C6-selective direct alkylation of pyridones with diazo compounds under Rh(III)-catalyzed mild conditions

Article abstract of DOI:10.1021/acs.joc.5b02349

A Rh(III)-catalyzed highly efficient C6-alkylation of 2-pyridones has been achieved successfully with α-diazo carbonyl compounds. The developed method is simple, mild, and highly regioselective with a broad range of substrate scope. The regioselectivity is guided by the pyridyl substituent attached to the nitrogen center of the pyridone ring. The directing group can be easily removed, and the only formed byproduct is nitrogen. Furthermore, other similar heterocyclic scaffolds can also be functionalized regioselectively under the developed conditions.

Full text of DOI:10.1021/acs.joc.5b02349

Subscriber access provided by UNIV OF CALIFORNIA SAN DIEGO LIBRARIES
Article
C6 Selective Direct Alkylation of Pyridones with Diazo
Compounds under Rh(III) Catalysed Mild Condition
Debapratim Das, Aniruddha Biswas, Ujjwal Karmakar, Santanu Chand, and Rajarshi Samanta
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02349 • Publication Date (Web): 07 Jan 2016
Downloaded from http://pubs.acs.org on January 8, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
C6 Selective Direct Alkylation of Pyridones with Diazo
Compounds under Rh(III) Catalysed Mild Condition
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Debapratim Das, Aniruddha Biswas, Ujjwal Karmakar, Santanu Chand, and Rajarshi Samanta*
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India.
ABSTRACT: A Rh(III)ꢀcatalyzed highly efficient C6ꢀalkylation of 2ꢀpyridones has been achieved successfully with
αꢀdiazo carbonyl compounds. The developed method is simple, mild, highly regioselective with broad range of
substrate scope. The regioselectivity guided by the pyridyl substituent attached with nitrogen center of pyridone ring.
The directing group can be easily removed and the only formed byproduct is nitrogen. Furthermore, other similar
heterocyclic scaffolds also can be functionalized regioselectively under the developed condition.
INTRODUCTION:
Regioselective direct functionalization of pyridone derivatives is a subject of great interest to the synthetic and
medicinal chemists due to its presence as prevalent heterocyclic core structure in many pharmaceuticals and
biologically active natural products (Figure 1).1
Figure 1: Pharmaceuticals and natural products having C6 alkylated 2ꢀpyridone core structure
In continuation with the recent advances on the transition metal catalysed direct regioselective CꢀH bond
functionalization2, a number of studies were carried out to directly introduce new carbonꢀcarbon bond regioselectively
on pyridone derivatives.3 Recently, Hirano and Miura group developed C3 selective alkylation and arytlation using
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 18
1
2
3
4
5
6
7
8
9
catalytic Ni(0) or Mn(III) salt in stoichiometric amount.3a,b Very recently, Maiti and coꢀworkers demonstrated a user
friendly method for C3 arylation using cheap iron catalyst and boronic acid as coupling partner.3c A Pd(II) catalysed
C3 arylation was achieved by Zografos and coꢀworkers though the method is restricted to the 4ꢀhydroxypyridone
moiety.3d With blocked C5 position, carbonꢀcarbon bond formations was achieved at C3 position of Nꢀprotected
pyridone using Pd(II) catalysis.3eꢀf, 4b After the leading discovery of palladium mediated oxidative C5 alkenylation of
2ꢀpyridone moiety by Itahara and coꢀworkers4a, recently its substoichiometric version was developed by Li group.4b
Nakao and Hiyama group demonstrated the redox neutral, stereo and C6 selective direct alkenylation and alkylation of
2ꢀpyridone scaffold using seminal Ni(0)/Lewis acid cooperative catalysis (Scheme 1a).5 Recently, in a great
advancement, Miura and Hirano group reported a copperꢀmediated C6 selective dehydrogenative heteroarylation of 2ꢀ
pyridones with 1,3 azoles (Scheme 1b).6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1: C6 selective functionalization of 2-pyridones
Previous work
cat. Ni(0)/Al
Cu(II)
60 - 80 °C
N
O
N
6
H
O
N
R'
O
N
PG = 2-Py,
PG
(b)
PG = Me,
PG
PG
O
(a)
150 C, heteroarene
alkyne/alkene
Our work
Rh(III)
PG = 2-Py, 40
CO2R'
(c)
O
N
6
O
N
H
C
PG
PG
CO2R'
diazo compound
Concerted direct metal carbene insertion into unactivated CꢀH bonds represents a traditional approach.7 Compared to
the well studied classical reactions of carbenoid, CꢀH metalation, metalꢀcarbene formation followed by migratory
insertion with diazo compounds has not yet well explored.8 After the report by Wang group on direct Cu(I) catalysed
benzylation and allylation of 1,3 azoles with Nꢀtosylhydrazones9, Yu group published the pioneering work on ortho Cꢀ
H alkylation of nonꢀheteroarenes bearing directing group with diazomalonates using Rh(III) catalysis in 2012.10 Since
then, a promising progress has been observed in Rh(III) catalysed directed CꢀH alkylation using diazo compounds by
various groups.11
Despite this advancement, mild C6ꢀselective 2ꢀpyridone alkylation is still challenging due to the use of drastic
reaction conditions or nonꢀremovable protecting group. Given these restrictions and the notable importance of
pyridone building blocks, we started the studies on regioselective alkylation of pyridone scaffolds using diazo
compounds as coupling partner. Herein, we reveal the Rh(III) catalysed C6 selective direct alkylation of 2ꢀpyridone
using carbonyl containing diazo compounds under mild2c conditions.
RESULT AND DISCUSSION:
Our synthetic attempt began to search for the optimal reaction conditions for the C6ꢀalkylation of 2ꢀpyridone, we
investigated the reaction of Nꢀproteced 2ꢀpyridone(1) with methyl diazomalonate(2a) in presence of [(Cp*RhCl2)2] (1
2
ACS Paragon Plus Environment

Page 3 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
mol%, Cp*=pentamethylcyclopentadiene) and AgSbF6 (4 mol%) in 1,2 dichloroethane (DCE) at 40 °C. Methyl (1a),
pivaloyl(1b) or carbamoyl(1c) group as protecting group did not provide our desired product. Gratifyingly, 1ꢀ(2ꢀ
pyridyl)ꢀ2ꢀpyridone(1d) afforded the desired C6 alkylated product (3d) in excellent yield (92%) (Table 1, entry 1ꢀ4).
8
9
Table 1. Optimization C6-selective alkylation of 2-pyridonesa
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry
1
PG
solvent
DCE
additive
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgNTf2
AgNO3
AgPF6
yieldb
n.d.
n.d.
n.d.
92
Me(1a)
Piv(1b)
CONMe2(1c)
2-Py (1d)
2ꢀPy
2
DCE
3
DCE
4
DCE
5
DMF
87
6
2ꢀPy
tꢀAmylalcohol
toluene
CH3CN
DCE
n.d.
trace
67
7
2ꢀPy
8
2ꢀPy
9
2ꢀPy
87
10
11
12
13
14c
2ꢀPy
DCE
65
2ꢀPy
DCE
89
2ꢀPy
DCE
AgOAc
AgBF4
trace
90
2ꢀPy
DCE
2ꢀPy
DCE
AgSbF6
62
aReaction conditions: 1 (0.1 mmol), 2a (0.12 mmol), [Cp*RhCl2]2 (1 mol%), additive (4 mol%), 0.1 M. Isolated
yields. cReaction conditions: [Cp*IrCl2]2 (2 mol%), additive (8 mol%), 0.1 M at 80 °C. DCE= 1,2 dichloroethane. n.d.
= not detected.
b
Change of other organic solvents did not improve the isolated yield rather the yield was decreased (Table 1, entry 5ꢀ
8). The isolated yields for the other screened halogen scavengers used as additive at mild conditions were also very
impressive though the best found AgSbF6 (Table 1, entry 9ꢀ13). Another transition metal catalyst [(Cp*IrCl2)2] was
also examined (Table 1, entry 14) under more drastic conditions with lower isolated yield. However, the use of
additional additive like NaOAc in catalytic or stoichimetric amount did not improve the highest isolated yield of the
desired product under reduced reaction time (see supporting information optimization table for further details).
