Rh-Catalyzed, Regioselective, C-H Bond Functionalization: Access to Quinoline-Branched Amines and Dimers

Article abstract of DOI:10.1021/acs.orglett.6b02848

Rh-catalyzed, chelation-induced, C-5 regioselective C-H functionalization of 8-amidoquinolines with a range of N-Boc aminals is reported for the first time. The addition of in situ generated imines to C(sp²)-H bonds afforded branched amines in

Full text of DOI:10.1021/acs.orglett.6b02848

Letter
pubs.acs.org/OrgLett
Rh-Catalyzed, Regioselective, C−H Bond Functionalization: Access to
Quinoline-Branched Amines and Dimers
M. Damoder Reddy,† Frank R. Fronczek,‡ and E. Blake Watkins*,†
†Department of Pharmaceutical Sciences, School of Pharmacy, Union University, 1050 Union University Drive, Jackson, Tennessee
38305, United States
‡Department of Chemistry, Louisiana State University, 608 Choppin Hall, Baton Rouge, Louisiana 70803, United States
S
* Supporting Information
ABSTRACT: Rh-catalyzed, chelation-induced, C-5 regiose-
lective C−H functionalization of 8-amidoquinolines with a
range of N-Boc aminals is reported for the first time. The
addition of in situ generated imines to C(sp2)−H bonds
afforded branched amines in good to excellent yields.
Moreover, this transformation features good functional group
compatibility, broad substrate scope, and mild reaction
conditions and is suitable for gram-scale synthesis. In addition, an unprecedented, chelation-induced, site-selective, remote
dimerization of quinolines led to the formation of dimer frameworks in moderate yields under Rh-catalyzed conditions.
etal catalyzed C−H functionalization has emerged as a
various research groups.8−10 However, an efficient method for
C−C bond formation at the remote C5 position of quinoline is
still rare.11 The remote C5−H functionalization remains
unsatisfied with regard to the development of novel trans-
formations, mild conditions, and selectivity.
M
powerful tool due to its ability to enable the direct
introduction of complex functional groups into an assortment of
organic molecules in an environmentally benign and efficient
manner.1 Among the rich array of metal catalysts that mediate C−
H functionalization, rhodium complexes have particularly
attracted considerable attention as versatile agents for C−H
bond activation due to their high functional group compatibility
and catalytic efficacy.2 While substantial progress has been made
forthe directing group-assisted dimerization (eq 1, Figure 1)3 and
Branched amines are an important class of organic molecules
due to their prevalence in natural products, pharmaceuticals, and
agrochemicals.12 One of the principle approaches to these
moleculesistheadditionoforganometallicreagentstoanimine.13
Recently, directing group-assisted addition of unactivated C−H
bonds to imines has been developed and provides a powerful
alternative for the synthesis of branched amines via mild and
atom-economic conditions.4 N-Boc aminal is an appropriate
precursor for in situ generation of the imine due to its stability and
ease of accessibility.14 To the best of our knowledge, there is no
report of chelation-induced, site-selective, remote C−H bond
functionalization of quinoline derivatives with imines. In
continuation of our efforts on C−H functionalization reactions,15
herein we report the first Rh-catalyzed, site-selective, remote C−
H bond functionalization with N-Boc aminals (eq 3, Figure 1).
Initially, N-(quinolin-8-yl)benzamide (1a) and di-tert-butyl
(phenylmethylene)dicarbamate (2a) were chosen as model
substrates for the optimization of reaction parameters (Table
1). When the reaction was carried out in the presence of catalytic
Pd(OAc)2 and AgSbF6 at 100 °C for 24 h in toluene, the
corresponding branched amine 3a was isolated in 12% yield as a
result ofC5-selective additionof 1atoN-Boc-aminal2a(entry1).
