), 7.73 (s, 1H), 7.85 (d, 1H, J = 8.4 Hz), 7.90 (d, 1H, J
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= 8.8 Hz), 8.91 (d, 1H, J = 8.4 Hz); C NMR (100 MHz, CDCl3):
δ (ppm) 113.4, 118.0, 119.8,
122.7, 122.8 (q, J = 3.6 Hz), 123.7 (q, J= 3.8 Hz), 123.9, 124.5, 127.4, 127.6, 129.8, 129.9,
19
130.0, 131.8, 137.2, 137.9, 138.3, 142.9, 147.5, 153.4; F NMR (CDCl3 + Hexafluorobenzene):
δ ꢀ66.0 (s); IR (KBr): 3448, 2921, 2851, 1626, 1587, 1523, 1321, 1127, 1073, 749, 697 cmꢀ1;
HRMS (ESI): calcd. for C22H16F3N2S [M+H]+ 397.0981; found 397.0994.
Nꢀ(4ꢀMethylꢀ2ꢀ(phenylthio)phenyl)quinolinꢀ2ꢀamine (1g):
1
Yield 64% (55 mg) as a brownish gummy; H NMR (600 MHz, CDCl3):
δ
(ppm) 2.34 (s, 3H),
6.76 (d, 1H, J = 9.0 Hz), 7.12 (t, 1H, J = 7.2 Hz), 7.16 (d, 2H, J = 8.4 Hz), 7.21 (t, 2H, J = 7.2
Hz), 7.29−7.32 (m, 2H), 7.42 (s, 1H), 7.58−7.63 (m, 2H), 7.69 (s, 1H), 7.85 (t, 2H, J = 8.4 Hz),
8.76 (d, 1H, J = 8.4 Hz); 13C NMR (150 MHz, CDCl3):
δ (ppm) 20.8, 113.4, 119.8, 123.5, 124.3,
126.1, 127.2, 127.4, 127.5, 129.4, 129.8, 131.6, 132.2, 136.5, 137.0, 137.6, 140.0, 147.5, 153.7;
IR (KBr): 3435, 2923, 2853, 1620, 1599, 1520, 1395, 1313, 814, 740, 690 cmꢀ1; HRMS (ESI):
calcd. for C22H19N2S [M+H]+343.1263; found 343.1275.
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Nꢀ(4ꢀFluoroꢀ2ꢀ(pꢀtolylthio)phenyl)quinolinꢀ2ꢀamine (1h):
F
6
7
N
N
H
S
8
9
Me
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1
Yield 62% (56 mg) as a brownish gummy; H NMR (600 MHz, CDCl3):δ (ppm) 2.29 (s, 3H),
6.75 (d, 1H, J = 8.4 Hz), 7.07−7.10 (m, 3H), 7.11−7.14 (m, 2H), 7.17 (d, 2H, J = 8.4 Hz), 7.31 (t,
1H, J = 7.8 Hz), 7.60 (t, 1H, J = 7.2 Hz), 7.64 (d, 1H, J = 8.4 Hz), 7.81 (d, 1H, J = 8.4 Hz), 7.89
13
(d, 1H, J = 9.0 Hz), 8.67 (dd, 1H, J = 9.0, 5.4 Hz); C NMR (150 MHz, CDCl3):
δ
(ppm) 21.2,
113.0, 116.4 (d, J = 21.6 Hz), 120.6 (d, J = 23.2 Hz), 122.0 (q, J = 7.4 Hz), 123.6, 124.4, 125.4
(d, J = 7.3 Hz), 127.1, 127.6, 128.2, 129.9, 130.0, 130.2, 130.5, 130.7, 137.1, 137.6, 137.9,
147.4, 153.9, 158.0 (d, J = 242.7 Hz); 19F NMR (CDCl3 + Hexafluorobenzene): δ ꢀ122.8 (s); IR
(KBr): 3361, 2924, 2854, 1619, 1526, 1396, 1314, 1256, 1119, 901, 811, 754 cmꢀ1; HRMS (ESI):
calcd. For C22H18FN2S [M+H]+ 361.1169; found 361.1179.