Scheme 2: C6-Alkylation of 2-pyridones with different diazo compounds
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 18
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Reaction Conditions: 1d (0.1 mmol), 2 (0.12 mmol), [Cp*RhCl2]2 (1 mol%), AgSbF6 (4 mol%), 0.1 M, 12 h.
aReaction Conditions: 1d (1.35 mmol), 2a (1.62 mmol), [Cp*RhCl2]2 (0.5 mol%), AgSbF6 (2 mol%), 0.1M at 40 °C
b
c
for 36 h. Reaction Conditions: [Cp*RhCl2]2 (2 mol%), AgSbF6 (8 mol%), 0.1 M at 80 °C for 12 h. mixture of
enol:keto= ~1.4:1, dReaction Conditions: [Cp*RhCl2]2 (2 mol%), AgSbF6 (8 mol%), 0.1 M at 100 °C for 24 h.
With the most favorable catalytic system established, we surveyed the scope and limitations of this reaction.
Subsequently, the substrate scope of different diazo substrates was explored (Scheme 2). A number of diazomalonates
worked smoothly in good to excellent yields (Scheme 2, 3d-3h). To our pleasure, thirteen fold increase in the starting
material and two fold decreases in catalyst loading provided the impressive turn over with little increase in reaction
time (Scheme 2, 3d). In general there is not much difference in yield for electronically variable diazo substrates
though when bis(2,2,2ꢀtrifluoroethyl)2ꢀdiazomalonate was used as coupling partner, a large amount of decarboxylated
product was obtained with the desired product. But elevation of reaction temperature (80 °C) offered solely the
decarboxylated product in very good yield (Scheme 2, 3h). Efficient couplings with diazo keto compounds were also
observed (Scheme 2, 3i-3j) under optimized condition. Additionally, moderate to excellent yield was also obtained
when one of the ester group of diazomalonates were changed with another electron deficient group like amide,
sulfonyl or phosphonate (Scheme 2, 3k-3m).
Scheme 3: C6-Alkylation of 2-pyridones with the diazo derivative of Meldrum’s Acid
Reaction Conditions: 1 (0.1 mmol), 4 (0.12 mmol), [Cp*RhCl2]2 (2 mol%), AgSbF6 (8 mol%), EtOH (0.1 M) at 80 °C
for 12 h. aUsed solvent was tBuOH.
4
ACS Paragon Plus Environment

Page 5 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
While α–diazotized Meldrum’s acid (4) was used as a coupling partner, the reaction proceeded smoothly with final
decarboxylated product (Scheme 3, 5a-d)11b,11k. Depending upon the alcohol used as solvent, different 6ꢀacetate
substituted pyridones were obtained in moderate to good yield (Scheme 3, 5d).
8
9
Satisfactorily, electronically and sterically variable substituents at C3, C4 or C5 position of 2ꢀpyridone
scaffold were well tolerated during the transformation (Scheme 4, 6e-6i). Electron donating group at C3 position of 2ꢀ
pyridone scaffolds (Scheme 4, 6f, 6g) works relatively better than electron withdrawing group at same position
(Scheme 4, 6h).To our delight, isoquinolone and quinazolone derivatives also provided the respective alkylated
product in good yields (Scheme 4, 6j-6k). Though a wide investigation of direct functionalization on enaminone
systems was carried out12, the transition metal catalysed regioselective direct functionalization of quinolones, a
privileged motif present in numerous bioactive compounds is a topic of recent interest.13 With our optimized catalytic
condition, 2ꢀpyridyl protected 4ꢀpyridone and quinolone scaffolds were also directly alkylated at its C2 postion to
provide corresponding products (Scheme 4, 6l and 6m) with moderate to good yield. Interestingly, in case of
quinolone there was no C8 alkylation observed.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4: Regioselective alkylation of various heterocycles with diazomalonate
Reaction Conditions: 1(0.1 mmol), 2a (0.12 mmol), [Cp*RhCl2]2 (1 mol%), AgSbF6 (4 mol%), 0.1 M, 12ꢀ24 h.
aReaction Conditions: [Cp*RhCl2]2 (2 mol%), AgSbF6 (8 mol%), 0.1 M at 80 °C for 12 h.
Furthermore, hydrogenation of 3d offered biologically relevant C6ꢀalkylated piperidinꢀ2ꢀone derivative 714 in 79%
yield (Scheme 5a). Finally, the 2ꢀpyridyl directing group was removed from 3d via the two step
quaternization−hydride reduction15 process at room temperature to provide decarboxylated product 8 in acceptable
yield with some Nꢀmethylated quartinized starting material (Scheme 5b).
Scheme 5: Transformation of product molecule
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 18
1
2
3
4
5
6
7
8
9
To elucidate the reaction mechanism, several control experiments were carried out. First, a H/D scrambling in
DCE/D2O revealed a reversible C–H bond cleavage in the absence of 2a (see the Supporting Information for details).
When 1d and 1g were allowed to react with 2a under standard condition, the reaction favored the formation of 6g over
3d in a 3.5:1 ratio. In a similar fashion, when 1d and 1h were taken for intermolecular competition experiment with
2a, the product ratio found 3d:6h in ~10:1 ratio which suggested more electron rich 2ꢀpyridone is kinetically favored
and the reaction might be preceded through electrophilic mode of activation (Scheme 6a).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In 2002, Sieburth and coꢀworkers demonstrated that 2m’ was a capable substrate to provide cyclopropane 9 under
Rh2(OAc)4 catalysis (Scheme 6b).16 Whereas, under our optimized condition, we found that 2m was efficiently giving
product 3n in 94% yield (Scheme 6c).11c This can be rationalized when the CꢀH metalation step is much faster than the
metalꢀcarbene formation under our developed conditions.
Scheme 6: Control experiments
Again, we investigated the possibility of a rhodacycle species as an intermediate in the plausible diazomalonate
insertion process. A stable cyclometalated Rh(III) complex 10 was prepared through Jones protocol17 (Scheme 7).
Thus, catalytic activity of the complex 10 was examined under the previously optimized alkylation condition.
Additionally, stoichiometric conversion of the rhodacycle 10 to compound 3d was also scrutinized. Gratifyingly, both
the cases the desired product formed in excellent yield (see the Experimental Section for more details). Based on
previous reports8, 10, 11, 18 and our preliminarily mechanistic experiments, a plausible alkylation pathway is proposed
(Scheme 8).
Scheme 7: Synthesis of stable rhodacycle
First, a cationic Rh(III) catalyst, generated with the help of Ag salt coordinates to the pyridine nitrogen atom and
undergoes electrophilic CꢀH bond cleavage to form rhodacyclic intermediate A. Coordination of the diazonium
species with A leads to form intermediate B. Now via a redox active pathway (pathway I), extrusion of N2 from B
would provide metalꢀcarbenoid species C. Subsequently, the 6ꢀmembered rhodacycle D could be obtained from C
through migratory insertion.
6
ACS Paragon Plus Environment

Page 7 of 18
The Journal of Organic Chemistry
1
2
3
Scheme 8: Proposed mechanism
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In an alternative redox neutral route (pathway II), species B could form intermediate D through E where
alkyl insertion can be coincided with the loss of N2 without formation of distinct metalꢀcarbenoid species. The
detailed mechanism of the diazo coupling remains unclear at this stage. Finally, protonation of D produces the desired
alkylated product with the active Rh(III) catalyst.
CONCLUSION:
In summary, we have developed a simple, efficient Rh(III) catalysed direct C6 selective CꢀH alkylation of 2ꢀpyridones
with αꢀdiazo compounds at mild conditions. The reaction proceeded with excellent regioselectivity and functional
group tolerance. The environmentally benign only byproduct is N2. The protocol enables the alkylation of the other
biologically relevant heterocycles too. Furthermore, the footprint of the directing group can smoothly be removed
after operation. Current efforts are directed to the total syntheses of natural products having these important
heterocyclic scaffolds using the developed method.
EXPERIMENTAL SECTION:
General procedure for synthesis of substituted 1-(2-Pyridyl)-2-pyiridones.19 Substituted 2ꢀhydroxypyridine (1
mmol), copper(I) iodide (10 mol%), and potassium carbonate(1 mmol) were taken in DMSO (2 mL) and 2ꢀ
bromopyridine (2 mmol) was added to the resulting mixture. The mixture was stirred at 150 °C for 12 h under
nitrogen atmosphere. The resulting mixture was allowed to cool to room temperature and then quenched with water.
Extraction with ethyl acetate, concentrated under reduced pressure, and silica gel column purification with hexane/
ethyl acetate afforded 2Hꢀ[1,2'ꢀBipyridin]ꢀ2ꢀone in 50ꢀ90% yield.
