Synthesis of quinolines via Rh(III)-catalyzed oxidative annulation of pyridines

Article abstract of DOI:10.1021/jo201266u

Selective synthesis of quinolines has been achieved via oxidative annulation of functionalized pyridines with two alkyne molecules under Rh(III)-catalyzed cascade C-H activation of pyridines using Cu(OAc)₂ as an oxidant. The selectivity of this reaction is oxidant-dependent, particularly on the anion of the oxidant.

Full text of DOI:10.1021/jo201266u

NOTE
pubs.acs.org/joc
Synthesis of Quinolines via Rh(III)-Catalyzed Oxidative Annulation
of Pyridines
Guoyong Song, Xue Gong, and Xingwei Li*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
S Supporting Information
b
ABSTRACT: Selective synthesis of quinolines has been achieved
via oxidative annulation of functionalized pyridines with two
alkyne molecules under Rh(III)-catalyzed cascade CꢀH activa-
tion of pyridines using Cu(OAc)2 as an oxidant. The selectivity
of this reaction is oxidant-dependent, particularly on the anion
of the oxidant.
uinolines represent an important class of heterocycles as
materials, natural products, and biologically active com-
pyridines. In addition, using an amide directing group, Yu has
Q
achieved Pd-catalyzed arylation of pyridines at the 3- and
4-positions.15 We now report chelation-assisted rhodium(III)-
catalyzed oxidative annulation of pyridines with alkynes for the
direct synthesis of quinolines, a process that involves 2-fold CꢀH
activation.
pounds.1 Various synthetic methods have been developed since
late 1800s.2 Traditional synthetic methods took advantage of the
condensation between amines and carbonyl compounds.2,3
Considering the accessibility of pyridines, transition-metal-
mediated synthesis of quinolines and isoquinolines via functio-
nalization of pyridines should be a desirable strategy. In this
context, Takahashi and co-workers have reported the stoichio-
metric coupling of dihalopyridines with zirconacyclopentadienes
for the synthesis of quinolines and isoquinolines.4 Satoh and
Miura recently reported synthesis of an isoquinoline starting
from a pyridylboronic ester and an alkyne.5
Rh(III)-catalyzed16 coupling between functionalized arenes
and alkynes,17,18 alkenes,18g,19,20 and imines21 via a CꢀH activa-
tion pathway has become a powerful tool for the synthesis of
isoquinolones,17a,e,18a,18e naphthalenes,5,17d,17e indoles,17b,18g inde-
nols,18b,d pyrroles,17b,18c isoquinolines,17f and pyridones.18f,h
Recently, we18e and others17e,18a have reported the oxidative
CꢀC and CꢀN coupling between benzamides and alkynes
for the synthesis of isoquinolones. This was achieved using
[RhCp*Cl2]2 as a catalyst and Cu(OAc)2 or Ag2CO3 as an
oxidant (eq 1).
Transition-metal-catalyzed direct functionalization of CꢀH
bonds has become an increasingly important tool for the con-
struction of complex organic molecules.6 Although significance
progress has been made, reported examples of direct and selec-
tive CꢀH functionalization of π-deficient heteroarenes such as
pyridines are still limited. Simple, direct, and atom-economic
access to quinolines via oxidative CꢀH functionalization of
pyridines should be of great advantage. However, CꢀH bond
activation of pyridines can be inhibited by the competitive
coordination of the pyridine nitrogen, resulting in lower catalytic
efficiency. A number of research groups have made progresses in
transition -metal-catalyzed direct functionalization of pyridine
rings.7ꢀ15 Catalytic CꢀH functionalization of unactivated pyr-
idines at the 2-position has been achieved using ruthenium,7
nickel,8 silver,9 and rhodium catalysts.10 Very recently, Ong11 and
Hiyama and Nakao12 independently reported direct 4-position
CꢀH functionalization of pyridines, which occurred via a nickel
η2-pyridine intermediate. Iridium13 and palladium14 catalysts have
also successfully enabled the direct C(3)ꢀH functionalization of
We initially chose isonicotinamide 1a as a substrate for the
coupling with diphenylacetylene using [RhCp*Cl2]2 (4 mol %)
as a catalyst and Ag2CO3 as an oxidant (CH3CN, 120 °C). As
expected, isoquinolone 4 was obtained (45% yield, entry 1,
Table 1).18e However, we felt that the pyridine ring is electro-
nically different from its carbocyclic counterpart, which might
gave rise to different reaction selectivity. Indeed, we found that
2 equiv of diphenylacetylene was oxidatively incorporated to give
Received: June 20, 2011
Published: August 05, 2011
r
2011 American Chemical Society
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NOTE
Table 1. Screening of Oxidantsa
entry
oxidant
Ag2CO3
solvent
3a (%)b
4 (%)b
1
2
3
4
5
6c
7
CH3CN
acetone
acetone
CH3CN
acetone
acetone
acetone
45
41
29
Ag2CO3
Ag2O
AgOAc
71
89
87
42
Cu(OAc)2
Cu(OAc)2
CuCO3 Cu(OH)2
14
3
a 1a (0.5 mmol), 2a (1.1 mmol), oxidant (2.2 equiv for Cu(OAc)2, AgOAc and CuCO3 Cu(OH)2 or 1.1 equiv for Ag2CO3 and Ag2O), 4.0 mol %
3
catalyst, solvent (5 mL), sealed tube under nitrogen, 120 °C, 6 h. b NMR yield using 1,3,5-trimethoxybenzene as an internal standard. c 2 mol % catalyst,
isolated yield.
a quinoline (3a) in high yield when Cu(OAc)2 was employed as
an oxidant (entry 5). This product corresponds to 2-fold CꢀH
activation of the pyridine ring at the 2-and 3-positions. Although
transition-metal-catalyzed annulation of carbocyclic arenes is
known,17d,e no analogous reaction of a pyridine ring has been
reported.5 A series of oxidants has been examined, where
significant anion effects of the oxidant were observed. Using
Ag2O and AgOAc as an oxidant, 4 (29%) and 3a (71%) were
obtained as the only product (entries 3 and 4), respectively. It is
especially noteworthy that both AgOAc and Cu(OAc)2 afforded
the same product in good yield, regardless of the cation of the
oxidant. In contrast, a mixture of 3a and 4 was obtained for
Substitutents at the 2-position of pyridine can be well toler-
ated as in the formation of quinolines 3l and 3m, which
indicates that the C(3)ꢀH activation occurred at the less
sterically hindered position. When quinoline-4-carboxamide
was subjected to the conditions, an acridine product (3n) was
obtained in good yield (73%).