Nꢀ(2ꢀ((4ꢀChlorophenyl)thio)ꢀ4ꢀfluorophenyl)quinolinꢀ2ꢀamine (1i):
1
Yield 57% (54 mg) as a brownish gummy; H NMR (400 MHz, CDCl3):
δ (ppm) 6.74 (d, 1H, J
= 8.8 Hz), 7.13−7.17 (m, 2H), 7.18−7.23 (m, 4H), 7.30−7.34 (m, 1H), 7.58−7.65 (m, 2H), 7.82
(d, 1H, J = 8.4 Hz), 7.90 (d, 1H, J = 8.8 Hz), 8.78 (dd, 1H, J = 8.8, 5.2 Hz); 13C NMR (100 MHz,
CDCl3):
δ (ppm) 113.0, 117.4 (d, J = 21.6 Hz), 121.5, 121.7, 122.0 (d, J = 7.4 Hz), 123.8, 124.5,
127.2, 127.6, 129.8, 129.9, 130.1, 133.1, 133.5, 138.0, 147.3, 153.6, 157.8 (d, J = 243.2 Hz); 19F
NMR (CDCl3 + Hexafluorobenzene): δ ꢀ122.7 (s); IR (KBr): 3445, 2924, 1620, 1525, 1476,
1395, 1188, 1091, 1011, 813, 753 cmꢀ1;HRMS (ESI): calcd. For C21H15ClFN2S [M+H]+
381.0623; found 381.0632.
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Nꢀ(4ꢀNitroꢀ2ꢀ(pꢀtolylthio)phenyl)quinolinꢀ2ꢀamine (1j):
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55
56
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59
60
Yield 43% (42 mg) as a yellowish solid; mp 156−158 oC; 1H NMR (400 MHz, CDCl3):
δ (ppm)
2.29 (s, 3H), 6.84 (d, 1H, J = 8.8 Hz), 7.09 (d, 2H, J = 8.0 Hz), 7.16 (d, 2H, J = 8.0 Hz), 7.41 (t,
1H, J= 8.0 Hz), 7.65−7.71 (m, 2H), 7.93 (d, 1H, J = 8.4 Hz), 8.01 (d, 1H, J = 8.4 Hz), 8.30 (s,
1H), 8.35 (dd, 1H, J = 9.6, 2.8 Hz), 8.51 (d, 1H, J = 2.8 Hz), 9.36 (d, 1H, J = 9.2 Hz); 13C NMR
(100 MHz, CDCl3):
δ (ppm) 21.2, 114.1, 117.5, 120.4, 124.9, 125.0, 126.7, 127.7, 127.8, 128.9,
130.4, 130.5, 130.7, 132.0, 137.8, 138.4, 140.9, 147.0, 147.7, 152.1; IR (KBr): 3447, 2921, 2853,
1630, 1584, 1504, 1321, 1266, 1121, 745 cmꢀ1; HRMS (ESI): calcd. for C22H18N3O2S [M+H]+
388.1114; found 388.1139.
3ꢀMethylꢀNꢀ(2ꢀ(phenylthio)phenyl)quinolinꢀ2ꢀamine (2a):
o
1
Yield 75% (64 mg) as a brownish solid; mp 97−99 C; H NMR (600 MHz, CDCl3):
δ (ppm)
2.17 (s, 3H), 7.06 (t, 1H, J = 7.2 Hz), 7.10−7.15 (m, 3H), 7.21 (t, 2H, J = 7.8 Hz), 7.30 (t, 1H, J
= 7.2 Hz), 7.54−7.59 (m, 3H), 7.67−7.68 (m, 2H), 7.89 (d, 1H, J = 8.4 Hz), 8.06 (s, 1H), 9.40 (d,
1H, J = 8.4 Hz); 13C NMR (150 MHz, CDCl3):
δ (ppm) 17.4, 118.0, 119.2, 121.3, 121.9, 123.6,
124.7, 126.0, 126.6, 126.7, 127.0, 128.2, 128.8, 129.4, 129.7, 131.6, 136.1, 136.5, 137.3, 142.7,
146.2, 152.5; IR (KBr): 3345, 2940, 2841, 1634, 1586, 1527, 1438, 1416, 1249, 1170, 1012, 830,
754, 708, 619 cmꢀ1; HRMS (ESI): calcd. for C22H19N2S [M+H]+ 343.1263; found 343.1289.