General procedure for synthesis of diazo malonates.20 Malonate (1 mmol) was dissolved in dry THF (10 mL) and
Cs2CO3 (1 mmol) followed by tosylazide (1 mmol) was added to it drop wise at room temperature. The reaction was
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 18
1
2
3
4
5
allowed to stir for overnight at the same temperature. After completion of the reaction, solvent was evaporated under
vaccum. Then diazo malonates were purified by silica gel column chromatography using hexane/ethyl acetate.
6
7
8
9
General procedure for Rhodium (III) catalysed C-6 selective alkylation of 2-pyridones with diazo malonates.1ꢀ
(2ꢀPyridyl)ꢀ2ꢀpyiridones (0.1 mmol) was dissolved in a 10 mL screw cap vial with 1 mL of dry 1,2 DCE . Then
[(Cp*RhCl2)2] (1 mol %), AgSbF6 (4 mol%),, dialkyl 2ꢀdiazomalonate (0.12 mmol) were added to the reaction
mixture at room temperature. Then the reaction mixture was allowed to warm up to 40 °Cꢀ100 °C and stirred for 6ꢀ24
h. After the completion of the reaction, reaction mixture was directly loaded to the column and purified with hexane/
ethyl acetate mixture.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Rhodium (III) catalysed C-6 selective alkylation of 2-pyridones with 5-diazo-2,2-dimethyl-1,3-dioxane-4,6-
dione. Substituted 1ꢀ(2ꢀPyridyl)ꢀ2ꢀpyiridones (0.1 mmol) was dissolved in a 10 mL screw cap vial with 1 mL of dry
alcohol. Then [(Cp*RhCl2)2] (2 mol%), AgSbF6 (8 mol%), and 5ꢀdiazoꢀ2,2ꢀdimethylꢀ1,3ꢀdioxaneꢀ4,6ꢀdione (0.12
mmol) were added to the reaction mixture at room temperature. Then the reaction mixture was allowed to warm up to
100 °C and stirred for 12 h. After the completion of the reaction product was purified by flash chromatography with
hexane/ ethyl acetate mixture.
Procedure for the synthesis of compound 8: Removal of directing group:15 Dimethyl 2ꢀ(2ꢀoxoꢀ2Hꢀ[1,2'ꢀ
bipyridin]ꢀ6ꢀyl) malonate (3d) (120.8 mg, 0.4 mmol) was dissolved in 5 mL CH3CN in a 25 mL round bottom flask,
filled with nitrogen. It was cooled to 0°C. Then MeOTf (66 µL, 0.6 mmol) was added to it. The reaction mixture was
allowed to warm to room temperature and stirred for 20 hr. Volatile materials were evaporated off in vacuum. It was
dissolved in 5 mL methanol and cooled to 0 °C. Then NaBH4 (60.5 mg, 1.6 mmol) was added and the flask was filled
with nitrogen again. The reaction mixture was allowed to warm to room temperature and stirred for 6 h. The reaction
mixture was quenched with water and extracted with ethyl acetate. Organic layer was dried over sodium sulphate,
concentrated in vaccuo. The product was purified by flash chromatography using NHꢀbind silica using ethyl
acetae/hexane mixture as solvent. Purification afforded methyl 2ꢀ(6ꢀOxoꢀ1,6ꢀdihydropyridinꢀ2ꢀyl)acetate (8) in 46%
yield.
Synthesis of dimethyl 2-(6-oxo-1-(pyridin-2-yl)piperidin-2-yl)malonate by hydrogenation:14 Dimethyl 2ꢀ(2ꢀoxoꢀ
2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)malonate(3d) (30.2 mg, 0.1 mmol) was taken in methanol in a 25 mL round bottom flask
charged with a magnetic stir bar, filled with nitrogen. Then palladium on carbon was added (10 mol%) to it. The
round bottom flask was evacuated and filled with H2 gas and allowed to stir for 45 minutes. The reaction mixture was
filtered through celite pad and washed with 10 mL ethyl acetate. Whole organic solution was concentrated under
vaccuo. The desired product was purified by flash column chromatography using ethyl acetae/hexane mixture as
solvent. Purification afforded 2ꢀ(6ꢀOxoꢀ1ꢀ(pyridinꢀ2ꢀyl)piperidinꢀ2ꢀyl)malonate (7) in 79% yield.
8
ACS Paragon Plus Environment

Page 9 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Synthesis of rhodacycle complex (10):17 1ꢀ(2ꢀPyridyl)ꢀ2ꢀpyiridone (1d) (34.4 mg, 0.2 mmol), [(Cp*RhCl2)2] (30.9
mg, 0.05 mmol, 0.25 equiv.) and NaOAc (65.6 mg, 0.8 mmol, 4 equiv.) were taken in a screw cap vial, then 2 mL 1,2ꢀ
DCE was added to it. The reaction mixture was allowed to stir at 40 °C for 24 h. The mixture was filtered through a
celite pad, solvent was evaporated under reduced pressure. The solid residue was washed with dry diethyl ether (2
mL) for 5 times. Then dried under vacuum to give a brickꢀred solid complex (10) (40 %). The rhodium complex was
characterised through analytical data.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Catalytic Alkylation using Rhodacycle complex (10): 1ꢀ(2ꢀPyridyl)ꢀ2ꢀpyiridone(1d) (17.2 mg, 0.1 mmol), dimethyl
2ꢀdiazo malonate (2a) (19 mg, 0.12 mmol), complex 10 (2mol %), AgSbF6 (8 mol %) and 1 mL 1,2ꢀDCE were added
to a 10 mL screw cap vial and the reaction was allowed to stir at 40 °C for 12 h. After the completion of the reaction
product was isolated through column chromatography using ethyl acetae/hexane mixture as solvent in 94% yield.
Stoichiometric alkylation with dimethyl 2-azo malonates: To a 10 mL screw cap vial 8.88 mg of intermediate
complex 10 (0.02 mmol), 6.9 mg of AgSbF6 (0.02 mmol) was added and then it was dissolved in 0.5 mL of 1,2ꢀDCE
under atmospheric condition. Then 5 mg of dimethyl 2ꢀazo malonate (0.024 mmol) was added to the reaction mixture.
The mixture was allowed to stir at 40 °C for 30 minutes. The crude mixture was quenched 5N HCl (aq.) followed by
aq. NaHCO3. Organic layer was separated and dried over anhydrous Na2SO4. Solvent was removed under reduced
pressure and product (3d) was separated by flash chromatography using ethyl acetae/hexane mixture as solvent in
86% yield.
Competition experiments for C-H metalation vs metal carbene formation:11c 2m´ is well known as a precursor of
cyclopropane (9) in presence of catalytic Rh2(OAc)4. But when 1ꢀ(2ꢀPyridyl)ꢀ2ꢀpyiridone (1d) was employed under
the standard condition with 2m, 3n formed exclusively in 94% yield. It proves that CꢀH metallation step is much
faster than metal carbene formation in the catalytic cycle.
Dimethyl 2ꢀ(2ꢀoxoꢀ2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)malonate (3d). Yellow oil, 27.8 mg (92%); 1H NMR (400 MHz, CDCl3) δ
8.58 (d, J = 4.7 Hz, 1H), 7.85 (t, J = 7.7, 1H), 7.37 (m, 3H), 6.61 (d, J = 9.3 Hz, 1H), 6.30 (d, J = 7.0 Hz, 1H), 4.31 (s,
1H), 3.67 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 166.2, 163.1, 150.7, 149.9, 140, 139.8, 138.7, 124.7, 124.5, 121.4,
~
107.2, 55.0, 53.3. FTꢀIR: ν
= 3054, 2957, 2927, 2854, 1766, 1734, 1678, 1605, 1545, 1469, 1437, 1396, 1297, 1248,
1205 cmꢀ1; HRMS: calculated for [M+H]+ C15H15N2O5: 303.0981 found: 303.1007.
1
Diethyl 2ꢀ(2ꢀoxoꢀ2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)malonate (3e). Yellow oil, 29.4 mg (89%); H NMR (600 MHz, CDCl3) δ
8.59 (m, 1H), 7.84 (td, J = 7.8, 2.0 Hz, 1H), 7.41 – 7.35 (m, 2H), 7.33 (dt, J = 7.8, 1.2 Hz, 1H), 6.61 (dd, J = 9.4, 1.2
Hz, 1H), 6.31 (dd, J = 7.1, 1.2 Hz, 1H), 4.28 (s, 1H), 4.12 (q, J = 7.2 Hz, 4H), 1.17 (t, J = 7.2 Hz, 6H); 13C NMR (150
MHz, CDCl3) δ 165.7, 163.2, 150.7, 149.9, 140.3, 139.8, 138.6, 124.8, 124.4, 121.2, 107.2, 62.5, 55.3, 13.9; FTꢀIR:
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 18
1
2
3
4
5
~
= 3059, 2984, 2927, 2738, 1674, 1602, 1548, 1468, 1435, 1395, 1369, 1308, 1243, 1209 cmꢀ1; HRMS: calculated
ν
for [M+H]+ C17H19N2O5: 331.1294 found 331.1334.
