Rhodium(III)-catalyzed one-pot access to isoquinolines and heterocycle-fused pyridines in aqueous medium through C-H cleavage

Article abstract of DOI:10.1002/ejoc.201403085

An efficient Rh^III-catalyzed ortho-C-H bond activation for the synthesis of substituted isoquinolines and heterocycle-fused pyridines in aqueous medium has been developed. This method involves the in situ generation of ketimines from ketones an

Full text of DOI:10.1002/ejoc.201403085

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FULL PAPER
DOI: 10.1002/ejoc.201403085
Rhodium(III)-Catalyzed One-Pot Access to Isoquinolines and Heterocycle-
Fused Pyridines in Aqueous Medium through C–H Cleavage
Jitan Zhang,[a] Hongsheng Qian,[a] Zhanxiang Liu,[a] Chunhua Xiong,*[b] and
Yuhong Zhang*[a,c]
Keywords: Synthetic methods / C–H activation / Nitrogen heterocycles / Annulation / Rhodium / Ketones / Alkynes
An efficient RhIII-catalyzed ortho-C–H bond activation for the
synthesis of substituted isoquinolines and heterocycle-fused
pyridines in aqueous medium has been developed. This
method involves the in situ generation of ketimines from
ketones and ammonium acetate and subsequent oxidative
C–H bond activation/annulation of ketimines with alkynes to
form the C–C/C–N bonds spontaneously. Various aryl
ketones and internal alkynes were smoothly transformed into
the desired heterocycles in moderate to excellent yields. The
reaction exploits molecular oxygen as the sole oxidant by
producing water as the only byproduct. Moreover, easily
available NH4OAc was utilized as the nitrogen source, which
makes this protocol practical and environmentally friendly.
vation of the substrate (i.e., halogenation and/or ortho-func-
tionalization) is required for these transformations.
Introduction
The efficient synthesis of heterocycles, especially nitro-
gen-containing heterocyclic compounds,[1] has been a sig-
nificant goal of synthetic organic chemists. In particular,
isoquinoline and pyridine structural motifs are ubiquitous
in natural products and pharmaceuticals,[2] and isoquin-
oline derivatives have been employed as chiral ligands in
transition-metal-catalyzed asymmetric syntheses.[3] Thus,
the efficient preparation of these heterocyclic scaffolds has
attracted extensive attention. Traditionally, several famous
name reactions (e.g., Bischler–Napieralski, Pomeranz–
Fritsch, and Pictet–Spengler reactions) have been widely
employed for the synthesis of isoquinoline derivatives by
condensation.[4] Although these reactions provide a facile
approach to give isoquinolines, they suffer from harsh reac-
tion conditions and an additional dehydrogenation step in
some cases. In recent years, transition-metal-catalyzed
cross-coupling reactions of aryl halides with alkynes have
appeared as an alternative and efficient method for the syn-
thesis of isoquinoline ring systems.[5] However, the preacti-
Currently, the strategy of direct C–H bond functionaliza-
tion[6] has prompted much attention in the synthesis of het-
erocycles because of its high atom- and step-economic na-
ture. In 2009, Fagnou and co-workers demonstrated an ele-
gant RhIII-catalyzed oxidative isoquinoline synthesis from
N-tert-butyl-benzaldimines and alkynes.[7a] In their reac-
tion, a stoichiometric amount of Cu(OAc)2 was used as an
external oxidant to regenerate the RhIII species. Later,
Miura and Satoh[7b] developed a method for synthesis of
isoquinoline derivatives by using the RhIII-catalyzed oxidat-
ive cyclization of benzophenone, N–H imines, and alkynes.