Other internal alkynes are also applicable. Thus alkynes
substituted by electron-neutral, -deficient, and -rich aryl groups
coupled with 1a to afford the corresponding quinolines 3oꢀq in
high yield. The present catalytic reaction was successfully ex-
tended to heteroaryl and aliphatic alkynes, where 3r and 3s were
isolated in 82% and 61% yield, respectively. To study the
regioselectivity of this reaction, unsymmetrical alkynes such as
1-phenyl-1-pentyne and 2-(pent-1-yn-1-yl)thiophene were em-
ployed, and in both cases single regioisomeric products 3t (68%)
and 3u (79%) were isolated. Pyridines bearing 4-position direct-
ing groups other than amides have been successfully applied for
quinolone synthesis. The reaction of 2,40-bipyridine with diphe-
nylacetylene gave 4-(2-pyridinyl)quinoline 3v in 87% yield.
Interestingly, when 4-(1-methylimidazol-2-yl)pyridine was used,
both quinoline 3w and acridine 3x were isolated, as a result of
2-fold and 4-fold CꢀH activation, respectively. The isolation of
3x indicates that the imidazole directing group is more sterically
accessible so that further directing effect can be exerted.
To further define the scope of this reaction, a nicotinamide 5
was used as a substrate with the expectation of an isoquinoline
product. However, no such product was generated in the
coupling between 5 and diphenylacetylene. Instead, two isomeric
naphthyridinones, 6a (58%) and 6b (29%), were isolated as a
result of different selectivities of CꢀH activation (eq 2). These
results suggest that C(2)ꢀH bond is more reactive than the
C(4)ꢀH ones in this reaction system. This is important not only
for controlling the regioselectivity of CꢀH activation but also for
shifting the possible activation of the 20-position CꢀH bond to
NꢀH bond cleavage and subsequent CꢀN bond formation.
We further carried out competition reactions to explore this
reaction mechanism. A mixture of 1c, 1d, and diphenylacetylene
in 1:1:2 molar ratio was subjected to the standard conditions,
and this coupling reaction is favored for isonicotinamides with
electron-poor N-aryl groups (eq 3). This observation agrees with
CuCO3 Cu(OH)2 (entry 7). However, essentially no coupling
3
product was detected using other oxidants such as CuCl2, AgF,
and AgOTf. These results suggest that the anion of the oxidant
plays a crucial role in controlling the reaction selectivity. Further
optimization indicated that by lowering the catalyst loading to 2
mol %, 3a was still isolated in 87% yield using Cu(OAc)2 as an
oxidant (entry 6).
With the optimized reaction conditions in hand, we explored
the scope and the limitation of this quinoline synthesis
(Scheme 1). Isonicotinamides bearing either an electron-rich
or -poor group in the N-phenyl ring reacted with diphenylace-
tylene to give products 3aꢀd in high yield under the standard
conditions. The use of N-alkyl groups, including N-Me (3e), N-
allyl (3f), and N-tBu (3g), can also be tolerated, although a lower
yield of 3g was obtained due to steric effects. Simple isonicoti-
namide 1h afforded the same type of product, and this is in
contrast to our previously reported tetracyclic products obtained
when PhC(O)NH2 was used, where formation of two CꢀC and
two CꢀN bonds was involved.18e Since this current reac-
tion involves no formal NH cleavage, oxidative coupling of N,
N-diethylisonicotinamide is expected. However, no desired
coupling product was observed under the standard conditions.
Moving to a more active [RhCp*(CH3CN)3]2[SbF6]2 catalyst,
coupling with diphenylacetylene was achieved to afford quinoline
3i (21%). Further examination of the reaction scope reveals
that pyridines bearing electron-withdrawing groups reacted in
good yield (3j, 3m), while the introduction of a methoxy group
at the 3-position tends to lower the catalytic efficiency (3k).
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NOTE
When AgOAc or Cu(OAc)2 is used, protonolysis of the RhꢀN
bond of 10 by acetic acid is proposed to give a vinyl intermediate
11, which subsequently undergoes a second ortho CꢀH activa-
tion to yield intermediate 12. A second regioselective insertion of
alkyne23 and subsequent reductive elimination generate the
quinoline product 3 and a Rh(I) species, and the latter is oxidized
by Cu(II) to complete the catalytic cycle. When Ag2CO3 or
Ag2O is employed as an oxidant, water is released after initial
cyclometalation. In this case, the RhꢀN bond in intermediate 10
is less susceptible to protonolysis due to the poor acidity of water,
and consequently 2,6-naphthyridinone product 4 is generated
from CꢀN reductive elimination of 10. In this catalytic cycle, the
role of oxidant probably is 3-fold. It forms a rhodium-bound
active catalyst to facilitate CꢀH activation likely via a concerted
metalation-deprotonation (CMD) mechanism.18a It releases a
HOAc or H2O byproduct so that the reaction selectivity can be
tuned. It also reoxidizes the Rh(I) specie to Rh(III).
In conclusion, we have developed a Rh(III)-catalyzed synthe-
sis of quinolines and acridines starting from isonicotinamides
and alkynes using Cu(OAc)2 as an oxidant. The selectivity of the
coupling reaction is oxidant-dependent. This coupling reaction
gives the first examples of chelation-assisted 2-fold CꢀH func-
tionalization of pyridine rings at the 2- and 3-positions. Pyridines
with various directing groups are applicable, allowing access to
diversified products. Additionally, the catalytic reaction is highly
regioselective for unsymmetrically substituted alkynes. We ob-
served significant anion effect of the oxidant in the efficiency and
selectivity of this coupling reaction.