6
7
8
9
Dibenzyl 2ꢀ(2ꢀoxoꢀ2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)malonate (3f). Yellow oil, 40.0 mg (88%); 1H NMR (600 MHz, CDCl3) δ
8.47 (dd, J = 4.9, 1.9 Hz, 1H), 7.70 (td, J = 7.7, 1.9 Hz, 1H), 7.42 – 7.21 (m, 13H), 6.66 (dd, J = 9.3, 1.2 Hz, 1H), 6.26
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(dd, J = 7.1, 1.2 Hz, 1H), 5.20 – 5.08 (m, 4H), 4.44 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 165.5, 163.1, 150.6, 149.8,
~
139.9, 139.7, 138.6, 134.6, 128.7, 128.6, 128.6, 124.7, 124.3, 121.4, 107.4, 68.1, 55.3; FTꢀIR: ν
= 3063, 3035, 2959,
1738, 1674, 1588, 1498, 1466, 1456, 1434, 1396, 1377, 1304, 1237, 1271, 1211 cmꢀ1; HRMS: calculated for
[M+H]+C27H23N2O5: 455.1607 found 455.1615.
Diꢀtbutyl 2ꢀ(2ꢀoxoꢀ2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)malonate (3g). Pale yellow oil, 34.0 mg, (88%); 1H NMR (600 MHz,
CDCl3) δ 8.65 (dd, J = 4.9, 1.9 Hz, 1H), 7.88 (td, J = 7.8, 1.9 Hz, 1H), 7.50 – 7.32 (m, 3H), 6.64 (dd, J = 9.3, 1.1 Hz,
1H), 6.37 (dd, J = 7.1, 1.1 Hz, 1H), 4.14 (s, 1H), 1.42 (s, 18H); 13C NMR (150 MHz, CDCl3) δ 165.1, 163.4, 151.1,
~
149.9, 141.3, 139.9, 138.6, 125, 124.3, 121, 106.8, 83.2, 57.4, 27.8; FTꢀIR: ν
= 2980, 1731, 1675, 1602, 1548, 1467,
1435, 1395, 1370, 1313, 1250 cmꢀ1; HRMS: calculated for [M+H]+ C21H27N2O5: 387.1920 found 387.1918.
1
2,2,2ꢀTrifluoroethyl 2ꢀ(2ꢀoxoꢀ2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)acetate (3h). Pale brown solid, 25.8 mg (83%); H NMR (600
MHz, CDCl3) δ 8.61 (ddd, J = 4.8, 1.9, 0.9 Hz, 1H), 7.87 (td, J = 7.7, 1.9 Hz, 1H), 7.46 – 7.33 (m, 3H), 6.64 (dd, J =
9.4, 1.3 Hz, 1H), 6.22 (dd, J = 6.8, 1.2 Hz, 1H), 4.31 (q, J = 8.4Hz, 2H), 3.51 (s, 2H); 13C NMR (150 MHz, CDCl3) δ
167.3, 163.5, 151.1, 149.8, 140.3, 140.0, 138.6, 124.8, 124.4, 122.6 (q, J = 278 Hz), 121.3, 108.8, 61.0 (q, J = 37.1
~
Hz) , 38.8; 19F NMR (376 MHz, CDCl3) δ ꢀ73.6; FTꢀIR: = 1758, 1670, 1596, 1421, 1269 cmꢀ1; HRMS: calculated
ν
for [M+H]+C14H12F3N2O3: 313.0800 found 313.0793.
Ethyl 3ꢀhydroxyꢀ2ꢀ(2ꢀoxoꢀ2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)butꢀ2ꢀenoate (3i). White solid, 27.0 mg (90%); 1H NMR (600
MHz, CDCl3) δ 12.70 (s, 1H), 8.51 (dd, J = 5.1, 1.9 Hz, 1H), 7.75 (td, J = 7.7, 1.9 Hz, 1H), 7.39 (dd, J = 9.3, 6.7 Hz,
1H), 7.28 (m, 1H), 7.23 (d, J = 7.9 Hz, 1H), 6.64 (dd, J = 9.3, 1.2 Hz, 1H), 6.13 (dd, J = 6.7, 1.2 Hz, 1H), 4.09 (q, J =
7.2 Hz, 2H), 2.00 (s, 3H), 1.22 (t, J = 7.2Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 177.9 , 170.6, 163.8, 152.1, 149.6,
~
142.6, 140.0, 137.9, 123.9, 123.2, 121.1, 109.8, 99.1, 61.1, 20.6, 14.3; FTꢀIR: ν
= 2984, 1667, 1644, 1595, 1548,
1467, 1434, 1382, 1337, 1277, 1234 cmꢀ1; HRMS: calculated for [M+H]+ C16H17N2O4: 301.1188 found 301.1171.
(E)ꢀEthyl 3ꢀhydroxyꢀ2ꢀ(2ꢀoxoꢀ2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)ꢀ3ꢀphenylacrylate compound and Ethyl 3ꢀoxoꢀ2ꢀ(2ꢀoxoꢀ2Hꢀ
1
[1,2'ꢀbipyridin]ꢀ6ꢀyl)ꢀ3ꢀphenylpropanoate (1.37:1) (3j). Yellow solid, 35.1 mg (97%); H NMR (600 MHz, CDCl3) δ
13.37 (s, 1H), 8.65 (dd, J = 4.9, 1.7 Hz, 1H), 8.46 (dd, J = 4.9, 1.7 Hz, 1H), 7.95 – 7.80 (m, 2H), 7.77 – 7.65 (m, 3H),
7.59 – 7.53 (m, 1H), 7.44 (t, J = 7.8 Hz, 2H), 7.40 – 7.34 (m, 3H), 7.33 – 7.28 (m, 3H), 7.26 – 7.22 (m, 2H), 7.05 (s,
1H), 6.61 (ddd, J = 10.5, 9.2, 1.2 Hz, 2H), 6.19 – 6.06 (m, 1H), 6.06 – 5.93 (m, 1H), 5.31 (s, 1H), 4.19 (m, 1H), 4.10
10
ACS Paragon Plus Environment

Page 11 of 18
The Journal of Organic Chemistry
1
2
3
(m, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 191.2, 173.2, 173.1, 171.4,
4
5
166.6, 163.8, 151.8, 151.1, 150.1, 149.0, 139.9, 139.8, 137.1, 134.2, 130.9, 129, 128.9, 128.0, 124.8, 124.5, 123.6,
6
7
~
121.3, 120.7, 111.5, 108.2, 99.2, 98.9, 62.3, 61.5, 57.7, 14.2, 14.0; FTꢀIR: ν
= 3056, 2928, 2854, 1743, 1665, 1613,
8
9
1595, 1584, 1545, 1492, 1468, 1446, 1434, 1408, 1372, 1316, 1291, 1273, 1228 cmꢀ1; HRMS: calculated for
[M+H]+C21H19N2O4: 363.1345 found 363.1340.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 3ꢀmorpholinoꢀ3ꢀoxoꢀ2ꢀ(6ꢀoxoꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ1,6ꢀdihydropyridinꢀ2ꢀyl)propanoate (3k).Pale yellow solid,
32.8 mg (92%); 1H NMR (600 MHz, CDCl3) δ 8.64 (ddd, J = 4.9, 2, 0.9 Hz, 1H), 7.89 (td, J = 7.7, 2.0 Hz, 1H), 7.48 –
7.39 (m, 2H), 7.34 – 7.28 (m, 1H), 6.67 (dd, J = 9.4, 1.2 Hz, 1H), 6.27 (dd, J = 7.0, 1.2 Hz, 1H), 4.60 (s, 1H), 3.70 (m,
2H), 3.67 – 3.57 (m, 5H), 3.54 – 3.44 (m, 2H), 3.42 – 3.28 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 166.9, 164.4,
~
163.3, 151.1, 150.1, 140.4, 139.9, 139, 125, 124.8, 121.8, 107.1, 66.6, 66.3, 53.7, 53.2, 46.7, 42.8; FTꢀIR: ν
= 3040,
2946.5, 2858.8, 1742.9, 1651.9, 1598, 1547, 1436, 1253 cmꢀ1; HRMS: calculated for [M+H]+C18H20N3O5: 358.1403
found 358.1407.