New approaches for the preparation of isoquinolines and
functionalized pyridines have been reported by Chiba,[8]
Cheng,[9a] and Dong,[10] respectively, by employing the ex-
ternal-oxidant-free strategy, in which the N–X (X = O, N,
S) bond of the directing groups performed as internal oxi-
dants. Hua and co-workers described an efficient three-
component cascade reaction of aryl ketones, hydroxyl-
amine, and alkynes to synthesize isoquinolines and hetero-
cycle-fused pyridines.[7e] Despite these significant advances,
limitations remain in this area. For examples, stoichiometric
amounts of metal oxidants are generally required to main-
tain the catalytic cycles. The installation of N–X bonds as
internal oxidants usually requires additional steps or com-
plex starting materials. Herein, we report the efficient and
practical access to isoquinolines and heterocycle-fused pyr-
idines by employing RhIII catalysis. A broad scope of aryl
ketones and alkynes participated in the reaction to afford
the corresponding heterocycles. Importantly, molecular
oxygen[11–13] was exploited as the sole oxidant in the reac-
tion, and water was produced as the only coproduct.
[a] Department of Chemistry, ZJU-NHU United R&D Center,
Zhejiang University,
Hangzhou 310027, P. R. China
E-mail: yhzhang@zju.edu.cn
http://www.chem.zju.edu.cn/~zhangyh/index.htm
[b] Department of Applied Chemistry, Zhejiang Gongshang
University,
Hangzhou 310018, P. R. China
E-mail: xiongch@163.com
http://spxy.zjgsu.edu.cn
[c] State Key Laboratory of Applied Organic Chemistry, Lanzhou
University,
Lanzhou 730000, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403085.
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Furthermore, easily available NH4OAc was utilized as the Table 1. Optimization of the reaction conditions.[a]
nitrogen source, which makes this method quite practical
and inexpensive. It is interesting that the reaction efficiently
proceeds in aqueous medium to give the desired products
in moderate to excellent yields.
Yield [%][b]
Results and Discussion
Entry
Catalyst
Additive Solvent T [°C]
1
2
3
4
5
6
7
8
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
RhCl(PPh3)3
RhCl3·3H2O
[(p-cymene)
RuCl2]2
–
DMF
DMF
DMF
H2O
H2O
H2O
100
100
100
100
100
100
100
100
100
100
100
100
100
trace
13[c]
37
Reactions for organic synthesis that are performed in
aqueous conditions have attracted tremendous attention
and are becoming some of the most exciting research
areas.[14] However, transition-metal-catalyzed C–H bond
transformations that take place in an aqueous medium are
underdeveloped.[15–18] We initiated our study by using ace-
tophenone (1a), ammonium acetate (2), and 1,2-diphenyl-
ethyne (3a) in the presence of 2.5 mol-% [Cp*RhCl2]2 (Cp*
= pentamethylcyclopentadienyl) in DMF (N,N-dimethyl-
formamide) at 100 °C with O2 as the sole oxidant. To our
delight, a trace amount of the desired product 4aa was ob-
served after 48 h by GC–MS analysis (see Table 1, Entry 1).
The efficiency of the reaction improved to give 4aa in 13
and 37% yield, respectively, when KOAc and AcOH were
used as additives (see Table 1, Entries 2 and 3). However,
the yield of the desired heterocyclic product 4aa increased
significantly to 65% when the reaction was conducted in
water with 1.0 mmol of AcOH as the additive (see Table 1,
KOAc
AcOH
AcOH
TFA[d]
TfOH[d]
65
n.d.[d]
Ͻ5
MsOH[d] H2O
trace
n.r.[d]
n.d.
82
n.r.
n.r.
TsOH
PhCO2H H2O
PivOH
PivOH
PivOH
PivOH
H2O
9
10
11
12
13
H2O
H2O
H2O
H2O
34
14
15
16
17
–
PivOH
PivOH
PivOH
PivOH
H2O
H2O
H2O
H2O
100
120
80
n.r.
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
85
79[e]
n.r.[f]
100
[a] Reagents and conditions: 1a (2.0 equiv.), 2 (6.0 equiv.), 3a
(0.2 mmol), catalyst (2.5 mol-%), and acid additive (5.0 equiv.) un-
der O2 (1 atm) at 100 °C for 48 h. [b] Isolated yields based on 3a.