The structure of 3a was unambiguously determined by single-
crystal X-ray diffraction (Scheme 1). Exposure of 1a and 2a to a
catalytic amount of Pd(OAc)2/Cu(OAc)2 afforded the desired
amine 3a in 16% yield (Table 1, entry 2). A variety of metal
Figure 1. Directing group assisted and remote C−H functionalization
reactions.
addition of C(sp2)−H bonds to polarized π-bonds for the
synthesisofaminesandotherheterocycles(eq2,Figure1),4,5 site-
selective functionalization of unactivated, remote C−H bonds
remains a fundamental and ongoing challenge in synthetic
chemistry.6 To this end, Stahl et al. reported the Cu-catalyzed,
remote C5-selective chlorination of 8-amidoquinolines.7 Sub-
sequently, Cu- orCo-catalyzed C−heteroatom bondformation at
the C5 and/or C7 positions of quinoline has been reported by
Received: September 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02848
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 1. Remote C-5 Functionalization of 1a with N-Boc
Aminals
a
h
additive/
base
temp/time
(°C/h)
yield
entry
1
catalyst
solvent
(3a/5a)
Pd(OAc)2
Pd(OAc)2
Cul
AgSbF6
Cu(OAc)2
K2CO3
toluene
toluene
DMF
100/24
100/24
100/24
100/24
12/0
16/0
0/0
b
2
c
3
4
[Ru(p-
cymene)
Cl2]2
AgSbF6
toluene
35/8
5
[Rh(COD)
Cl]2
AgSbF6
toluene
100/24
68/14
d
6
Ni(OTf)2
Fe(OTf)3
AgSbF6
AgSbF6
AgSbF6
toluene
toluene
DCE
100/24
100/24
65/18
0/0
0/0
e
7
8
[Rh(COD)]
OTf
65/2
9
Rh2(esp)2
AgSbF6
AgNO3
DCE
DCE
65/18
65/18
42/3
74/0
10
[Rh(COD)
Cl]2
11
12
13
14
15
16
[Rh(COD)
Cl]2
Ag2CO3
AgOTf
AgOAc
AgSbF6
DCE
DCE
DCE
DCE
DCE
65/18
65/18
65/18
65/18
65/24
6/0
75/4
11/2
95/0
0/0
a
Reaction conditions: 1a (0.4 mmol), 2a−s (0.5 mmol), [Rh(COD)-
Cl]2 (2 mol %), AgSbF6 (20 mol %), 1,2-dichloroethane (DCE) (4
mL), 65 °C, 18 h. Dibenzyl (phenylmethylene)dicarbamate (2r) used
as a coupling partner. Dimethyl (phenylmethylene)dicarbamate (2s)
used as a coupling partner. (E)-N-Benzylidene-4-methylbenzenesul-
fonamide (2t) used as a coupling partner. The values in parentheses
refer to the amount of recovered starting material.
[Rh(COD)
Cl]2
b
c
[Rh(COD)
Cl]2
d
[Rh(COD)
Cl]2
[Rh(COD)
Cl]2
AgSbF6
AgSbF6
DCE
DCE
65/24
65/24
0/0
with 4 mol % of AgSbF6 (entry 17), and no product was observed
with 100 mol % of [Rh(COD)Cl]2 (entry 18).17
f
17
[Rh(COD)
Cl]2
69/0
Having determined the optimized reaction conditions, we
initially probed the versatility of site-selective, remote C−H
functionalization with regard to a diverse class of N-Boc aminals
using 1a as the coupling partner (Scheme 1). N-Boc aminals
bearing various functional groups, including electron-donating or
electron-withdrawing groups, all gave the corresponding
branched amines in good to excellent yields (Scheme 1, 3a−e).
Notably, halogenated aminals (2f−h) were also well-tolerated in
this protocol and provided the corresponding amines in good
yields (3f−h). Moreover, meta-substituted N-Boc aminals were
successful under the reaction conditions, delivering branched
aminesin81%(3i)and75%(3j)yields, respectively. Importantly,
ortho-substituted aminals were compatible in the reaction,
furnishing the desired products in good, although lower, yields
(3k, 62%; 3l, 48%). Di-tert-butyl (naphthalen-1-ylmethylene)-
dicarbamate(2m)reactedwellundertheRh-catalyzedconditions
and provided the corresponding product 3m in 62% yield.