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Nꢀ(2ꢀ((4ꢀMethoxyphenyl)thio)phenyl)ꢀ3ꢀmethylquinolinꢀ2ꢀamine (2c):
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o
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Yield 73% (68 mg) as a brownish solid; mp 74−76 C; H NMR (400 MHz, CDCl3):
δ (ppm)
2.27 (s, 3H), 3.72 (s, 3H), 6.79 (d, 2H, J = 8.8 Hz), 7.04 (t, 1H, J = 7.6 Hz), 7.15 (d, 2H, J = 8.8
Hz), 7.30 (t, 1H, J = 6.8 Hz), 7.52−7.59 (m, 3H), 7.64 (d, 1H, J = 7.6 Hz), 7.70 (s, 1H), 7.89 (d,
13
1H, J = 8.4 Hz), 8.08 (s, 1H), 9.34 (d, 1H, J = 8.4 Hz); C NMR (100 MHz, CDCl3):
δ (ppm)
17.6, 55.5, 115.1, 119.3, 120.1, 121.2, 121.9, 123.5, 124.7, 126.4, 126.7, 127.0, 128.8, 129.3,
130.9, 136.4, 136.5, 142.2, 146.3, 152.6, 158.6; IR (KBr): 3344, 2938, 2842, 1632, 1587, 1526,
1436, 1417, 1248, 1172, 1011, 829, 753, 709, 617 cmꢀ1; HRMS (ESI): calcd. for C23H21N2OS
[M+H]+ 373.1369; found 373.1379.
Nꢀ(2ꢀ((4ꢀChlorophenyl)thio)phenyl)ꢀ3ꢀmethylquinolinꢀ2ꢀamine (2e):
Yield 71% (67 mg) as a white solid; mp 139−141 oC; 1H NMR (400 MHz, CDCl3):
δ (ppm) 2.20
(s, 3H), 7.05–7.09 (m, 3H), 7.18 (d, 2H, J = 8.4 Hz), 7.31 (t, 1H, J = 6.8 Hz), 7.58 (q, 3H, J = 8.4
Hz), 7.65 (d, 1H, J = 7.6 Hz), 7.69 (s, 1H), 7.89 (d, 1H, J = 8.4 Hz), 8.01 (s, 1H), 9.41 (d, 1H, J =
13
8.4 Hz); C NMR (100 MHz, CDCl3):
δ (ppm) 17.4, 117.5, 119.3, 121.1, 122.0, 123.7, 124.7,
126.7, 127.1, 127.8, 128.9, 129.5, 131.8, 131.9, 134.9, 136.6, 137.3, 142.7, 146.2, 152.4; IR
(KBr): 3370, 2920, 2859, 1637, 1587, 1522, 1438, 1304, 1152, 1088, 1007, 900, 808, 757, 710
cmꢀ1; HRMS (ESI): calcd. for C22H18ClN2S [M+H]+ 377.0874; found 377.0875.
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3ꢀMethylꢀNꢀ(2ꢀ((3ꢀ(trifluoromethyl)phenyl)thio)phenyl)quinolinꢀ2ꢀamine (2f):
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o
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Yield 85% (87 mg) as a light brownish solid; mp 123−125 C; H NMR (400 MHz, CDCl3):
δ
(ppm) 1H NMR (400 MHz, CDCl3) δ 2.15 (s, 3H), 7.06 (t, 1H, J = 7.6 Hz), 7.16 (d, 1H, J = 7.6
Hz), 7.27 (dd, 2H, J = 17.6, 8.4 Hz), 7.34 (d, 1H, J = 8.0 Hz), 7.48 (s, 1H), 7.52–7.61 (m, 3H),
13
7.65 (d, 2H, J = 9.6 Hz), 7.87 (d, 1H, J = 8.4 Hz), 7.94 (s, 1H), 9.38 (d, 1H, J = 8.4 Hz); C
NMR (100 MHz, CDCl3):
δ (ppm) 17.3, 116.8, 119.5, 121.0, 122.8 (q, J = 3.7 Hz), 123.3 (q, J =
3.8 Hz), 123.7, 124.8, 126.7, 127.1, 128.9, 129.5, 129.9, 132.1, 136.6, 137.4, 138.1, 142.9, 146.2,
19
152.4; F NMR (CDCl3 + Hexafluorobenzene): δ ꢀ66.0 (s); IR (KBr): 3379, 2923, 2856, 1632,
1586, 1526, 1417, 1319, 1166, 1120, 1071, 893, 795, 760, 699 cmꢀ1; HRMS (ESI): calcd. for
C23H18F3N2S [M+H]+ 411.1173; found 411.1178.