[c] KOAc (0.4 mmol) was used. [d] TFA = trifluoroacetic acid, n.d.:
Entry 4). The investigation of other acidic additives iden- not determined, TfOH = triflic acid, MsOH = methanesulfonic
acid, n.r.: no reaction. [e] Reaction time prolonged to 72 h. [f] Reac-
tion performed under N2.
tified pivalic acid (PivOH) to be optimal, as it gave the cor-
responding product in 82% yield (see Table 1, Entry 10).
Further experiments showed that [Cp*RhCl2]2 was the first
choice for the catalyst precursor, and other metal salts such
as RhCl(PPh3)3, RhCl3·3H2O, and [(p-cymene)RuCl2]2 were an electron-withdrawing substituent (e.g., –CF3; see Table 2,
not effective (see Table 1, Entries 11–13). No reaction was Entries 1–4). A fluoro, chloro, or bromo group on the aro-
observed in the absence of the rhodium catalyst (see matic ring of the ketone was tolerated and afforded halo-
Table 1, Entry 14), and we determined that 100 °C was the gen-containing products 4ea–4ga in good yields, which
optimal temperature to perform the transformation. Tem- could undergo further cross-coupling reactions to facilitate
peratures above or below 100 °C did not lead to a better expedient syntheses of complex isoquinolines (see Table 2,
outcome (see Table 1, Entries 15 and 16). When the cata- Entries 5–7). To our surprise, 1-(4-aminophenyl)ethanone
lytic system was employed under N2, no reaction was ob- was well tolerated and afforded product 4ha in moderate
served (see Table 1, Entry 17). This result indicates that O2 yield (see Table 2, Entry 8). The steric effects of substituents
is crucial for the success of the annulation reaction. Thus, on the aryl ring of the ketones had an obvious impact on
the optimum reaction conditions, which were used for all the outcome of the reaction, as 1-(o-tolyl)ethanone gener-
subsequent transformations, involved 2.5 mol-% of ated the corresponding product 4ia in low yield (see Table 2,
[Cp*RhCl2]2, 1.0 mmol of PivOH, 1.2 mmol of NH4OAc, Entry 9). This method also allowed for the construction of
0.20 mmol of the alkyne, and 0.4 mmol of the ketone in a heterocycle-fused pyridine structure. 1-(1H-Indol-3-yl)-
1.0 mL of H2O. The reaction mixture was stirred at 100 °C ethanone, the N–H bond of which needs protection in some
for 48 h under O2.
transition-metal-catalyzed C–H bond activations,[19] partici-
On the basis of the optimization studies, we then evalu- pated in the reaction easily to furnish the desired product
ated the scope and generality of this transformation by 4ja in good yield (see Table 2, Entry 10). The cyclization
using 1,2-diphenylethyne (3a) and a variety of aryl ketones reaction also proceeded smoothly for 1-(thiophen-3-yl)-
1 as shown in Table 2. Several aryl ketones were suitable ethanone and 1-(thiophen-2-yl)ethanone to afford the cor-
substrates to give the desired products in moderate to good responding heterocycles 4ka and 4la in moderate to good
yields. The electronic properties of the substituents on the yields (see Table 2, Entries 11 and 12).
aryl ring of the ketone influenced the efficiency of the reac-
Benzophenone was examined in the reaction, and 1,3,4-
tion. In general, aryl ketones that contained an electron- triphenylisoquinoline was generated smoothly in a good
donating substituent (e.g., –CH3, –OCH3) produced a yield of 75% (see Table 2, Entry 13). (2-Aminophenyl)-
higher yield of product than their analogues that contained (phenyl)methanone was also well tolerated, and the corre-
2
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Access to Isoquinolines in Aqueous Medium
Table 2. Reaction of different ketones.[a]
[a] Reaction conditions: 1 (2.0 equiv.), 2 (6.0 equiv.), 3a (0.2 mmol), [(Cp*RhCl2)2] (2.5 mol-%), and PivOH (5.0 equiv) under 1 atm of
O2, 100 °C, 48 h. [b] Isolated yields based on 3a. [c] Cu(OAc)2·H2O was added. [d] Ketone was 1-tetralone. [e] Only decarboxylic result
was observed.