N-ligation of the substrate in the catalytic cycle,18a although the
O-atom can also offer chelation-assistance as in the case of
1i.18b,19a A competition reaction between 1l and 1m also led to
the conclusion that electron-poor pyridine rings in isonicotina-
mides react with alkynes in slight preference (eq 4).18a,e,20a
Considering the important role of C(2)ꢀH activation in controlling
the reaction selectivity, an intermolecular competition reaction
between 1h and 1h-D was conducted (eq 5). A kinetic isotope
effect of 2.8 was obtained,22 which indicates that cleavage of C(2)ꢀ
H bond in amide 1h is involved in the rate-determining step.
’ EXPERIMENTAL SECTION
General Procedure for Rh(III)-Catalyzed Quinoline (3)
Synthesis. Isonicotinamide 1a (106 mg, 0.5 mmol), diphenylacetylene
2a (196 mg, 1.1 mmol, 2.2 equiv), Cu(OAc)2 (200 mg, 1.1 mmol, 2.2
equiv), and [RhCp*Cl2]2 (6.2 mg, 0.01 mmol, 2 mol %) were charged
into a 25 mL pressure tube, and acetone (5 mL) was added. After being
purged with nitrogen, the mixture was stirred at 120 °C for 6 h. The
mixture was then diluted with CH2Cl2 (20 mL) and washed with
saturated sodium bicarbonate solution. The organic phase was sepa-
rated, dried with sodium sulfate, and filtered through Celite. All volatiles
were removed under reduced pressure. The purification was performed by
flash column chromatography on silica gel using EtOAc in petroleum ether.
Compound 3a. White solid, 87%. 1H NMR (400 MHZ, DMSO-d6):
δ 10.05 (s, 1H, NH), 8.93 (d, J = 4.0 Hz, 1H), 7.53 (d, J = 4.0 Hz, 1H),
7.10ꢀ7.21 (m, 10H), 6.64ꢀ6.99 (m, 14H), 2.25 (s, 3H). 13C NMR (100
MHZ, DMSO-d6): 165.9, 149.9, 146.9, 144.7, 142.7, 141.6, 140.07,
140.03, 139.98, 139.5 (two overlapping signals), 138.2, 138.1, 136.6,
132.3, 131.7 (two overlapping signals), 131.1 (two overlapping signals),
128.7, 127.2, 126.9, 126.7, 126.6, 126.3, 126.0, 125.8, 122.6, 121.6, 119.8,
20.9. HRMS (ESI): calcd for [C41H30N2O + H]+ 567.2431, found
567.2437.
Compound 3b. White solid, 84%. 1H NMR (500 MHZ, DMSO-d6):
δ 10.12 (s, 1H, NH), 8.90 (d, J = 4.0 Hz, 1H), 7.50 (d, J = 4.0 Hz, 1H),
7.12ꢀ7.21 (m, 9H), 7.04 (d, J = 6.0 Hz, 2H), 6.64ꢀ7.01 (m, 14H). 13C
NMR (125 MHZ, DMSO-d6): 165.7, 149.4, 146.4, 144.1, 142.3, 141.2,
139.6, 139.5 (two overlapping signals), 139.0, 138.6, 137.7, 137.6, 131.2
(two overlapping signals), 130.6 (two overlapping signals), 130.5, 127.8,
126.7, 126.4, 126.2, 126.1, 125.8, 125.5, 125.3, 123.0, 122.0, 121.1, 119.3.
HRMS (ESI): calcd for [C40H28N2O + H]+ 553.2274, found 553.2269.
Compound 3c. White solid, 79%. 1H NMR (400 MHZ, DMSO-d6):
δ 9.97 (s, 1H, NH), 8.91 (d, J = 4.0 Hz, 1H), 7.50 (d, J = 4.0 Hz, 1H),
7.08ꢀ7.18 (m, 7H), 7.03 (d, J = 6.0 Hz, 2H), 6.62ꢀ6.87 (m, 15H), 3.68
(s, 3H). 13C NMR (100 MHZ, DMSO-d6): 165.2, 155.0, 149.4, 146.4,
On the basis of these results and previous reports,18a
a
plausible catalytic cycle is proposed to account for this present
reaction (Scheme 2). The catalytic cycle starts from RhCp*-
(OAc)2, which is derived from the ligand exchange between the
rhodium dimer and the acetate oxidant. Nitrogen coordination of
isonicotinamide and subsequent ortho CꢀH activation generates
a five-membered rhodacyclic intermediate 8 with the liberation
of an acetic acid molecule. Regioselective insertion of the alkyne into
the RhꢀC bond of 8 affords a seven-membered intermediate 10.
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NOTE
Scheme 1. Scope of Rh(III)-Catalyzed Quinoline Synthesisa
a Conditions: 1 (0.5 mmol), 2 (1.1 mmol), [RhCp*Cl2]2 (0.01 mmol, 2 mol %), Cu(OAc)2 (1.1 mmol), acetone (5 mL), sealed tube under nitrogen, 120
°C, 6 h, isolated yield. b [RhCp*(CH3CN)3](SbF6)2 (5 mol %) was used as catalyst, o-xylene (5 mL), 140 °C, 12 h. c 1 mmol (2 0 equiv) of
diphenylacetylene was used, acetone (5 mL), 80 °C, 12 h. d 2.5 mmol (5.0 equiv) of diphenylacetylene was used, acetone (5 mL), 120 °C, 12 h.
144.3, 142.2, 141.2, 139.6, 139.55, 139.52, 139.0, 137.8, 137.6, 131.9,
131.2 (two overlapping signals), 130.7 (two overlapping signals), 130.5,
126.7, 126.4, 126.2, 126.1, 125.8, 125.5, 125.3, 122.1, 121.1, 120.7, 113.0,
55.0. HRMS (ESI): calcd for [C41H30N2O2 + H]+ 583.2380, found
583.2378.