Similarly, a heteroaromatic aminal (2n) was also well-tolerated
and furnished the expected branched amine 3n in 60% yield.
Besides the aromatic aminals, aliphatic N-Boc aminals (2o and
2p) were also suitable for this transformation, delivering the
aliphatic amines 3o in 43% and 3p in 52% yields, respectively.
Surprisingly, di-tert-butyl (3-phenylprop-2-yne-1,1-diyl) dicarba-
mate (2q) was compatible with these conditions and afforded the
propargylamine derivative (3q) in 74% yield. It is worth noting
that the remote C−H functionalization was also suitable with
aminals (2r and 2s) prepared from Cbz-NH2 and methyl
carbamate, respectively, andgavethedesiredproducts(3rand3s)
in good yields. The N-Ts-branched amine (3t) was prepared
using the imine (E)-N-benzylidene-4-methylbenzenesulfona-
mide (2t) as a coupling partner with 1a under optimal conditions.
g
18
[Rh(COD)
Cl]2
DCE
65/24
trace
a
Reaction conditions: 1a (0.4 mmol), 2a (0.5 mmol), Rh or Ru
catalyst (2 mol %), Pd(OAc)2 (10 mol %), CuI (20 mol %), additive
(20 mol %), solvent (4 mL). Cu(OAc)2 (0.4 mmol). K2CO3 (0.4
mmol). Ni(OTf)2 (10 mol %). Fe(OTf)3 (10 mol %). AgSbF6 (4
mol %). [Rh(COD)Cl]2 (100 mol %). Isolated yields.
b
c
d
e
f
g
h
catalysts and additives were examined (entries 3−7). Under
rutheniumcatalysis, compound 3awasisolated in35%yieldalong
with the dimer 5a in 8% yield (entry 4). With the [Rh(COD)-
Cl]2/AgSbF6 catalytic system at 100 °C in toluene, a mixture of
amine 3a (68%) and dimer 5a (14%) was isolated (entry 5). Cu,
Fe, and Ni catalytic conditions were ineffective in this
transformation (entries 3, 6, and 7). By careful analysis of remote
C5-selective functionalization reaction outcomes with these
metal catalysts, Rh catalysis was shown to exhibit favorable
efficiencyandthebestyieldtowardremotefunctionalization. This
advantage inspired us to conduct further screening with Rh as the
optimal catalyst. Further investigation and optimization involved
changing the solvent to DCE and lowering the reaction
temperature as well as utilizing various Rh catalysts (entries 8−
10) and diverse silver salts (entries 11−14). These studies
revealed that [Rh(COD)Cl]2 in combination with AgSbF6 was
excellent for improving the reaction efficiency and gave 3a in 95%
yield as a single product (entry 14). Other rhodium catalysts and
silver salts such as AgNO3, Ag2CO3, AgOAc, and AgOTf were
found to be less effective in this transformation. The reaction
failed in the absence of either [Rh(COD)Cl]2 or AgSbF6 (entries
15 and 16).16 Additionally, the reaction also proceeded smoothly
B
DOI: 10.1021/acs.orglett.6b02848
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Next, the scope and generality of substituted 8-amidoquino-
lines were explored under the optimal reaction conditions
(Scheme 2). A range of quinoline amides bearing various
With the amine derivatives of 8-amidoquinoline in hand, the
feasibility of Rh-catalyzed, remote C-5 dimerization was
investigated. Based on our initial results during the reaction
optimization process, we knew dimerization was feasible and a
consistent byproduct of the remote functionalization method.
Having successfully accomplished our goal of C-5 functionaliza-
tion, we set out to optimize conditions under which dimerization
would predominate (see the Supporting Information). For that
purpose, we performed the reaction of 1a in the presence of 2 mol
% of [Rh(COD)Cl]2 and 40 mol % of AgSbF6 using elevated
temperatures and extended reaction times. The reaction
proceeded at the remote C-5 position, and the symmetrical
quinoline dimer 5a was obtained in 66% yield (Scheme 4).20 We
Scheme 2. Substrate Scope of 8-Amidoquinolines for Remote
a
Functionalization.
a
Scheme4. SubstrateScopefortheC-5DimerizationReaction
a
Reaction conditions: 1b−w (0.4 mmol), 2a (0.5 mmol), [Rh(COD)-
Cl]2 (2 mol %), AgSbF6 (20 mol %), DCE (4 mL) and 65 °C, 18 h.