1
Ethyl 2ꢀ(2ꢀoxoꢀ2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)ꢀ2ꢀ(phenylsulfonyl)acetate (3l). White solid, 35.1 mg (88%); H NMR (600
MHz, CDCl3) δ 8.57 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.67 (tt, J= 7.4, 1.3 Hz, 1H), 7.59
(dd, J = 8.3, 1.3 Hz, 2H), 7.53 – 7.46 (m, 2H), 7.43 – 7.37 (m, 2H), 7.15 (dt, J = 8, 1.1 Hz, 1H), 6.90 (dd, J = 7.1, 0.9
Hz, 1H), 6.67 (dd, J = 9.3, 1.1 Hz, 1H), 4.74 (s, 1H), 4.16 (qd, J = 7.1, 2.6 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 162.9, 162.4, 150.4, 149.9, 139.2, 138.6, 137.0, 134.9, 134.7, 129.6, 129.2, 125.5, 124.5, 123.1,
~
= 2985, 1745, 1674, 1600, 1543, 1466, 1448, 1435, 1395, 1368, 1312, 1237 cmꢀ1;
110.4, 69.7, 63.4, 13.9; FTꢀIR: ν
HRMS: calculated for [M+H]+C20H18N2O5S: 399.1014 found 399.0997.
1
Ethylꢀ2ꢀ(dimethoxyphosphoryl)ꢀ2ꢀ(2ꢀoxoꢀ2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)acetate (3m). Brown oil, 25.2 mg (69%); H NMR
(600 MHz,CDCl3) δ8.64 (dd, J = 4.8, 2.0 Hz, 1H), 7.89 (td, J = 7.7, 2.0 Hz, 1H), 7.42 (dt, J = 7.4, 5.6 Hz, 2H), 7.36
(d, J = 8.0 Hz, 1H), 6.86 (dd, J = 7.4, 2.8 Hz, 1H), 6.62 (d, J = 9.4 Hz, 1H), 4.23 – 4.08 (m, 2H), 3.84 (d, J = 25.9 Hz,
1H), 3.74 (s, 3H), 3.72 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H).13C NMR (150 MHz, CDCl3); 13C NMR (150 MHz, CDCl3) δ
165.1 (d, J = 4.3 Hz), 163.5, 151.1, 150.1, 139.8 (d, J = 3.1 Hz), 138.8, 138.2 (d, J = 3.9 Hz), 124.8, 124.6, 121.3,
108.8 (d, J = 6.1 Hz), 62.8, 54.3 (d, J = 6.8 Hz), 54.1 (d, J = 6.8 Hz), 47.8 (d, J = 137.1 Hz), 14.0; 31P NMR (162
~
ν
MHz, CDCl3) δ 20.1; FTꢀIR:
= 3058, 2959, 2854, 1737, 1671, 1596, 1544, 1467, 1435, 1394, 1367, 1302, 1241,
1210 cmꢀ1; HRMS: calculated for [M+H]+C16H20N2O6P: 367.1059 found 367.1048.
(E)ꢀEthyl 3ꢀhydroxyꢀ2ꢀ(6ꢀoxoꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ1,6ꢀdihydropyridinꢀ2ꢀyl)heptaꢀ2,6ꢀdienoate (3n). Pale yellow oil, 31.9
mg (94%); 1H NMR (600 MHz, CDCl3) δ 12.83 (s, 1H), 8.51 (m, 1H), 7.75 (td, J = 7.7, 1.9 Hz, 1H), 7.40 (dd, J = 9.4,
6.8 Hz, 1H), 7.29 (ddd, J = 7.7, 4.8, 1.1 Hz, 1H), 7.23 (dt, J = 7.9, 1.1 Hz, 1H), 6.66 (dd, J = 9.4, 1.2 Hz, 1H), 6.12
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 18
1
2
3
(dd, J = 6.8, 1.2 Hz, 1H), 5.77 (m, 1H), 5.11 – 4.92 (m, 2H), 4.11 (qd, J = 7.2, 1.8 Hz, 2H), 2.50 – 2.23 (m, 4H), 1.23
4
5
(t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 170.9, 163.9, 152.1, 150, 149.5, 142.3, 139.9, 137.8, 137, 124,
6
7
~
123.3, 121.2, 115.8, 110.1, 98.9, 61.2, 33.3, 29.9, 14.3; FTꢀIR: ν
= 2986, 2366, 1665, 1411, 1377, 1343, 1269, 1234
8
9
cmꢀ1; HRMS: calculated for [M+H]+C19H21N2O4: 341.1501 found 341.1498.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Ethyl 2ꢀ(2ꢀoxoꢀ2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)acetate (5a). Pale yellow oil, 16.0 mg (62%); H NMR (600 MHz, CDCl3) δ
8.73 – 8.53 (m, 1H), 7.86 (td, J = 7.7, 2.0 Hz, 1H), 7.44 – 7.31 (m, 3H), 6.62 (d, J = 9.4 Hz, 1H), 6.20 (d, J = 6.7 Hz,
1H), 3.97 (q, J = 7.1 Hz, 2H), 3.41 (s, 2H), 1.12 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz,CDCl3) δ 168.6, 163.6,
~
ν
151.4, 149.8, 141.8, 140.1, 138.4, 125, 124.3, 120.7, 108.4, 61.5, 39.6, 14.1; FTꢀIR:
= 3058, 2983, 1734, 1669,
1596, 1549, 1467, 1435, 1396, 1369, 1333, 1297, 1276, 1248 cmꢀ1; HRMS: calculated for [M+H]+C14H15N2O3:
259.1082 found 259.1075.
Ethyl 2ꢀ(4ꢀmethylꢀ2ꢀoxoꢀ2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)acetate (5b). Yellow oil, 20.9 mg (77%); 1H NMR (600
MHz,CDCl3) δ 8.68 – 8.53 (m, 1H), 7.84 (td, J = 7.7, 2.0 Hz, 1H), 7.37 (dd, J = 7.7, 3.3 Hz, 2H), 6.42 (s, 1H), 6.05 (s,
1H), 3.95 (q, J = 7.2 Hz, 2H), 3.38 (s, 2H), 2.21 (s, 3H), 1.11 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz,CDCl3) δ 168.8,
~
163.6, 151.8, 151.3, 149.7, 140.4, 138.3, 125.1, 124.1, 118.8, 111.3, 61.5, 39.5, 21.6, 14.1; FTꢀIR: ν
= 2983, 1735,
1670, 1549, 1467, 1436, 1361, 1329, 1246, 1219 cmꢀ1; HRMS: calculated for [M+H]+C15H17N2O3: 273.1239 found
273.1241.
1
Ethyl 2ꢀ(3ꢀ(benzyloxy)ꢀ2ꢀoxoꢀ2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)acetate (5c). Yellow oil, 29.8 mg (82%); H NMR (600 MHz,
CDCl3) δ 8.68 – 8.55 (m, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.45 – 7.28 (m, 7H), 6.70 (d, J = 7.7 Hz, 1H), 6.05 (d, J = 7.7
Hz, 1H), 5.15 (s, 2H), 3.94 (q, J = 7.2 Hz, 2H), 3.35 (s, 2H), 1.10 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
169.2, 159.3, 151.3, 149.7, 148.4, 138.3, 136.4, 132.9, 128.7, 128.1, 127.4, 125.1, 124.2, 116.5, 107.2, 71, 61.4, 39.1,
~
= 2927, 1735, 1664, 1611, 1467, 1436, 1284, 1220 cmꢀ1; HRMS: calculated for [M+H]+C21H21N2O4:
14.1; FTꢀIR: ν
365.1501 found 365.1497.
tꢀButyl 2ꢀ(2ꢀoxoꢀ2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)acetate (5d). Yellow oil, 22.3 mg (78%); 1H NMR (600 MHz, CDCl3) δ 8.71
– 8.59 (m, 1H), 7.88(dt, J = 7.5, 4.5 Hz, 1H), 7.40 (m, 3H), 6.62 (d, J = 9.4 Hz, 1H), 6.20 (d, J = 6.9 Hz, 1H), 3.35 (s,
2H), 1.32 (s, 9H); 13C NMR (150 MHz,CDCl3) δ 167.9, 163.7, 151.5, 149.8, 142.2, 140.1, 138.5, 125.1, 124.2, 120.5,
~
108.3, 82.0, 40.6, 28.0; FTꢀIR: ν
= 2979, 2931, 1734, 1671, 1598, 1550, 1467, 1435, 1395, 1369, 1334, 1275, 1252,
1208 cmꢀ1; HRMS: calculated for [M+H]+: C16H19N2O3: 287.1395 found 287.1399.