3ꢀBromoꢀNꢀ(2ꢀ(phenylthio)phenyl)quinolinꢀ2ꢀamine (3a):
o
1
Yield 59% (60 mg) as a light brownish solid; mp 116−118 C; H NMR (400 MHz, CDCl3):
δ
(ppm) 7.10 (dd, 2H, J = 13.6, 8.0 Hz), 7.16−7.22 (m, 4H), 7.32 (t, 1H, J = 7.2 Hz), 7.56 (t, 2H, J
= 8.0 Hz), 7.61 (t, 1H, J = 8.4 Hz), 7.86 (d, 1H, J = 8.4 Hz), 8.16 (s, 1H), 8.85 (s, 1H), 9.25 (d,
1H, J= 8.0 Hz); 13C NMR (100 MHz, CDCl3):
δ (ppm) 109.2, 119.2, 119.6, 122.7, 124.2, 125.1,
126.1, 126.6, 127.2, 127.3, 129.3, 130.2, 131.2, 136.2, 137.3, 139.5, 142.3, 146.0, 149.1; IR
(KBr): 3432, 2924, 2855, 1602, 1527, 1474, 1401, 1318, 1227, 1089, 10007, 895, 813, 747 cmꢀ1;
HRMS (ESI): calcd. for C21H16BrN2S [M+H]+ 407.0212; found 407.0216.
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3ꢀBromoꢀNꢀ(2ꢀ(pꢀtolylthio)phenyl)quinolinꢀ2ꢀamine (3b):
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o
1
Yield 78% (82 mg) as a light brownish solid; mp 104−106 C; H NMR (600 MHz, CDCl3):
δ
(ppm) 2.26 (s, 3H), 7.04 (d, 2H, J = 7.8 Hz), 7.01 (t, 1H, J = 7.2 Hz), 7.13 (d, 2H, J= 8.4 Hz),
7.31 (t, 1H, J = 7.8 Hz), 7.54 (d, 2H, J = 7.2 Hz), 7.60−7.62 (m, 1H), 7.68 (d, 1H, J = 7.8 Hz),
7.86 (d, 1H, J= 8.4 Hz), 8.14 (s, 1H), 8.91 (s, 1H), 9.25 (d, 1H, J= 8.4 Hz); 13C NMR (100 MHz,
CDCl3):
δ (ppm) 21.1, 109.2, 119.2, 120.6, 122.6, 124.2, 125.1, 126.6, 127.2, 128.0, 130.0,
130.1, 130.8, 132.5, 136.2, 137.0, 139.5, 142.0, 146.0, 149.0; IR (KBr): 3299, 2922, 2854, 1581,
1528, 1438, 1402, 1301, 1204, 1158, 1004, 907, 800, 755, 612 cmꢀ1; HRMS (ESI): calcd. for
C22H18BrN2S [M+H]+ 421.0369; found 421.0343.
3ꢀBromoꢀNꢀ(2ꢀ((4ꢀchlorophenyl)thio)phenyl)quinolinꢀ2ꢀamine (3e):
Yield 94% (103 mg) as a brownish solid; mp 141−143 oC; 1H NMR (400 MHz, CDCl3):
δ (ppm)
7.10 (t, 3H, J= 8.4 Hz), 7.17 (d, 2H, J = 8.8 Hz), 7.32 (t, 1H, J = 7.6 Hz), 7.56 (d, 2H, J = 9.8
Hz), 7.61 (d, 1H, J = 8.0 Hz), 7.66 (t, 1H, J = 8.0 Hz), 7.86 (d, 1H, J = 8.4 Hz), 8.15 (s, 1H), 8.80
13
(s, 1H), 9.26 (d, 1H, J = 8.4 Hz); C NMR (100 MHz, CDCl3):
δ (ppm) 109.1, 119.1, 119.3,
122.8, 124.3, 125.2, 126.6, 127.2, 128.5, 129.4, 130.2, 131.5, 132.0, 134.9, 137.3, 139.6, 142.2,
145.9, 148.9; IR (KBr): 3321, 3053, 2922, 1581, 1526, 1441, 1315, 1160, 1117, 1070, 1002, 851,
793, 746, 693 cmꢀ1; HRMS (ESI): calcd. for C21H15BrClN2S [M+H]+ 440.9822; found 440.9831.