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J. Zhang, H. Qian, Z. Liu, C. Xiong, Y. Zhang
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Scheme 1. X-ray crystal structure of 4da.
sponding product 4na was produced in moderate yield (see results revealed that the weak electron-withdrawing-substi-
Table 2, Entry 14). Fortunately, benzil was compatible in tuted alkynes had better reactivity than the electron-donat-
this transformation and afforded 4oa in 41% yield (see ing-substituted ones. For instance, methyl- and methoxy-
Table 2, Entry 15). 1-Tetralone was successfully employed substituted alkynes gave the corresponding cyclization
for the preparation of 2,3-diphenyl-8,9-dihydro-7H- products in 73 and 69% yield, respectively (see Table 3, En-
benzo[de]quinoline (4pa) in a yield of 62% (see Table 2, En- tries 1 and 2), whereas the chloro-substituted alkyne af-
try 16). Interestingly, only the result of a decarboxylation forded the corresponding product in 81% yield (see Table 3,
was observed when ethyl 3-oxo-3-phenylpropanoate partici- Entry 3). On the other hand, the presence of the strong elec-
pated in the reaction (see Table 2, Entry 17). In addition, tron-withdrawing fluoro substituent significantly decreased
the reaction of 3a with propiophenone (1r) and 1-phenyl- the yield to 30% (see Table 3, Entry 4). The product was
butan-1-one (1s) resulted in the formation of the corre- isolated in 79% yield when the aliphatic alkyne oct-4-yne
sponding desired products 4ra and 4sa in 67 and 83% yield, was employed (see Table 3, Entry 5). Significantly, unsym-
respectively (see Table 2, Entries 18 and 19). 1-[3-(Trifluoro- metrical alkyne but-1-yn-1-ylbenzene yielded the product in
methyl)phenyl]ethanone easily participated in this reaction, a moderate yield with high regioselectivity (see Table 3, En-
which proceeded regioselectively, as the reaction predomi- try 6). An explanation for this occurrence is that in the
nantly occurred at the less congested position (see Table 2, seven-membered rhodacycle, the phenyl group of the alkyne
Entry 4). The structure of the final product 4da was further is close to the Rh atom but far away from the C atom.[21]
confirmed by X-ray crystal structure analysis (see
On the basis of previous studies[22] and our experimental
results, we propose that this RhIII-catalyzed C–H bond acti-
Scheme 1).[20]
We next examined the reactivity of other alkynes. As vation proceeds through one of two possible pathways as
shown in Table 3, the reaction of acetophenone (1a) with shown in Scheme 2. In path I, ketimine A is formed in situ
various substituted alkynes 3 furnished the annulation from acetophenone (1a) and NH4OAc in an aqueous me-
products 4 in moderate to good yields. The experimental dium and coordinates to the RhIII catalyst to generate the
Scheme 2. Two possible mechanisms of RhIII-catalyzed C–H bond activation/annulation of aryl ketones.