Dimethyl 2ꢀ(4ꢀmethylꢀ2ꢀoxoꢀ2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)malonate (6e). Yellow oil, 28.7 mg (91%); 1H NMR (600 MHz,
CDCl3) δ 8.69 – 8.52 (m, 1H), 7.84 (td, J = 7.7, 1.9 Hz, 1H), 7.45 – 7.29 (m, 2H), 6.44 (s, 1H), 6.16 (s, 1H), 4.32 (s,
1H), 3.68 (s, 6H), 2.21 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 166.3, 163.2, 151.7, 150.7, 149.8, 138.7, 138.6, 124.9,
12
ACS Paragon Plus Environment

Page 13 of 18
The Journal of Organic Chemistry
1
2
3
4
5
~
124.4, 119.5, 110, 54.8, 53.3, 21.7; FTꢀIR: ν
= 2955, 1741, 1674, 1608, 1587, 1547, 1436, 1384, 1357, 1311, 1244,
1201 cmꢀ1; HRMS: calculated for [M+H]+C16H17N2O5: 317.1137 found 317.1137.
6
7
8
9
Dimethyl 2ꢀ(3ꢀmethylꢀ2ꢀoxoꢀ2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)malonate (6f). Pale yellow solid, 27.5 mg (87%); 1H NMR (600
MHz, CDCl3) δ 8.59 (dd, J = 5.0, 1.9 Hz, 1H), 7.86 (td, J = 7.9, 1.9 Hz, 1H), 7.45 – 7.29 (m, 2H), 7.30 – 7.18 (m, 1H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6.25 (d, J = 7.1 Hz, 1H), 4.31 (s, 1H), 3.68 (s, 6H), 2.13 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 165.7, 163.2, 150.7,
~
149.9, 140.3, 139.8, 138.6, 124.8, 124.4, 121.2, 107.2, 62.5, 55.3, 13.9; FTꢀIR: ν
= 2955, 1741, 1664, 1612, 1563,
1467, 1435, 1312, 1263, 1220 cmꢀ1; HRMS: calculated for [M+H]+C16H17N2O5: 317.1137 found 317.1147.
1
Dimethyl 2ꢀ(3ꢀ(benzyloxy)ꢀ2ꢀoxoꢀ2Hꢀ[1,2’ꢀbipyridin]ꢀ6ꢀyl) malonate (6g). Yellow solid, 37.9 mg (93%); H NMR
(600 MHz, CDCl3) δ 8.59 (dd, J = 5.0, 2.5 Hz, 1H), 7.86 (m, 1H), 7.43 – 7.31 (m, 6H), 7.31 – 7.25 (m, 1H), 6.71 (dd,
J = 7.8, 2.5 Hz, 1H), 6.21 (dd, J = 7.8, 2.5 Hz, 1H), 5.12 (s, 2H), 4.28 (s, 1H), 3.67 (s, 6H); 13C NMR (150
MHz,CDCl3) δ 166.6, 158.8, 150.7, 149.8, 148.9, 138.6, 136.1, 131.0, 128.7, 128.0, 127.3, 124.9, 124.5, 115.3, 106.4,
~
= 3643, 1955, 1739, 1669, 1616, 1590, 1571, 1467, 1435, 1291, 1364, 1227 cmꢀ1; HRMS:
70.9, 54.5, 53.3; FTꢀIR: ν
calculated for [M+H]+C22H21N2O6: 409.1399 found 409.1388.
1
Dimethyl 2ꢀ(2ꢀoxoꢀ3ꢀ(trifluoromethyl)ꢀ2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)malonate (6h). Pale yellow solid, 30.0 mg (81%); H
NMR (600 MHz, CDCl3) δ 8.63 (ddd, J = 4.9, 1.9, 0.8 Hz, 1H), 7.91 (td, J = 7.6, 1.9 Hz, 1H), 7.82 (d, J = 7.6 Hz,
1H), 7.46 – 7.40 (m, 2H), 6.45 (d, J = 7.6 Hz, 1H), 4.38 (s, 1H), 3.73 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 165.7,
159.0, 150.2, 149.8, 144.6 , 139.2 (q, J = 4.5 Hz), 138.9, 125.0, 124.8, 122.4 (q, J = 271 Hz), 121.2 (q, J = 31.3 Hz),
~
105.6, 55.3, 53.7; 19F NMR (376 MHz, CDCl3) δ ꢀ66.14; FTꢀIR: = 2959, 2853, 1758, 1690, 1566, 1437, 1321, 1249
ν
cmꢀ1; HRMS: calculated for [M+H]+ C16H14F3N2O5: 371.0855 found 371.0842.
1
Dimethyl 2ꢀ(5ꢀchloroꢀ2ꢀoxoꢀ2Hꢀ[1,2'ꢀbipyridin]ꢀ6ꢀyl)malonate (6i). Pale Yellow oil, 29.6 mg (88%); H NMR (600
MHz, CDCl3) δ 8.68 – 8.53 (m, 1H), 7.90 (td, J = 7.8, 1.9 Hz, 1H), 7.42 (m,3H), 6.65 (d, J = 9.9 Hz, 1H), 4.32 (s,
1H), 3.75 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 164.9, 161.8, 151.0, 150.2, 142.3, 139.0, 137.6, 124.9, 124.5, 122.5,
~
115.5, 54.6, 53.5; FTꢀIR: ν
= 3058, 2959, 2854, 1737, 1671, 1596, 1545, 1467, 1435, 1394, 1367, 1302, 1241, 1210
cmꢀ1; HRMS: calculated for [M+H]+ C15H1435ClN2O5: 337.0591 found 337.0584.
1
Dimethyl 2ꢀ(1ꢀoxoꢀ2ꢀ(pyridinꢀ2ꢀyl)ꢀ1,2ꢀdihydroisoquinolinꢀ3ꢀyl)malonate (6j). Pale yellow solid, 26.1 mg (74%); H
NMR (600 MHz, CDCl3) δ 8.72 – 8.55 (m, 1H), 8.46 – 8.32 (m, 1H), 7.89 (td, J = 7.7, 1.9 Hz, 1H), 7.69 (ddd, J = 8.3,
7.3, 1.4 Hz, 1H), 7.63 – 7.47 (m, 2H), 7.47 – 7.34 (m, 2H), 6.67 (s, 1H), 4.45 (s, 1H), 3.73 (s, 6H); 13C NMR (150
MHz, CDCl3) δ 166.8, 163.2, 151.3, 149.9, 138.5, 136.3, 133.7, 133.2, 128.2, 127.7, 126.7, 125.8, 125.4, 124.2,
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 18
1
2
3
4
5
~
= 2956, 1752, 1667, 1630, 1588, 1566, 1484, 1469, 1433, 1398, 1302.6, 1240 cmꢀ1;
ν
107.9, 55.1, 53.4; FTꢀIR:
HRMS: calculated for [M+H]+ C19H17N2O5: 353.1137 found 353.1130.
6
7
1
Dimethyl 2ꢀ(4ꢀoxoꢀ3ꢀ(pyridinꢀ2ꢀyl)ꢀ3,4ꢀdihydroquinazolinꢀ2ꢀyl)malonate (6k). White solid, 27.5 mg (78%); H NMR
8
9
(600 MHz, CDCl3) δ 8.64 (dd, J = 5.0, 2.0 Hz, 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.91 (td, J = 8.0 Hz, 2.0 Hz, 1H), 7.77
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(m, 2H), 7.52 (m, 1H), 7.48 – 7.39 (m, 2H), 4.78 (s, 1H), 3.74 (s, 6H); 13C NMR (150 MHz,CDCl3) δ 165.6, 161.9,
~
150.1, 149.7, 148.1, 146.9, 138.7, 134.9, 128.3, 127.9, 127.1, 124.9, 124.8, 121.4, 58.8, 53.4; FTꢀIR: ν
= 3069, 3010,
2957, 1759, 1740, 1697, 1637, 1610, 1589, 1567, 1508, 1474, 1466, 1433, 1354, 1322, 1305, 1292, 1235, 1202 cmꢀ1;
HRMS: calculated for [M+H]+ C18H16N3O5: 354.1090 found 354.1100.