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3ꢀBromoꢀNꢀ(2ꢀ((3ꢀ(trifluoromethyl)phenyl)thio)phenyl)quinolinꢀ2ꢀamine (3f):
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o
1
Yield 81% (96 mg) as a light yellowish solid; mp 155−157 C; H NMR (400 MHz, CDCl3):
δ
(ppm) 7.11 (t, 1H, J = 7.6 Hz), 7.20−7.35 (m, 4H), 7.50−7.62 (m, 4H), 7.68 (d, 1H, J = 7.6 Hz),
13
7.84 (d, 1H, J = 8.0 Hz), 8.14 (s, 1H), 8.73 (s, 1H), 9.26 (d, 1H, J = 8.4 Hz); C NMR (100
MHz, CDCl3):
δ (ppm) 109.0, 118.2, 119.6, 122.9 (t, J= 3.2 Hz), 124.0 (q, J = 3.8 Hz), 124.4,
125.2, 126.6, 127.3, 129.7, 130.0, 130.2, 131.4, 131.8, 137.5, 138.0, 139.6, 142.3, 145.9, 148.9;
19F NMR (CDCl3 + Hexafluorobenzene): δ ꢀ66.0 (s); IR (KBr) 3327, 3059, 2924, 1583, 1528,
1443, 1318, 1165, 1120, 1071, 1003, 854, 794, 750, 695 cmꢀ1; HRMS (ESI): calcd. for
C22H15BrF3N2S [M+H]+ 475.0086; found 475.0088.
6ꢀMethylꢀNꢀ(2ꢀ(phenylthio)phenyl)quinolinꢀ2ꢀamine (4a):
o
1
Yield 71% (61 mg) as a light brownish solid; mp 122−124 C; H NMR (400 MHz, CDCl3):
δ
(ppm) 2.48 (s, 3H), 6.76 (d, 1H, J = 8.8 Hz), 7.04 (t, 1H, J = 7.6 Hz), 7.13 (t, 1H, J = 7.2 Hz),
7.18 (d, 2H, J = 7.2 Hz), 7.20–7.25 (m, 2H), 7.41 (s, 1H), 7.45 (d, 1H, J = 8.8 Hz), 7.51 (t, 1H, J
= 8.4 Hz), 7.62 (d, 1H, J = 7.6 Hz), 7.79 (t, 3H, J = 8.4 Hz), 8.95 (d, 1H, J = 8.4 Hz); 13C NMR
(100 MHz, CDCl3):
δ (ppm) 21.4, 113.6, 119.16, 119.2, 122.2, 124.4, 126.2, 126.7, 127.1, 127.4,
129.2, 129.4, 131.1, 131.9, 133.3, 136.5, 136.9, 137.1, 142.7, 145.7, 153.0; IR (KBr) 3362, 3054,
2960, 2922, 1611, 1587, 1521, 1435, 1314, 1127, 1023, 808, 755, 738, 688 cmꢀ1; HRMS (ESI):
calcd. for C22H19N2S [M+H]+ 343.1263; found 343.1266.
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6ꢀMethylꢀNꢀ(2ꢀ(pꢀtolylthio)phenyl)quinolinꢀ2ꢀamine (4b):
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8
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Yield 73% (65 mg) as a brownish solid; mp 150−152 oC; 1H NMR (400 MHz, CDCl3):
δ (ppm)
2.26 (s, 3H), 2.47 (s, 3H), 6.77 (d, 1H, J = 8.8 Hz), 6.99−7.04 (m, 3H), 7.09 (d, 2H, J = 8.4 Hz),
7.41−7.48 (m, 3H), 7.55 (d, 1H, J = 7.6 Hz), 7.78 (dd, 3H, J = 21.6, 8.8 Hz), 8.87 (d, 1H, J = 8.0
Hz); 13C NMR (100 MHz, CDCl3):
δ (ppm) 21.1, 21.5, 113.6, 119.3, 120.4, 122.2, 124.4, 126.7,
127.1, 128.1, 130.2, 130.7, 131.9, 132.6, 133.3, 136.4, 137.1, 142.4, 145.8, 153.1; IR (KBr)
3361, 3052, 2958, 2921, 1610, 1585, 1518, 1434, 1315, 1125, 1020, 810, 754, 687 cmꢀ1;HRMS
(ESI): calcd. for C23H21N2S [M+H]+ 357.1420; found 357.1428.