139.6, 139.5, 139.4, 138.9, 137.3, 137.6, 137.5, 131.9, 131.2 (two over-
lapping signals), 130.6 (two overlapping signals), 127.7, 126.7, 126.6, 126.4,
126.3, 126.2, 125.8, 125.6, 125.3, 121.9, 121.1, 120.7. HRMS (ESI): calcd
for [C40H27ClN2O + H]+ 587.1885, found 587.1893.
Compound 3e. White solid, 90%. 1H NMR (500 MHZ, CDCl3): δ
8.89 (d, J = 4.5 Hz, 1H), 7.31 (d, J = 4.0 Hz, 1H), 7.15ꢀ7.21 (m, 5H),
7.11 (5H), 6.82ꢀ6.86 (m, 7H), 6.77ꢀ6.79 (m, 2H), 6.69ꢀ6.71 (m,
2H), 2.32 (d, J = 5 Hz, 3H). 13C NMR (125 MHZ, CDCl3): 169.2, 149.4,
147.4, 143.8, 143.0, 141.9, 140.3, 139.8, 139.7, 138.9, 138.8, 137.3, 132.2,
Compound 3d. White solid, 89%. 1H NMR (500 MHZ, DMSO-d6):
δ 10.21 (s, 1H, NH), 8.90 (d, J = 4.0 Hz, 1H), 7.52 (d, J = 4.0 Hz, 1H),
7.11ꢀ7.25 (m, 10H), 7.04 (d, J = 7.5 Hz, 2H), 6.59ꢀ6.90 (m, 12H). 13C
NMR (125 MHZ, DMSO-d6): 165.8, 149.4, 146.4, 143.8, 142.3, 141.3,
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NOTE
Scheme 2. A Plausible Mechanism of Rh(III)-Catalyzed Quinoline Synthesis
131.4, 131.0, 130.9, 127.1, 126.9, 126.8, 126.7, 126.6, 126.4, 125.6, 125.5,
122.8, 120.7, 26.2. HRMS (ESI): calcd for [C35H26N2O + H]+
491.2118, found 491.2123.
125.7, 125.5, 125.3, 122.4, 120.8. HRMS (ESI): calcd for [C34H24N2O +
H]+ 477.1961, found 477.1956.
Compound 3i. Reaction conditions: 1g (89 mg, 0.5 mmol), diphe-
nylacetylene (196 mg, 1.1 mmol, 2.2 equiv), Cu(OAc)2 (200 mg, 1.1
mmol, 2.2 equiv), [RhCp*(CH3CN)3](SbF6)2 (20.8 mg, 0.025 mmol, 5
mol %), and o-xylene (5 mL) in a sealed pressure tube, 140 °C, 12 h.
White solid, 21%. 1H NMR (500 MHZ, CDCl3): δ 8.88 (d, J = 4.0 Hz,
1H), 7.30 (d, J = 7.5 Hz, 1H), 7.03ꢀ7.23 (m, 8H), 6.99ꢀ7.01 (m, 2H),
6.74ꢀ6.85 (m, 9H), 6.63ꢀ6.66 (m, 1H), 3.27ꢀ3.34 (m, 1H),
2.96ꢀ3.03 (m, 1 h), 2.68ꢀ2.75 (m, 1H), 2.48ꢀ2.55 (m, 1H), 1.07 (t,
J = 7.0 Hz, 3H), 0.91 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHZ, CDCl3):
168.6, 149.1, 147.3, 144.0, 142.9, 142.0, 140.4, 139.9, 139.8, 139.0, 138.0,
137.6, 133.5, 131.1, 131.0, 130.8, 130.72, 130.68, 127.09, 127.05, 126.7,
126.5, 126.4, 126.32, 126.29, 125.7, 125.5, 125.3, 122.7, 119.7, 45.3, 40.1,
14.1, 13.7. HRMS (ESI): calcd for [C38H32N2O + H]+ 533.2587, found
533.2591.
Compound 3f. White solid, 78%. 1H NMR (500 MHZ, DMSO-d6): δ
8.83 (d, J = 4.5 Hz, 1H), 8.22 (t, J = 5.5 Hz, 1H, NH), 7.34 (d, J = 4.0 Hz,
1H), 7.03ꢀ7.18 (m, 10H), 6.76ꢀ6.85 (m, 10H), 5.61ꢀ5.66 (m, 1H),
5.08 (dq, J = 17.0, 1.5 Hz, 1H), 5.00 (dq, J = 10.0, 1.5 Hz, 1H), 3.09 (br,
2H). 13C NMR (125 MHZ, DMSO-d6): 167.2, 149.3, 146.3, 144.5,
142.1, 141.0, 139.62, 139.55, 139.49, 139.0, 137.9, 137.6, 134.7, 131.1,
130.7, 130.5, 126.7, 126.4, 126.24, 126.20, 126.0 (two overlapping
signals), 125.7, 125.5, 125.3, 122.2, 121.0, 115.3, 41.0. HRMS (ESI):
calcd for [C37H28N2O + H]+ 517.2274, found 517.2270.
Compound 3g. Reaction conditions: 1g (89 mg, 0.5 mmol), diphe-
nylacetylene 2a (196 mg, 1.1 mmol, 2.2 equiv), Cu(OAc)2 (200 mg, 1.1
mmol, 2.2 equiv), [RhCp*(CH3CN)3](SbF6)2 (20.8 mg, 0.025 mmol, 5
mol %), and o-xylene (5 mL) in a sealed pressure tube, 140 °C, 12 h.
White solid, 23%. 1H NMR (500 MHZ, CDCl3): δ 8.88 (d, J = 4.0 Hz,
1H), 7.31 (d, J = 4.0 Hz, 1H), 7.05ꢀ7.21 (m, 11H), 6.80ꢀ6.85 (m, 6H),
6.75ꢀ6.77 (m, 2H), 6.64ꢀ6.65 (m, 2H), 1.04 (s, 9H). 13C NMR (125
MHZ, CDCl3): 167.7, 149.4, 147.6, 145.1, 142.9, 141.9, 140.0, 139.9,
139.8, 139.4, 139.0, 137.6, 132.3, 131.4, 131.0, 130.9, 127.07, 127.03,
126.97, 126.6, 126.5, 126.3, 125.5, 125.3, 122.7, 121.2, 51.7, 28.6. HRMS
(ESI): calcd for [C38H32N2O + H]+ 533.2587, found 533.2581.