Dimethyl 2ꢀ(4ꢀoxoꢀ4Hꢀ[1,2'ꢀbipyridin]ꢀ2ꢀyl)malonate (6l). Yellow oil, 16.0 mg (53%); 1H NMR (600 MHz, CDCl3) δ
8.53 (dd, J = 4.9, 2.0 Hz, 1H), 7.96 (td, J = 7.7, 1.9 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.45 (dd, J = 7.7, 4.9 Hz, 1H),
7.36 (d, J = 7.9 Hz, 1H), 6.50 (s, 1H), 6.44 (dd, J = 7.7, 2.6 Hz, 1H), 4.62 (s, 1H), 3.73 (s, 6H); 13C NMR (150 MHz,
~
ν
CDCl3) δ 179.3, 166.1, 153.3, 149.4, 142.5, 140.9, 140.1, 124.6, 120.6, 120.5, 118.1, 55.2, 54.5; FTꢀIR:
1636, 1438, 1280 cmꢀ1; HRMS: calculated for [M+H]+ C15H15N2O5: 303.0981 found 303.0981.
=1752,
1
Dimethyl 2ꢀ(4ꢀoxoꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ1,4ꢀdihydroquinolinꢀ2ꢀyl)malonate (6m). Yellow oil, 28.8 mg (82%); H NMR
(600 MHz, CDCl3) δ 8.82 – 8.75 (m, 1H), 8.44 (d, J = 8.1 Hz, 1H), 8.03 (t, J = 7.8 Hz, 1H), 7.59 (t, J = 6.6 Hz, 1H),
7.45 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 6.55 (d, J = 8.7 Hz, 1H), 6.50 (s, 1H), 4.32
(s, 1H), 3.73 (s, 6H); 13C NMR (150 MHz,CDCl3) δ 178.2, 165.9, 151.4, 151.3, 144.7, 142.2, 139.9, 132.5, 126.5,
~
ν
125.8, 125.6, 125.2, 124.4, 117.4, 112.1, 55.7, 53.6; FTꢀIR:
= 3050, 2960, 2853, 1758, 1742, 1627, 1604, 1487,
1464, 1427, 1316, 1299, 1221 cmꢀ1; HRMS: calculated for [M+H]+ C19H17N2O5: 353.1137 found 353.1143.
1
Dimethyl 2ꢀ(6ꢀoxoꢀ1ꢀ(pyridinꢀ2ꢀyl)piperidinꢀ2ꢀyl)malonate (7). Colourless oil, 24.1 mg (79%); H NMR (600 MHz,
CDCl3) δ 8.48 – 8.43 (m, 1H), 7.68 (td, J = 7.8, 1.9 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.12 (m, 1H), 5.39 (q, J = 6.3
Hz, 1H), 3.68 (s, 3H), 3.67 (d, J = 6.8 Hz, 1H), 3.51 (s, 3H), 2.66 – 2.52 (m, 2H), 2.19 (q, J = 6.3 Hz, 2H), 1.95 (m,
1H), 1.87 (m, 1H); 13C NMR (150 MHz,) δ 171.2, 167.7, 167.6, 153.0, 148.4, 137.1, 123.5, 121.6, 55.4, 54.0, 52.62,
~
= 2955, 1736, 1665, 1588, 1467, 1435, 1402, 1281 cmꢀ1; HRMS: calculated for
52.61, 32.7, 25.3, 18.1; FTꢀIR: ν
[M+H]+C15H19N2O5: 307.1294 found 307.1308.
Methyl 2ꢀ(6ꢀoxoꢀ1,6ꢀdihydropyridinꢀ2ꢀyl)acetate (8). Pale brown solid, 30.8 mg (46%); 1H NMR (600 MHz, CDCl3) δ
12.71 (br, 1H), 7.39 (dd, J = 9.2, 6.8 Hz, 1H), 6.48 (d, J = 9.2 Hz, 1H), 6.16 (d, J = 6.8 Hz, 1H), 3.74 (s, 3H), 3.64 (s,
~
13
ν
2H); C NMR (150 MHz, CDCl3) δ:169.2, 165.5, 141.7, 141.2, 118.8, 107.0, 52.7, 38.3; FTꢀIR:
= 3037, 2951,
14
ACS Paragon Plus Environment

Page 15 of 18
The Journal of Organic Chemistry
1
2
3
4
5
2766, 1733, 1660, 1552, 1475, 1348, 1227, 1202 cmꢀ1; HRMS: calculated for [M+H]+ C8H10NO3: 168.0660 found
168.0657.
6
7
8
9
Analytical data for the rhodacycle (10). Brick red solid, 35.6 mg (40%); 1H NMR (600 MHz, CDCl3) δ 9.38 (d, J = 9
Hz, 1H), 8.58 (d, J = 5.7, 1.9 Hz, 1H), 7.86 (t, J = 1.9 Hz, 1H), 7.26 – 7.23 (m, 1H), 7.15 (dd, J = 9, 6.8 Hz, 1H), 6.56
(dd, J = 6.8, 1.4 Hz, 1H), 6.18 (dd, J = 9.0, 1.4 Hz, 1H), 1.64 (s, 15H); 13C NMR (150 MHz, CDCl3) δ 183.9 (d, J = 37
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
~
Hz), 166.4, 158.5, 150.2, 139.8, 139.2, 122.5, 119, 115.4, 114.5, 97.7 (d, J = 6.2 Hz), 9.2; FTꢀIR: ν
= 3434, 2956,
2925, 2851, 1629, 1457, 1375 cmꢀ1; HRMS: calculated for [C20H22N2ORh]+: 409.0709 found 409.0739.
ASSOCIATED CONTENT
Supporting Information
General procedures along with results from optimization, control, and deuteration experiments. Crystallographic data
and NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: rsamanta@chem.iitkgp.ernet.in
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank for the generous financial support for this project from the Indian Institute of Technology Kharagpur
through ISIRD project grant (IIT/SRIC/CHY/QBE/2013ꢀ14/170) and the Science & Engineering Research Board
(SERB), India through Start Up Research Grant (Young Scientists) YSS/2014/000383. The authors wish to thank
CSIR, New Delhi (D.D. and A.B.) and IIT Kharagpur (U. K. and S. C.) for their research fellowships. We thank Dr. S.
K. Patra and Dr. M. C. Das, Department of Chemistry, IIT Kharagpur for helpful discussions.
REFERENCES
(1) (a) Crozet, M. D.; George, P.; Crozet, M. P.; Vanelle, P. Molecules 2005, 10, 1318. (b) Magedov, I. V.; Manpadi,
M.; Ogasawara, M. A.; Dhawan, A. S.; Rogelj, S.; Slambrouck, S. V.; Steelant, W. F. A.; Evdokimov, N. M.; Uglinskii,
P. Y.; Elias, E. M.; Knee, E. J.; Tongwa, P.; Antipin, M. Y.; Kornienko, A. J. Med. Chem. 2008, 51, 2561. (c) Heeb, S.;
Fletcher, M. P.; Chhabra, S. R.; Diggle, S. P.; Williams, P.; Camara, M. FEMS Microbiol Rev. 2011, 35, 247.
(2) Recent reviews on transition metal catalysed CꢀH functionalization: (a) CꢀH Activation: Topics in Current
Chemistry (Eds.: Yu, J. Q.; Shi, Z. J.), Springer, Heidelberg, 2010 and references cited there in. (b) Satoh,T.; Miura,
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 18
1
2
3
4
5
6
7
8
9
M. Chem. Eur. J. 2010, 16, 11212. (c) WencelꢀDelord, J.; Dröge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40,
4740; (d) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651; (e) WencelꢀDelord, J.; Glorius, F. Nat. Chem.
2013, 5, 369; (f) Zhang, X.ꢀS.; Chen, K.; Shi, Z.ꢀJ. Chem. Sci. 2014, 5, 2146; (g) Ackermann, L. Acc. Chem. Res.
2014, 47, 281; (h) Kuhl, N.; Schröder, N.; Glorius, F. Adv. Synth. Catal.2014, 356, 1443; (i) Chen, Z.; Wang, B.;
Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Org. Chem. Front. 2015, 2, 1107 and references cited there in; (j) Hu, F.; Xia, Y.;
Ma, C.; Zhang, Y.; Wang, J. Chem. Commun. 2015, 51, 7986. (k) Yadav, M. R.; Rit, R. K.; Majji, S.; Sahoo, A. K.
Asian J. Org. Chem. 2015, 4, 846.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3) (a) Nakatani, A.; Hirano, K.; Satoh, T.; Miura, M. Chem. ꢀEur. J. 2013, 19, 7691. (b) Nakatani, A.; Hirano, K.;
Satoh, T.; Miura, M. J. Org. Chem. 2014, 79, 1377. (c) Modak, A.; Rana, S.; Maiti, D. J. Org. Chem. 2015, 80, 296.