Nꢀ(2ꢀ((4ꢀChlorophenyl)thio)phenyl)ꢀ6ꢀmethylquinolinꢀ2ꢀamine (4e):
Yield 89% (84 mg) as a white solid; mp 158−160 oC; 1H NMR (400 MHz, CDCl3):
δ (ppm) 2.48
(s, 3H), 6.77 (d, 1H, J = 8.8 Hz), 7.01−7.08 (m, 3H), 7.17 (d, 2H, J = 8.8 Hz), 7.42−7.46 (m,
2H), 7.51 (t, 1H, J = 8.4 Hz), 7.58 (d, 1H, J = 7.6 Hz), 7.71 (s, 1H), 7.76 (d, 1H, J = 8.4 Hz),
13
7.82 (d, 1H, J = 8.8 Hz), 8.91 (d, 1H, J = 8.0 Hz); C NMR (100 MHz, CDCl3):
δ (ppm) 21.5,
113.5. 118.7, 119.3, 122.3, 124.5, 126.7, 127.1, 128.5, 129.5, 131.4, 132.0, 132.1, 133.5, 135.1,
136.9, 137.3, 142.8, 145.7, 152.9; IR (KBr) 3365, 3059, 2961, 2924, 1614, 1590, 1523, 1431,
1315, 1128, 1025, 809, 759, 740, 697 cmꢀ1;HRMS (ESI): calcd. for C22H18ClN2S [M+H]+
377.0874; found 377.0882.
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6ꢀMethylꢀNꢀ(2ꢀ((3ꢀ(trifluoromethyl)phenyl)thio)phenyl)quinolinꢀ2ꢀamine (4f):
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Yield 75% (77 mg) as a brownish solid; mp 89−91 C; H NMR (400 MHz, CDCl3):
δ (ppm)
2.47 (s, 3H), 6.80 (d, 1H, J = 8.8 Hz), 7.06 (t, 1H, J = 7.6 Hz), 7.19 (d, 1H, J = 7.6 Hz), 7.28 (d,
1H, J = 8.0 Hz), 7.34 (d, 1H, J = 7.6 Hz), 7.42 (s, 1H), 7.43 (d, 2H, J = 8.8 Hz), 7.53 (t, 1H, J =
7.8 Hz), 7.60 (d, 1H, J = 7.6 Hz), 7.69 (s, 1H), 7.75 (d, 1H, J = 8.4 Hz), 7.83 (d, 1H, J = 8.8 Hz),
8.88 (d, 1H, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3):
δ (ppm) 21.5, 113.4, 117.4, 119.5, 122.5,
122.8 (q, J = 3.7 Hz), 123.7 (q, J = 3.7 Hz), 124.5, 125.2, 126.7, 127.1, 129.8, 129.9, 131.5,
131.8, 131.9, 132.1, 133.5, 137.3, 137.4, 138.4, 143.0, 145.7, 152.8; 19F NMR (CDCl3 +
Hexafluorobenzene): δ ꢀ66.0 (s); IR (KBr) 3386, 2924, 2857, 1635, 1589, 1527, 1419, 1320,
1167, 1124, 1077, 895, 797, 761, 703 cmꢀ1; HRMS (ESI): calcd. for C23H18F3N2S [M+H]+
411.1137; found 411.1142.