4
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Access to Isoquinolines in Aqueous Medium
Table 3. Reaction of different alkynes.[a]
volves a ketone-directed C–H bond activation to give
metallacycle E. The alkyne insertion into metallacycle E af-
fords seven-membered rhodacycle F, which generates com-
pound G after protonation. Ketimine H is formed sponta-
neously under the reaction conditions and proceeds in the
intramolecular cyclization. The subsequent aromatization
gives the desired isoquinoline derivative 4aa (see Scheme 2,
Path II). To explore the mechanism, the reactions of ketone
1m and diphenylmethanimine K were performed under our
standard conditions, but in the absence of NH4OAc. The
olefination product J was not observed [see Scheme 3,
Equation (1)], which implies that a ketone-directed ole-
fination might not occur in this transformation. In contrast,
the desired product 4ma was isolated from the reaction of
diphenylmethanimine
K
with 1,2-diphenylethyne [see
Scheme 3, Equation (2)]. This result shows that the reaction
might occur through path I. In addition, the oxidant is not
needed according to the catalytic cycle of path II. However,
we found the reaction did not occur under nitrogen (see
Table 1, Entry 17). This result also supports path I, as oxy-
gen is required as an oxidant to regenerate the RhIII catalyst
from RhI in this path.
Conclusions
In summary, we have successfully developed an efficient
rhodium-catalyzed C–H bond activation/annulation of aryl
ketones with alkynes for the synthesis of isoquinolines and
heterocycle-fused pyridines in aqueous medium. This
method, which tolerates a wide range of functional groups,
follows a reliable procedure for the rapid conversion of
readily available aryl ketones into a variety of valuable het-
erocycles in moderate to good yields. More importantly,
this reaction employs oxygen at ambient pressure as the ter-
minal oxidant, which obviates the need for stoichiometric
amounts of metal oxidants. The employment of readily
available NH4OAc as a nitrogen source makes the reaction
highly valuable in terms of economics and safety. Further
attempts to expand this catalytic system to other useful
transformations in an aqueous medium are currently un-
derway.
Experimental Section
General Methods: All materials and solvents were purchased from
common commercial sources and used without additional purifica-
tion. The 1H NMR spectroscopic data were recorded at 400 or
500 MHz, and the 13C NMR spectroscopic data were recorded at
100 or 125 MHz. TMS was used as the internal standard. The pat-
terns of the signals are described as singlet (s), doublet (d), triplet
(t), and multiplet (m). The mass spectrometry data were collected
by using MS-ESI and HRMS-EI instruments.
[a] Reaction conditions: 1 (2.0 equiv.), 2 (6.0 equiv.), 3 (0.2 mmol),
[Cp*RhCl2]2 (2.5 mol-%), and PivOH (5.0 equiv.) under 1 atm of
O2, 100 °C, 48 h. [b] Isolated yields based on 3.
five-membered rhodacycle B by releasing HX. The insertion
of alkyne 3a into intermediate B gives seven-membered
rhodacycle complex C, which undergoes a reductive elimi-
nation to yield the desired product 4aa and RhI species D.
The subsequent oxidation of RhI species by molecular oxy-
gen under acidic conditions regenerates the RhIII catalyst
General Procedure for Products 4aa–4pa, 4ra, 4sa, and 4ab–4ag: A
flask with a magnetic stir bar was charged with the aryl ketone
(0.4 mmol), the alkyne (0.2 mmol), [Cp*RhCl2]2 (3.1 mg,
0.005 mmol), PivOH (102 mg, 1.0 mmol), and H2O (1.0 mL). The
mixture was stirred at 100 °C in an oil bath for 48 h under O2
(see Scheme 2, Path I). Another reasonable pathway in- (1 atm). Upon completion of the reaction, the mixture was cooled
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J. Zhang, H. Qian, Z. Liu, C. Xiong, Y. Zhang
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Scheme 3. Control experiments to explore mechanism.
and made neutral to slightly alkaline by the addition of a saturated
(125 MHz, CDCl3): δ = 158.7, 151.5, 140.4, 137.6, 136.8, 131.3,
K2CO3 solution (5 mL). The resulting mixture was stirred for 130.3, 129.1, 128.6, 128.5, 128.4, 128.1, 127.9, 127.8, 127.6, 127.6,
30 min. H2O (10 mL) and EtOAc (20 mL) were then added success-
ively to the cooled reaction mixture. The organic phase was sepa-
rated, and the aqueous phase was further extracted with EtOAc
(2ϫ 10 mL). The combined organic layers were dried with
anhydrous Na2SO4. The solvent was evaporated to give a residue,
which was purified by flash chromatography on a silica gel column
[petroleum ether (PE)/EtOAc] to give the desired product 4.