(d) Anagnostaki, E. E.; Fotiadou, A. D.; Demertzidou, V.; Zografos, A. L. Chem. Commun. 2014, 50, 6879. (e) Min,
M.; Kim, Y.; Hong, S.; Chem. Commun. 2013, 49, 196. (f) Cheng, D.; Gallagher, T. Org. Lett. 2009, 11, 2639.
(4) (a) Itahara, T.; Ouseto, F. Synthesis, 1984, 488; (b) Chen, Y.; Wang, F.; Jia, A.; Li, X. Chem. Sci. 2012, 3, 3231.
(5) (a) Nakao, Y.; Idei, H.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2009, 131, 15996. (b) Tamura, R.; Yamada,
Y.; Nakao, Y.; Hiyama, T. Angew. Chem. Int. Ed. 2012, 51, 5679.
(6) Odani, R.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem. Int. Ed. 2014, 53, 10784.
(7)Recent reviews on metal carbene insertion in CꢀH bonds: (a) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L.
Chem. Rev. 2010, 110, 704. (b) Slattery, C. N.; Ford, A.; Maguire, A. R. Tetrahedron 2010, 66, 6681. (c) Davies, H. M.
L.; Morton, D. Chem. Soc. Rev. 2011, 40, 1857.
(8) (a) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2012, 41, 560. (b) Yao, T.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem.
Int. Ed. 2012, 51, 775. (c) Liu, Z.; Wang, J. J. Org. Chem. 2013, 78, 10024. (d) Xia, Y.; Zhang, Y.; Wang, J. ACS
Catal. 2013, 3, 2586. (e) Hu, F.; Xia, Y.; Ma, C.; Zhang, Y.; Wang, J. Chem. Commun. 2015, 51, 7986. (f) Xia, Y.; Liu,
Z.; Feng, S.; Zhang, Y.; Wang, J. J. Org. Chem. 2015, 80, 223. (g) Zhao, D.; Kim, J. H.; Stegemann, L.; Strassert, C.
A.; Glorius, F. Angew. Chem. Int. Ed. 2015, 54, 4508. (h) Kim, J. H.; Gensch, T.; Zhao, D.; Stegemann, L.; Strassert,
C. A.; Glorius, F. Angew.Chem. Int.Ed. 2015, 54,10975. (i) Mishra, N. K.; Choi, M.; Jo, H.; Oh, Y.; Sharma, S.; Han,
S. H.; Jeong, T.; Han, S.; Leea, S.ꢀY.; Kim, I. S. Chem. Commun. 2015, 51, 17229.
(9) Zhao, X.; Wu, G.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, 133, 3296.
(10) Chan, W.ꢀW.; Lo, S.ꢀF.; Zhou, Z.; Yu, W.ꢀY. J. Am. Chem. Soc. 2012, 134, 13565.
(11) (a) Hyster, T. K.; Ruhl, K. E.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 5364. (b) Yu, X.; Yu, S.; Xiao, J.; Wan, B.;
Li, X. J. Org. Chem. 2013, 78, 5444. (c) Shi, Z.; Koester, D. C.; BoultadakisꢀArapinis, M.; Glorius, F. J. Am. Chem.
Soc. 2013, 135, 12204. (d) Cui, S.; Zhang, Y.; Wang, D.; Wu, Q. Chem. Sci. 2013, 4, 3912. (e) Hu, F.; Xia, Y.; Ye, F.;
Liu, Z.; Ma, C.; Zhang, Y.; Wang, J. Angew. Chem. Int. Ed. 2014, 53, 1364. (f) Jeong, J.; Patel, P.; Hwang, H.; Chang,
16
ACS Paragon Plus Environment

Page 17 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
S. Org. Lett. 2014, 16, 4598. (g) Shi, J.; Yan, Y.; Li, Q.; Xu, H. E.; Yi, W. Chem. Commun. 2014, 50, 6483. (h) Liang,
Y.; Yu, K.; Li, B.; Xu, S.; Song, H.; Wang, B. Chem. Commun. 2014, 50, 6130. (i) Zhang, Y.; Zheng, J.; Cui, S. J. Org.
Chem. 2014, 79, 6490. (j) Ai, W.; Yang, X.; Wu, Y.; Wang, X.; Li, Y.; Yang, Y.; Zhou, B. Chem.ꢀEur. J. 2014, 20,
17653. (k) Sharma, S.; Han, S. H.; Han, S.; Ji, W.; Oh, J.; Lee, S.ꢀY.; Oh, J. S.; Jung, Y. H.; Kim, I. S. Org. Lett. 2015,
17, 2852. (l) Yang, Y.; Wang, X.; Li, Y.; Zhou, B. Angew.Chem. Int.Ed. 2015, 54,15400. (m) Zhou, J.; Shi, J.; Liu, X.;
Jia, J.; Song, H.; Xu, H. E.; Yi, W. Chem. Commun. 2015, 51, 5868. (n) Yu, S.; Liu, S.; Lan, Y.; Wan, B.; Li, X. J. Am.
Chem. Soc. 2015, 137, 1623. (o) Li, X. G.; Sun, M.; Liu, K.; Jin, Q.; Liu, P. N. Chem. Commun. 2015, 51, 2380. (p)
Shi, J.; Zhou, J.; Yan, Y.; Jia, J.; Liu, X.; Song, H.; Xu, H. E.; Yi, W. Chem. Commun. 2015, 51, 668. (q) Son, J.ꢀY.;
Kim, S.; Jeon, W. H.; Lee, P. H. Org. Lett. 2015, 17, 2518.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(12) Direct functionalization of enaminone system: (a) Ge, H.; Niphakis, M. J.; Georg, G. I. J. Am. Chem. Soc. 2008,
130, 3708. (b) Kim, Y. W.; Niphakis, M. J.; Georg, G. I. J. Org. Chem. 2012, 77, 9496. (c) Bi, L.; Georg, G. I. Org.
Lett. 2011, 13, 5413. (d) Yu, Y.ꢀY.; Bi, L.; Georg. G. I. J. Org. Chem. 2013, 78, 6163. (e) Yu, Y.ꢀY.; Niphakis, M. J.;
Georg, G. I. Org. Lett. 2011, 13, 5932. (f) Kim, Y. W.; Georg. G. I. Org. Lett. 2014, 16, 1574. (g) Carrër, A.; Brion, J.ꢀ
D.; Messaoudi, S.; Alami. M. Org. Lett. 2013, 15, 5606.
(13) Recent direct quinolone functionalization: (a) Li, M.; Li, L.; Ge, H. Adv. Synth. Catal. 2010, 352, 2445. (b)
Moon, Y.; Kwon, D.; Hong, S. Angew. Chem. Int. Ed. 2012, 51, 11333. (c) Kang, D.; Hong, S. Org. Lett. 2015, 17,
1938. (d) Metal free version for C2 alkylation in chromone: Narayan, R.; Antonchick, A. P. Chem. ꢀEur. J. 2014, 20,
4568.
(14) Meissner, R. S.; Perkins, J. J.; Duong, L. T.; Hartman, G. D.; Hoffman, W. F.; Huff, J. R.; Ihle, N. C.; Leu, C.ꢀT.;
Nagy, R. M.; NaylorꢀOlsen, A.; Rodan, G. A.; Rodan, S. B.; Whitman, D. B.; Wesolowski, G. A.; Duggan, M. E.
Bioorg. Med. Chem. Lett. 2002, 12, 25.
(15) Smout, V.; Peschiulli, A.; Verbeeck, S.; Mitchell, E. A.; Herrebout, W.; Bultinck, P.; Velde, C. M. L. V.; Berthelot,
D.; Meerpoel, L.; Maes, B. U. W. J. Org. Chem. 2013, 78, 9803.
(16) Lim, Y.ꢀH.; McGee, Jr. K. F.; Sieburth, S. M. J. Org. Chem. 2002, 67, 6535.
(17) (a) Li, L.; Brennessel, W. W.; Jones, W. D. J. Am. Chem. Soc. 2008, 130, 12414. (b) Li, L.; Brennessel, W. W.;
Jones, W. D. Organometallics 2009, 28, 3492.
(18) (a) Park, S. H.; Kwak, J.; Shin, K.; Ryu, J.; Park, Y.; Chang, S. J. Am. Chem. Soc. 2014, 136, 2492. (b) Zhou, T.;
Guo, W.; Xia, Y. Chem. ꢀEur. J. 2015, 21, 9209.
(19) Sughara, M.; Ukita, T.; Chem. Pharm. Bull. 1997, 45, 719.
(20) Lee, J. C.; Yuk, J. Y. Synth. Commun. 1995, 25, 1511.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 18
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
18
ACS Paragon Plus Environment