6ꢀMethoxyꢀNꢀ(2ꢀ(phenylthio)phenyl)quinolinꢀ2ꢀamine (5a):
o
1
Yield 67% (60 mg) as a brownish solid; mp 93−95 C; H NMR (400 MHz, CDCl3):
δ (ppm)
3.89 (s, 3H), 6.78 (d, 1H, J = 8.8 Hz), 6.98−7.03 (m, 2H), 7.11−7.17 (m, 3H), 7.21 (t, 2H, J = 8.0
Hz), 7.26−7.29 (m, 1H), 7.49 (t, 1H, J = 8.8 Hz), 7.59 (d, 1H, J = 7.6 Hz), 7.75 (s, 1H), 7.79 (dd,
13
2H, J = 11.6, 9.2 Hz), 8.88 (d, 1H, J = 8.4 Hz); C NMR (100 MHz, CDCl3):
δ (ppm) 55.7,
106.4, 113.9, 118.9, 121.5, 122.0, 125.0, 126.2, 127.3, 128.8, 129.4, 131.1, 136.5, 136.7, 137.0,
142.9, 152.1, 156.1; IR (KBr) 3426, 2923, 2855, 1611, 1585, 1520, 1451, 1364, 1229, 1090,
1032, 813, 750 cmꢀ1; HRMS (ESI): calcd. for C22H19N2OS [M+H]+359.1213; found 359.1237.
6ꢀMethoxyꢀNꢀ(2ꢀ(pꢀtolylthio)phenyl)quinolinꢀ2ꢀamine (5b):
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Yield 70% (65 mg) as a brownish solid; mp 123−125 oC; 1H NMR (400 MHz, CDCl3):
δ (ppm)
5
6
2.15 (s, 3H), 3.78 (s, 3H), 6.68 (d, 1H, J = 8.8 Hz), 6.87−6.94 (m, 4H), 7.00 (d, 2H, J = 8.4 Hz),
7
8
9
7.17 (dd, 1H, J = 8.8, 2.8 Hz), 7.36 (t, 1H, J = 8.8 Hz), 7.46 (d, 1H, J = 7.6 Hz), 7.64 (s, 1H),
13
7.69 (dd, 2H, J = 8.8, 5.6 Hz), 8.75 (d, 1H, J = 8.4 Hz); C NMR (100 MHz, CDCl3):
δ (ppm)
10
11
12
13
14
15
16
17
18
19
20
21
22
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21.1, 55.7, 106.3, 113.9, 118.9, 120.1, 121.4, 122.0, 124.9, 128.0, 128.7, 130.2, 130.7, 132.6,
136.3, 136.4, 136.6, 142.5, 142.9, 152.1, 156.0; IR (KBr) 3420, 2921, 2852, 1610, 1583, 1520,
1449, 1362, 1227, 1085, 1031, 808, 746 cmꢀ1; HRMS (ESI): calcd. for C23H21N2OS [M+H]+
373.1369; found 373.1375.
Nꢀ(2ꢀ((4ꢀChlorophenyl)thio)phenyl)ꢀ6ꢀmethoxyquinolinꢀ2ꢀamine (5e):
Yield 60% (59 mg) as a brownish solid; mp 122−124 oC; 1H NMR (400 MHz, CDCl3):
δ (ppm)
3.89 (s, 3H), 6.80 (d, 1H, J = 8.8 Hz), 6.98−7.04 (m, 2H), 7.06 (d, 2H, J = 8.8 Hz), 7.17 (d, 2H, J
= 8.8 Hz), 7.27−7.30 (m, 1H), 7.50 (t, 1H, J = 7.6 Hz), 7.57 (d, 1H, J= 7.6 Hz), 7.68 (s, 1H), 7.80
(dd, 2H, J = 18.8, 9.2 Hz), 8.86 (d, 1H, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3):
δ (ppm) 55.7,
106.4, 113.8, 118.4, 119.0, 121.6, 122.2, 125.0, 128.5, 128.7, 129.5, 131.4, 132.0, 135.2, 136.8,
137.0, 142.9, 142.94, 152.0, 156.1; IR (KBr) 3438, 2926, 2857, 1613, 1587, 1521, 1452, 1363,
1230, 1091, 1034, 811, 753 cmꢀ1; HRMS (ESI): calcd. for C22H18ClN2OS [M+H]+ 393.0823;
found 393.0831.