127.4, 125.5, 125.5, 125.5, 125.1, 123.5, 123.4, 123.4, 123.3, 123.0,
22.7 ppm. IR: ν = 2926, 2855, 1703, 1630, 1432, 1305, 1168, 1126,
˜
968, 699 cm–1. MS: m/z (%) = 364 (17), 363 (83) [M]+, 362 (100),
294 (2), 69 (8). HRMS (EI-TOF): calcd. for C23H16F3N [M]+
363.1235; found 363.1233.
6-Fluoro-1-methyl-3,4-diphenylisoquinoline
(4ea):[7g]
Flash
chromatography on a silica gel column (petroleum ether/ethyl acet-
ate, 20:1) afforded a white solid. 1H NMR (400 MHz, CDCl3): δ =
8.19 (dd, J = 9.2 Hz, J = 5.6 Hz, 1 H), 7.37–7.31 (m, 6 H), 7.29–
7.23 (m, 1 H), 7.20–7.16 (m, 5 H), 3.05 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 163.2 (JC,F = 249.7 Hz), 157.6, 150.5,
Characterization Data of the Products
1-Methyl-3,4-diphenylisoquinoline (4aa).[7g] Flash chromatography
on a silica gel column (petroleum ether/ethyl acetate, 20:1) afforded
a white solid. 1H NMR (400 MHz, CDCl3): δ = 8.22–8.20 (m, 1
H), 7.68–7.65 (m, 1 H), 7.62–7.59 (m, 2 H), 7.38–7.32 (m, 5 H),
7.24–7.17 (m, 5 H), 3.10 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 157.8, 149.4, 141.0, 137.6, 136.0, 131.5, 130.3, 130.0,
129.3, 128.2, 127.2, 127.0, 126.6, 126.3, 126.2, 125.6, 22.8 ppm.
MS: m/z (%) = 296 (81), 295 (100) [M]+, 294 (100), 252 (54), 77
(10).
140.7, 138.1 (JC,F = 9.3 Hz), 137.2, 131.2, 130.3, 128.7 (JC,F
=
8.2 Hz), 128.5, 127.7, 127.4, 127.2, 123.5, 116.7 (JC,F = 25.7 Hz),
109.9 (JC,F = 22.4 Hz), 124.6, 22.8 ppm. MS: m/z (%) = 314 (20),
313 (93) [M]+, 312 (100), 270 (19), 155 (12), 77 (4).
6-Chloro-1-methyl-3,4-diphenylisoquinoline
(4fa):[7g]
Flash
chromatography on a silica gel column (petroleum ether/ethyl acet-
1
1,6-Dimethyl-3,4-diphenylisoquinoline (4ba):[7g] Flash chromatog-
ate, 5:1) afforded a white solid. H NMR (400 MHz, CDCl3): δ =
8.11 (d, J = 8.4 Hz, 1 H), 7.62 (d, J = 2.0 Hz, 1 H), 7.63 (dd, J =
9.1 Hz, J = 2.0 Hz, 1 H), 7.35–7.34 (m, 5 H), 7.20–7.17 (m, 5 H),
3.04 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.7, 150.7,
140.6, 137.2, 136.9, 136.4, 131.3, 130.3, 128.5, 128.5, 127.7, 127.5,
127.4, 127.2, 125.2, 124.4, 22.8 ppm. MS: m/z (%) = 331 (25), 330
(58), 329 (62) [M]+, 328 (100), 295 (12), 294 (25), 77 (6).
raphy on a silica gel column (petroleum ether/ethyl acetate, 20:1)
afforded a white solid. H NMR (400 MHz, CDCl3): δ = 8.05 (d,
1
J = 8.4 Hz, 1 H), 7.40–7.30 (m, 7 H), 7.21–7.15 (m, 5 H), 3.02 (s,
3 H), 2.40 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.4,
149.6, 141.2, 140.3, 137.8, 136.3, 131.5, 130.3, 128.8, 128.7, 128.2,
127.6, 127.1, 126.9, 125.5, 125.2, 124.6, 22.7, 22.2 ppm. MS: m/z
(%) = 309 (61) [M]+, 308 (100), 252 (15), 77 (5).