Compound 3h. White solid, 87%. 1H NMR (500 MHZ, DMSO-d6):
δ 8.81 (d, J = 4.5 Hz, 1H), 7.49 (br, 1H, NH), 7.34 (d, J = 4.5 Hz, 1H),
7.12ꢀ7.16 (m, 4H), 7.04ꢀ7.10 (m, 4H), 6.99 (d, J = 7.5 Hz, 2H),
6.76ꢀ6.86 (m, 10H), 6.73 (br, 1H, NH). 13C NMR (125 MHZ, DMSO-
d6): 169.4, 149.3, 146.4, 145.1, 142.1, 140.9, 139.7, 139.6, 139.4, 139.1,
138.1, 137.7, 132.3, 131.2, 130.7, 130.5, 126.7, 126.5, 126.4, 126.3, 126.1,
Compound 3j. White solid, 71%. 1H NMR (500 MHZ, CDCl3): δ
8.85 (s, 1H), 7.14ꢀ7.25 (m, 6H), 6.95ꢀ7.04 (m, 7H), 6.68ꢀ6.86 (m,
12H), 2.28 (s, 3H). 13C NMR (125 MHZ, CDCl3): 160.3, 153.1 (d, JFꢀC
= 257 Hz), 144.2, 143.4, 142.4, 140.8, 140.6, 140.4, 139.5 (d, JFꢀC = 9.5
Hz), 138.5, 137.6 (d, JFꢀC = 4.7 Hz), 137.5, 134.5, 134.2, 133.1, 131.1,
130.9 (two overlapping signals), 129.7, 129.0, 127.4 (d, JFꢀC = 15 Hz),
127.17, 127.14, 126.7 (two overlapping signals), 126.5, 125.7 (d, JFꢀC
=
15.8 Hz), 123.3, 121.2, 119.7, 20.8. HRMS (ESI): calcd for
[C41H29FN2O + H]+ 585.2337, found 585.2334.
Compound 3k. White solid, 24%. 1H NMR (500 MHZ, CDCl3): δ
8.90 (s, 1H), 7.15ꢀ7.23 (m, 6H), 6.95ꢀ6.99 (m, 7H), 6.70ꢀ6.86 (m,
12H), 3.99 (s, 3H), 2.28 (s, 3H). 13C NMR (125 MHZ, CDCl3): 163.0,
149.4, 142.9, 142.8, 140.9, 140.0, 139.9 (two overlapping signals), 139.1,
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NOTE
139.0, 137.9, 136.9, 135.0, 133.6, 131.4 (two overlapping signals), 131.1,
130.8, 128.9, 128.8, 127.1, 126.8 (two overlapping signals), 126.6, 126.4,
126.3, 125.5, 125.4, 123.5, 119.5, 58.0, 20.9. HRMS (ESI): calcd for
[C42H32N2O2 + H]+ 597.2537, found 597.2544.
(m, 2H), 6.71 (dd, J = 5.0, 3.6 Hz, 1H), 6.65ꢀ6.69 (m, 2H), 6.61 (dd, J =
3.5, 1.0 Hz, 1H), 6.56 (dd, J = 3.5, 1.0 Hz, 1H), 2.30 (s, 3H). 13C NMR
(125 MHZ, CDCl3): 165.5, 150.3, 147.9, 147.6, 143.9, 140.2, 139.8,
138.4, 138.2, 137.2, 136.0, 134.9, 134.1, 133.6, 132.8, 132.6, 132.0, 129.9,
129.6, 129.3, 129.1, 128.1, 127.0, 126.5, 126.2, 125.8, 125.7, 124.6, 121.9,
119.5, 20.8. HRMS (ESI): calcd for [C33H22N2OS4 + H]+ 591.0688,
found 591.0684.
Compound 3l. White solid, 88%. 1H NMR (500 MHZ, DMSO-d6): δ
9.97 (s, 1H, NH), 7.39 (s, 1H), 7.01ꢀ7.16 (m, 9H), 6.93 (d, J = 8.5 Hz,
2H), 6.61ꢀ6.85 (m, 13H), 2.52 (s, 3H), 2.20 (s, 3H). 13C NMR (125
MHZ, DMSO-d6): 165.5, 157.5, 145.9, 144.4, 142.1, 140.1, 139.8, 139.7,
139.0, 138.9, 137.9, 137.4, 136.2, 131.7, 131.4 (two overlapping signals),
130.7, 130.6, 128.2, 126.5, 126.4, 126.2, 126.1, 126.0, 125.7, 125.4, 125.2,
121.7, 120.6, 119.3, 24.7, 20.4. HRMS (ESI): calcd for [C42H32N2O +
H]+ 581.2587, found 581.2583.
Compound 3s. White solid, 61%. 1H NMR (500 MHZ, CDCl3): δ
8.76 (d, J = 4.1 Hz, 1H), 7.49ꢀ7.51 (m, 3H), 7.20 (d, J = 4.1 Hz, 1H),
7.16 (d, J = 8.2 Hz, 2H), 3.19ꢀ3.30 (m, 2H), 2.95ꢀ2.98 (m, 2H),
2.77ꢀ2.81 (m, 2H), 2.71ꢀ2.74 (m, 2H), 2.34 (s, 3H), 1.48ꢀ1.67 (m,
8H), 1.06ꢀ1.13 (m, 9H), 0.84 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHZ,
CDCl3): 168.8, 147.3, 146.7, 141.9, 141.5, 140.3, 137.9, 135.4, 134.4,
133.9, 129.7, 121.3, 119.6, 119.3, 32.8, 32.4, 32.3, 30.5, 25.8, 25.0, 24.8,
24.6, 20.8, 15.03, 15.0, 14.9, 14.5. HRMS (ESI): calcd for [C29H38N2O +
H]+ 431.3057, found 431.3061.