6ꢀMethoxyꢀNꢀ(2ꢀ((3ꢀ(trifluoromethyl)phenyl)thio)phenyl)quinolinꢀ2ꢀamine (5f):
Yield 74% (79 mg) as a brownish solid; mp 108−110 oC; 1H NMR (400 MHz, CDCl3):
δ (ppm)
3.88 (s, 3H), 6.81 (d, 1H, J = 8.8 Hz), 6.97 (d, 1H, J = 2.8 Hz), 7.04 (t, 1H, J= 7.6 Hz), 7.18 (d,
1H, J = 7.6 Hz), 7.25−7.29 (m, 2H), 7.33 (d, 1H, J = 8.0 Hz), 7.44 (s, 1H), 7.52 (t, 1H, J = 8.0
Hz), 7.59 (d, 1H, J = 7.6 Hz), 7.65 (s, 1H), 7.77 (d, 1H, J = 9.2 Hz), 7.82 (d, 1H, J = 8.8 Hz),
8.84 (d, 1H, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3):
δ (ppm) 55.7, 106.3, 113.7, 117.4, 119.2,
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121.7, 122.3, 122.5, 122.7 (q, J = 3.7 Hz), 123.6 (q, J = 3.9 Hz), 125.1, 125.2, 128.8, 129.8,
129.9, 131.5, 131.8, 136.9, 137.3, 138.4, 142.9, 143.2, 151.9, 156.2; 19F NMR (CDCl3 +
Hexafluorobenzene): δ ꢀ66.0 (s); IR (KBr): 3369, 2945, 2849, 1613, 1589, 1520, 1450, 1365,
1319, 1245, 1162, 1122, 1072, 906, 833, 751, 693 cmꢀ1; HRMS (ESI): calcd. for C23H18F3N2OS
[M+H]+ 427.1036; found 427.1039.
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8ꢀMethylꢀNꢀ(2ꢀ(phenylthio)phenyl)quinolinꢀ2ꢀamine (6a):
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Yield 56% (47 mg) as a yellowish gummy; H NMR (400 MHz, CDCl3):
δ (ppm) 2.75 (s, 3H),
6.68 (d, 1H, J= 8.8 Hz), 7.01 (t, 1H, J= 7.2 Hz), 7.09 (t, 1H, J = 7.2 Hz), 7.13−7.21 (m, 5H), 7.45
(d, 2H, J = 8.4 Hz), 7.51 (t, 1H, J = 8.8 Hz), 7.61 (d, 1H, J = 8.0 Hz), 7.81 (d, 1H, J = 8.8 Hz),
7.94 (s, 1H), 9.23 (d, 1H, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3):
δ (ppm) 18.6, 113.5, 118.4,
119.1, 121.9, 123.4, 124.1, 125.4, 126.1, 127.2, 129.4, 130.1, 131.2, 135.2, 136.6, 137.1, 137.8,
142.9, 146.3, 152.4; IR (KBr) 3357, 3053, 2919, 1619, 1589, 1524, 1433, 1342, 1312, 1142,
1025, 822, 741, 690 cmꢀ1; HRMS (ESI): calcd. for C22H19N2S [M+H]+ 343.1263; found
343.1290.
Nꢀ(2ꢀ((4ꢀMethoxyphenyl)thio)phenyl)ꢀ8ꢀnitroquinolinꢀ2ꢀamine (7c):
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Yield 47% (47 mg) as a yellowish gummy; H NMR (400 MHz, CDCl3):
δ (ppm) 3.75 (s, 3H),
6.82 (d, 2H, J = 8.8 Hz), 7.12−7.16 (m, 3H), 7.38 (t, 1H, J = 8.0 Hz), 7.43−7.51 (m, 2H),
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7.57−7.60 (m, 2H), 7.64 (t, 1H, J = 2.0 Hz), 8.56 (d, 1H, J = 8.4 Hz), 8.95 (s, 1H); C NMR
(100 MHz, CDCl3):
δ (ppm) 55.6, 115.5, 121.0, 122.8, 124.9, 125.3, 125.4, 127.5, 130.3, 130.4,
130.7, 132.1, 135.2, 135.8, 136.8, 139.1, 159.2, 164.1; IR (KBr) 3430, 2923, 2853, 1624, 1592,
1519, 1449, 1313, 1262, 1085, 1017, 756 cmꢀ1; HRMS (ESI): calcd. for C22H18N3O3S [M+H]+
404.1063; found 404.1069.
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