6-Bromo-1-methyl-3,4-diphenylisoquinoline
(4ga):[7g]
Flash
6-Methoxy-1-methyl-3,4-diphenylisoquinoline
(4ca):[7g]
Flash
chromatography on a silica gel column (petroleum ether/ethyl acet-
ate, 20:1) afforded a white solid. 1H NMR (400 MHz, CDCl3): δ =
8.02 (d, J = 8.8 Hz, 1 H), 7.80 (d, J = 2.0 Hz, 1 H), 7.63 (dd, J =
8.8 Hz, J = 2.0 Hz, 1 H), 7.35–7.33 (m, 5 H), 7.20–7.17 (m, 5 H),
3.03 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.8, 150.7,
140.7, 137.5, 136.9, 131.3, 130.3, 130.1, 128.5, 128.5, 128.4, 127.7,
127.5, 127.4, 127.3, 125.1, 124.6, 22.8 ppm. MS: m/z (%) = 375
(53), 374 (100), 373 (52) [M]+, 372 (89), 294 (18), 292 (25), 77 (5).
chromatography on a silica gel column (petroleum ether/ethyl acet-
ate, 10:1) afforded a pale yellow solid. 1H NMR (400 MHz,
CDCl3): δ = 8.06 (d, J = 9.2 Hz, 1 H), 7.35–7.27 (m, 5 H), 7.22–
7.15 (m, 6 H), 6.90 (s, 1 H), 3.68 (s, 3 H), 3.00 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 160.6, 157.0, 150.2, 141.2, 138.1,
137.9, 131.4, 130.3, 128.6, 128.3, 127.6, 127.5, 127.1, 126.9, 121.9,
118.7, 104.5, 55.2, 22.7 ppm. MS: m/z (%) = 325 (65) [M]+, 324
(100), 281 (39), 280 (12), 125 (6).
1-Methyl-3,4-diphenylisoquinolin-6-amine (4ha): Flash chromatog-
raphy on a silica gel column (petroleum ether/ethyl acetate, 20:1)
afforded a white solid; m.p. 189–191 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.97 (d, J = 8.8 Hz, 1 H), 7.32–7.23 (m, 5 H), 7.19–
1-Methyl-3,4-diphenyl-7-(trifluoromethyl)isoquinoline (4da): Flash
chromatography on a silica gel column (petroleum ether/ethyl acet-
ate, 20:1) afforded a white solid; m.p. 130–131 °C. 1H NMR
(500 MHz, CDCl3): δ = 8.48 (s, 1 H), 7.80–7.23 (m, 2 H), 7.38– 7.11 (m, 5 H), 6.92 (dd, J = 8.0 Hz, J = 2.0 Hz, 1 H), 6.64 (d, J =
7.34 (m, 5 H), 7.22–7.19 (m, 5 H), 3.12 (s, 3 H) ppm. 13C NMR 2.0 Hz, 1 H), 4.12 (s, 2 H), 2.94 (s, 3 H) ppm. 13C NMR (100 MHz,
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43085
/KAP1
Date: 29-10-14 17:25:56
Pages: 10
Access to Isoquinolines in Aqueous Medium
CDCl3): δ = 156.9, 149.6, 148.0, 141.1, 138.2, 138.1, 131.5, 130.2,
2923, 2853, 1615, 1543, 1498, 1451, 1253, 1080, 964, 701 cm–1. MS:
128.2, 127.7, 127.5, 127.5, 126.9, 126.8, 120.7, 118.0, 106.1, m/z (%) = 372 (42) [M]+, 371 (100), 292 (12), 277 (5), 77 (13).