Compound 3m. White solid, 78%. 1H NMR (500 MHZ, CDCl3): δ
7.42 (s, 1H), 7.14ꢀ7.22 (m, 5H), 7.05 (d, J = 7.0 Hz, 2H), 6.99 (d, J = 8.4
Hz, 2H), 6.93ꢀ6.95 (m, 3H), 6.81ꢀ6.90 (m, 9H), 6.76ꢀ6.78 (m, 2H),
6.68ꢀ6.70 (m, 2H), 2.28 (s, 3H). 13C NMR (125 MHZ, DMSO-d6):
163.7, 148.6, 148.0, 146.2, 143.6, 141.8, 139.2, 139.1, 138.7, 138.0, 137.9,
137.2, 135.9, 132.1, 131.17, 131.09, 130.6, 130.4, 128.3, 126.8, 126.5,
126.34, 126.30, 126.2, 126.0, 125.7, 125.4, 121.8, 121.4, 119.4, 20.4.
HRMS (ESI): calcd for [C41H29BrN2O + H]+ 645.1536, found
645.1541.
Compound 3t. White solid, 68%. 1H NMR (500 MHZ, CDCl3): δ
8.91 (d, J = 4.2 Hz, 1H), 7.75 (br, 1H), 7.50 (d, J = 8.4 Hz, 2H), 8.91 (d,
J = 4.2 Hz, 1H), 7.00ꢀ7.17 (m, 8H), 6.92ꢀ6.99 (m, 4H), 2.97ꢀ3.04 (m,
2H), 2.75ꢀ2.83 (m, 2H), 2.33 (s, 3H), 1.54ꢀ1.63 (m, 2H), 1.33 (br,
2H), 0.81 (t, J = 7.3 Hz, 3H), 0.50 (t, J = 7.2 Hz, 3H). 13C NMR (125
MHz, CDCl3): 168.3, 147.86, 147.84, 143.3, 142.7, 142.4, 140.8, 140.6,
138.2, 135.2, 134.7, 134.5, 130.1 (two overlapping signals), 129.9, 129.7,
127.1, 126.10, 126.06, 121.9, 120.0, 119.7, 33.5, 31.9, 25.7, 24.6, 20.9,
14.7, 14.2. HRMS (ESI): calcd for [C35H34N2O + H]+ 499.2744, found
499.2746.
Compound 3n. White solid, 73%. 1H NMR (500 MHz, DMSO-d6) δ
10.23 (s, 1H, NH), 7.85ꢀ7.89 (m, 2H), 7.77 (t, J = 7.4 Hz, 1H), 7.57 (t,
J = 7.4 Hz, 1H), 7.16ꢀ7.24 (m, 8H), 7.11 (d, J = 7.3 Hz, 1H), 6.71ꢀ7.01
(m, 13H), 6.68 (t, J = 7.2 Hz, 1H), 6.57 (d, J = 7.4 Hz, 1H), 2.23 (s, 3H).
13C NMR (125 MHz, DMSO-d6): 164.2, 147.2, 147.0, 142.8, 142.4,
141.3, 139.7, 139.6, 139.0, 138.9, 137.5, 137.2, 136.1, 132.5, 132.0, 131.9,
131.53 (two overlapping signals), 131.49, 130.6 (two overlapping
signals), 130.4, 130.2, 129.4, 128.4 (two overlapping signals), 127.0,
126.7 (two overlapping signals), 126.5, 126.4, 126.22, 126.17, 126.14
(two overlapping signals), 126.0, 125.57, 125.54, 125.46, 125.3, 123.0,
119.8, 119.2 (two overlapping signals), 20.4. HRMS (ESI): calcd for
[C45H32N2O + H]+ 617.2587, found 617.2591.
Compound 3u. White solid, 79%. 1H NMR (500 MHZ, CDCl3): δ
9.00 (d, J = 4.1 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 4.1 Hz, 1H),
7.44 (br, 1H), 7.21 (dd, J = 5.1, 1.1 Hz, 1H), 7.15ꢀ7.19 (m, 3H), 6.87
(dd, J = 5.1, 3.5 Hz, 1H), 6.83 (dd, J = 5.1, 3.5 Hz, 1H), 6.71 (dd, J = 3.4,
1.1 Hz, 1H), 6.69 (dd, J = 3.4, 1.0 Hz, 1H), 3.04ꢀ3.18 (m, 2H),
2.79ꢀ2.98 (m, 2H), 2.34 (s, 3H), 1.61ꢀ1.73 (m, 2H), 1.46 (br, 2H),
0.91 (t, J = 7.3 Hz, 3H), 0.64 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz,
CDCl3): 167.8, 148.6, 148.0, 142.8, 141.3, 140.9, 140.6, 137.9, 136.6,
135.5, 135.1, 134.7, 129.8, 128.6, 128.2, 126.0 (two overlapping signals),
125.5, 125.4, 122.3, 120.6, 119.7, 33.9, 32.4, 26.6, 25.2, 20.9, 14.8, 14.3.
HRMS (ESI): calcd for [C31H30N2OS2 + H]+ 511.1872, found
511.1876.
Compound 3o. White solid, 88%. 1H NMR (500 MHZ, CDCl3): δ
8.89 (d, J = 4.2 Hz, 1H), 7.33 (d, J = 4.2 Hz, 1H), 7.06 (d, J = 8.1 Hz, 2H),
7.03ꢀ6.94 (m, 7H), 6.91 (d, J = 7.5 Hz, 2H), 6.71ꢀ6.60 (m, 8H), 6.57
(d, J = 8.0 Hz, 2H), 2.28 (s, 3H), 2.27 (s, 3H), 2.10 (s, 3H), 2.08 (s, 3H),
1.92 (s, 3H). 13C NMR (125 MHZ, CDCl3): 166.3, 149.1, 147.7, 143.7,
143.4, 142.1, 140.1, 137.3, 137.0, 136.8, 136.4, 136.0, 135.8, 135.5, 135.0,
134.7, 134.6, 133.6, 131.7, 131.3, 130.83, 130.76, 128.9, 127.9, 127.8,
127.3, 127.2, 122.9, 120.4, 119.4, 21.3, 21.05, 21.01, 20.86, 20.8. HRMS
(ESI): calcd for [C45H38N2O + H]+ 623.3057, found 623.3060.