The values in the parentheses refer to the amount of recovered starting
material.
electron-donating, electron-withdrawing, or halogen substituents
at the para position all reacted smoothly with 2a, and the desired
branched amines were isolated in 66−95% yields (4b−i). In a
similar way, meta-substituted amides (1j,l,m) and disubstituted
quinoline benzamides (1k,n,o) were also tolerated. Electron-rich
substrates gave slightly higher yields than electron-poor
substrates. A diverse class of heterocyclic amides could generate
the corresponding branched amines in moderate to good yields
(4p−t, 68−77%). Surprisingly, the aliphatic amide (1u) proved
amenable to the standard conditions, delivering 4u in 63% yield.
An examination of the 8-amidoquinolines with rhodium-
catalyzed conditions revealed that the reaction is compatible
with variously substituted aromatic amides, heteroaromatic
amides, aswellasaliphaticamides. N,N-Dialkylquinolin-8-amines
(1v and 1w) failed to give the corresponding products under
standard conditions.
As a further demonstration of the synthetic expediency of this
method, a gram-scale (4 mmol) reaction was conducted with 1a
and 2a using standard reaction conditions to furnish the branched
amide 3a in 79% yield (Scheme 3). The amide bond was cleaved
using NaOH in EtOH at 80 °C to provide the 8-aminoquinoline
derivative 6 in 75% yield.18 Furthermore, N-Boc-deprotection of
3a under acidic conditions provided the corresponding benzylic
amine 7 in 89% yield (Scheme 3).19
a
Reaction conditions: 1 (0.4 mmol), [Rh(COD)Cl]2 (2 mol %),
AgSbF6 (40 mol %), DCE (4 mL), 90 °C, 36 h. The values in
parentheses refer to the amount of recovered starting material.
then surveyed additional substrates with various groups to gauge
the usefulness of the Rh-catalyzed dimerization and obtained the
expected C-5 dimers (5b−i) in moderate yields. When
heterocyclic amides were used as substrates, site-selective
dimerization products were also obtained in reasonable yields
(5j, 54% and 5k, 61%). Gratifyingly, aliphatic amides (1u and 1x)
also afforded the desired products in 48% (5l) and 54% (5m)
yields, respectively. The structures were confirmed using HRMS
and 2D-NMR.
In conclusion, we report the first successful example of Rh-
catalyzed, chelation-induced, C5-selective, remote functionaliza-
tion of 8-amidoquinoline derivatives using N-Boc aminals as
coupling partners. Further benefits include complete site
selectivity, a broad substrate scope, and high functional group
tolerance. We have also successfully extended the Rh-catalyzed
conditions for the synthesis of a quinolone-based dimer
framework. Further efforts to extend the applications of this
new protocol are underway in our laboratory.
Scheme 3. Gram-Scale Synthesis and Functional Group
Modification of 3a
ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b02848.
General experimental procedures and spectroscopic data
of all the compounds; 2D-NMR and HRMS spectral data
for representative compounds; and X-ray crystallographic
data for 3a (PDF)
C
DOI: 10.1021/acs.orglett.6b02848
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Organic Letters
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bwatkins@uu.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Thisresearchwasfunded byUnionUniversity. Wearegrateful for
the HRMS data provided by D. R. Phillips and C.-W. Chou
[Proteomics and Mass Spectrometry (PAMS) Facility, NIH
Grant No. 1S10RR1028859] at the Department of Chemistry,
University of Georgia, and to Professor Gerald Dyker of Ruhr-
UniversitatBochuminBochum, Germany, forhelpfulmechanism
̈
discussions.
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D
DOI: 10.1021/acs.orglett.6b02848
Org. Lett. XXXX, XXX, XXX−XXX