Compound 3p. White solid, 84%. 1H NMR (500 MHZ, CDCl3): δ
8.94 (d, J = 4.2 Hz, 1H), 7.43 (d, J = 4.1 Hz, 1H), 7.22 (d, J = 8.4 Hz, 2H),
7.03ꢀ7.12 (m, 5H), 6.84ꢀ7.01 (m, 10H), 6.69 (d, J = 8.5 Hz, 2H), 6.61
(d, J = 8.0 Hz, 2H), 2.30 (s, 3H). 13C NMR (125 MHZ, CDCl3): 165.6,
150.0, 147.3, 143.6, 141.8, 140.6, 139.8, 137.6, 137.4, 136.9, 136.6, 136.4,
134.5, 134.4, 133.6, 132.9, 132.64, 132.59, 132.4, 132.3, 132.02, 131.95,
129.4, 127.8, 127.5 (two overlapping signals), 127.4, 122.9, 120.9, 119.4,
20.9. HRMS (ESI): calcd for [C41H26Cl4N2O + H]+ 703.0872, found
703.0870.
Compound 3v. White solid, 87%. 1H NMR (400 MHZ, CDCl3): δ
8.95 (d, J = 4.2 Hz, 1H), 8.28 (d, J = 4.4 Hz, 1H), 7.31 (d, J = 4.2 Hz, 1H),
7.16ꢀ7.26 (m, 6H), 6.95 (d, J = 7.8 Hz, 1H), 6.67ꢀ6.86 (m, 16H). 13C
NMR (125 MHz, CDCl3): 159.4, 149.1, 148.5, 147.86, 147.80, 142.5,
141.5, 140.3, 140.17, 140.13, 140.03, 139.4, 137.8, 135.1, 131.5, 131.2,
131.0, 127.1, 126.6, 126.5, 126.4 (two overlapping signals), 126.2, 125.7,
125.5, 125.2, 124.9, 124.8, 124.2, 121.0. HRMS (ESI): calcd for
[C38H26N2 + H]+ 511.2169, found 511.2176.
Compound 3w. Reaction conditions: 4-(1-methyl-1H-imidazol-2-
yl)pyridine (79.5 mg, 0.5 mmol), diphenylacetylene (178 mg, 1.0 mmol,
2.0 equiv), Cu(OAc)2 (181 mg, 1.0 mmol, 2.0 equiv), [RhCp*Cl2]2
(6.2 mg, 2.0 mol %), and acetone (5 mL) in a pressure tube, 80 °C, 12 h.
White solid, 68%. 1H NMR (500 MHz, CDCl3) δ 8.93 (d, J = 4.2 Hz,
1H), 7.29 (d, J = 4.2 Hz, 1H), 7.12ꢀ7.27 (m, 5H), 6.94 (d, J = 7.7 Hz,
1H), 6.72ꢀ6.90 (m, 12H), 6.70 (d, J = 1.2 Hz, 1H), 6.69ꢀ6.61 (m, 2H),
6.27 (d, J = 1.2 Hz, 1H), 3.24 (s, 3H). 13C NMR (125 MHz, CDCl3):
148.8, 147.6, 146.0, 142.8, 142.1, 140.2, 139.9, 139.8, 139.1, 138.4, 137.7,
137.4, 132.5, 131.5, 131.3, 131.1, 130.9, 130.9, 129.0, 128.7, 127.1, 127.0,
126.9, 126.6 (two overlapping signals), 126.4, 126.2, 126.2 (two over-
lapping signals), 125.9, 125.7, 125.5 (two overlapping signals), 125.5,
125.2, 124.8, 33.5. HRMS (ESI): calcd for [C37H27N3 + H]+ 514.2278,
found 514.2282.
Compound 3q. White solid, 79%. 1H NMR (500 MHZ, CDCl3): δ
8.88 (d, J = 3.0 Hz, 1H), 7.32ꢀ7.36 (m, 3H), 6.98ꢀ7.22 (m, 9H),
6.58ꢀ6.88 (m, 10H), 3.79 (br, 6H), 3.72 (s, 3H), 3.58 (s, 3H), 2.32 (s,
3H). 13C NMR (125 MHZ, CDCl3): 166.1, 159.6, 159.2, 158.3, 158.1,
149.5, 147.7, 143.8, 143.1, 140.3, 139.7, 135.0, 133.9, 132.7, 132.6, 132.5
(two overlapping signals), 131.9, 131.5, 130.5, 129.0, 125.5, 123.0, 120.6,
119.4, 115.3, 113.7, 113.1, 112.9, 112.7, 55.2 (two overlapping signals),
55.0 (two overlapping signals), 20.8. HRMS (ESI): calcd for
[C45H38N2O5 + H]+ 687.2853, found 687.2850.
Compound 3r. Yellow solid, 82%. 1H NMR (500 MHZ, CDCl3): δ
9.02 (d, J = 4.2 Hz, 1H), 7.51 (d, J = 4.1 Hz, 1H), 7.39 (dd, J = 5.1, 1.1 Hz,
1H), 7.15 (d, J = 8.4 Hz, 2H), 7.12 (dd, J = 5.1, 1.0 Hz, 1H), 7.09 (dd, J =
5.1, 1.1 Hz, 1H), 7.03ꢀ7.05 (m, 3H), 6.97ꢀ6.98 (m, 2H), 6.91ꢀ6.94
Compound 3x. Reaction conditions: 4-(1-methyl-1H-imidazol-2-
yl)pyridine (79.5 mg, 0.5 mmol), diphenylacetylene (445 mg, 2.5 mmol,
5.0 equiv), Cu(OAc)2 (455 mg, 2.5 mmol, 2.5 equiv), [RhCp*Cl2]2
(6.2 mg, 2.0 mol %), and acetone (5 mL) in a pressure tube, 120 °C, 12 h.
7588
dx.doi.org/10.1021/jo201266u |J. Org. Chem. 2011, 76, 7583–7589

The Journal of Organic Chemistry
NOTE
White solid, 55%. 1H NMR (500 MHz, CDCl3) δ 7.03 (d, J = 7.0 Hz,
4H), 6.90ꢀ6.98 (m, 6H), 6.78ꢀ6.83 (m, 8H), 6.72ꢀ6.77 (m, 10H),
6.68ꢀ6.70 (m, 4H), 6.56ꢀ6.64 (m, 8H), 6.19 (d, J = 1.1 Hz, 1H), 5.39
(d, J = 1.0 Hz, 1H), 2.98 (s, 3H). 13C NMR (125 MHz, CDCl3): 146.6,
143.4, 142.5, 142.3, 140.2, 140.1, 138.9, 138.5, 138.1, 137.2, 133.7, 132.4,
131.6, 131.1, 131.0, 130.8, 129.6, 128.6, 126.6, 126.5 (two overlapping
signals), 126.3, 126.0, 125.5, 125.48, 125.47, 125.3, 125.2, 125.1, 124.9,
120.5, 33.8. HRMS (ESI): calcd for [C65H45N3 + H]+ 868.3686, found
868.3682.
Synthesis of Compound 4. Compound 4 was synthesized in 45%
yield by following a literature report.18e 1H NMR (400 MHz, CDCl3) δ
8.61ꢀ8.74 (m, 2H), 8.29 (d, J = 5.1 Hz, 1H), 7.18ꢀ7.27 (m, 3H), 7.14
(d, J = 6.6 Hz, 2H), 7.03 (d, J = 8.2 Hz, 2H), 6.97 (d, J = 8.3 Hz, 2H),
6.90ꢀ6.94 (m, 5H), 2.23 (s, 3H). 13C NMR (125 MHz, CDCl3) 161.6,
149.3, 146.4, 143.0, 137.7, 136.2, 134.6, 134.1, 131.7, 131.4, 130.9, 130.3,
129.4, 128.8, 128.2, 127.5, 127.3, 127.2, 120.0, 116.9, 21.0. HRMS (ESI):
calcd for [C27H20N2O + H]+ 389.1648, found 389.1644.
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Compounds 6a and 6b were synthesized by following the same
procedure for the quinolines. Compound 6a: orange solid, yield 58%. 1H
NMR (500 MHz, CDCl3) δ 8.94 (dd, J = 4.5, 1.9 Hz, 1H), 8.79 (dd, J =
8.0, 1.9 Hz, 1H), 7.42 (dd, J = 8.0, 4.5 Hz, 1H), 7.17ꢀ7.20 (m, 2H),
7.12ꢀ7.15 (m, 3H), 7.02 (d, J = 8.2 Hz, 2H), 6.97 (d, J = 8.3 Hz, 2H),
6.89ꢀ6.94 (m, 5H), 2.24 (s, 3H). 13C NMR (126 MHz, CDCl3): 162.9,
154.7, 153.3, 145.3, 137.6, 136.5, 136.3, 135.5, 134.5, 131.8, 130.8, 129.4,
129.0, 127.5, 127.4, 127.1, 126.7, 121.6, 121.3, 120.6, 21.0. HRMS (ESI):
calcd for [C27H20N2O + H]+ 389.1648, found 389.1645. Compound
6b: orange solid, yield 29%. 1H NMR (500 MHz, CDCl3) δ 9.71 (s, 1H),
8.67 (d, J = 5.6 Hz, 1H), 7.17 ꢀ7.24 (m, 3H), 7.06 ꢀ7.11 (m, 3H), 7.03
(d, J = 8.1 Hz, 2H), 6.92ꢀ6.97 (m, 5H), 6.87ꢀ6.91(m, 2H), 2.24 (s,
3H). 13C NMR (126 MHz, CDCl3) δ 162.2, 151.8, 151.4, 146.2, 143.0,
137.8, 136.0, 134.9, 134.2, 131.4, 130.5, 129.4, 129.0, 128.2, 127.7, 127.3
(two overlapping signals), 120.3, 118.2, 117.2, 21.1. HRMS (ESI): calcd
for [C27H20N2O + H]+ 389.1648, found 389.1644.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures for
b
KIE studies and copies of 1H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: xwli@dicp.ac.cn.
’ ACKNOWLEDGMENT
(20) (a) Wang, F.; Song, G.; Li, X. Org. Lett. 2010, 12, 5430.
(b) Wang, F.; Song, G.; Du, Z.; Li, X. J. Org. Chem. 2011, 76, 2926.
(21) (a) Tsai, A. S.; Tauchert, M. E.; Bergman, R. G.; Ellman, J. A.
J. Am. Chem. Soc. 2011, 133, 1248. (b) Li, Y.; Li, B.-J.; Wang, W.-H.;
Huang, W.-P.; Zhang, X.-S.; Chen, K.; Shi, Z.-J. Angew. Chem., Int. Ed.
2011, 50, 2115.
(22) In a control experiment, 1h, 2a, [RhCp*Cl2]2, and Cu(OAc)2
were allowed to react in acetone-d6 (120 °C, 12 h). 1H NMR analysis
indicated essentially no (<5%) H/D exchange in the 2-position of the
pyridine ring in 3h (see the Supporting Information). In contrast,
significant H/D exchange was observed at the 3-position of the product,
suggesting that the KIE at the 3-position cannot be accurately measured
using competitive studies.
We thank the Dalian Institute of Chemical Physics, CAS, for
generous financial support. This work was also supported by the
NSFC (No. 21072188).
’ REFERENCES
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(23) Alkyne migratory insertion of 13 may occur with a different
selectivity to give an isomer of 14.
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