22.3 ppm. IR: ν = 3346, 2966, 2922, 1613, 1535, 1502, 1414, 1270,
HRMS (EI-TOF): calcd. for C27H20N2 [M]+ 372.1626; found
˜
1048, 969, 699 cm–1. MS: m/z (%) = 310 (62) [M]+, 309 (100), 267 372.1624.
(6), 113 (2), 77 (5). HRMS (EI-TOF): calcd. for C22H18N2 [M]+
(3,4-Diphenylisoquinolin-1-yl)(phenyl)methanone
(4oa):
Flash
310.1470; found 310.1474.
chromatography on a silica gel column (petroleum ether/ethyl acet-
ate, 10:1) afforded a white solid; m.p. 129–130 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.24–8.22 (m, 1 H), 8.11–8.09 (m, 2 H),
1,8-Dimethyl-3,4-diphenylisoquinoline (4ia):[7g] Flash chromatog-
raphy on a silica gel column (petroleum ether/ethyl acetate, 20:1)
afforded a white solid. 1H NMR (400 MHz, CDCl3): δ = 7.50–7.48 7.74 (d, J = 8.0 Hz, 1 H), 7.63–7.54 (m, 3 H), 7.50–7.46 (m, 2 H),
(m, 1 H), 7.40–7.30 (m, 7 H), 7.21–7.15 (m, 5 H), 3.24 (s, 3 H), 7.42–7.34 (m, 5 H), 7.30–7.28 (m, 2 H), 7.16–7.13 (m, 3 H) ppm.
3.00 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.6, 148.5, 13C NMR (100 MHz, CDCl3): δ = 194.8, 155.8, 148.9, 140.1, 137.0,
140.8, 138.3, 138.1, 136.0, 131.5, 130.2, 130.1, 129.5, 129.2, 128.2,
127.6, 127.2, 127.1, 127.0, 125.1, 29.9, 26.0 ppm. MS: m/z (%) =
309 (63) [M]+, 308 (100), 294 (7), 252 (14), 77 (5).
136.9, 136.7, 133.7, 132.5, 131.2, 131.0, 130.7, 130.4, 128.5, 128.5,
127.9, 127.7, 127.7, 127.4, 126.3, 126.0, 125.1 ppm. IR: ν = 2925,
˜
2853, 1710, 1619, 1329, 1125, 1168, 968, 890, 699 cm–1. MS: m/z
(%) = 385 (12), 384 (12) [M]+, 299 (27), 298 (100), 105 (99), 77
(67). HRMS (EI-TOF): calcd. for C28H19NO [M]+ 385.1467; found
385.1468.
1-Methyl-3,4-diphenyl-5H-pyrido[4,3-b]indole
(4ja):[7e]
Flash
chromatography on a silica gel column (petroleum ether/ethyl acet-
1
ate, 5:1) afforded a white solid. H NMR (400 MHz, CDCl3): δ =
8.46 (s, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 7.47–7.24 (m, 10 H), 7.19– 2,3-Diphenyl-8,9-dihydro-7H-benzo[de]quinoline (4pa):[8] Flash
7.17 (m, 3 H), 3.13 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ chromatography on a silica gel column (petroleum ether/ethyl acet-
= 151.9, 151.4, 144.0, 139.9, 139.6, 135.9, 130.5, 130.3, 129.1, 127.6,
127.3, 126.3, 122.7, 122.5, 121.0, 117.1, 117.0, 111.0, 23.3 ppm.
ate, 20:1) afforded a white solid. 1H NMR (400 MHz, CDCl3): δ =
7.50–7.45 (m, 2 H), 7.36–7.27 (m, 6 H), 7.24–7.13 (m, 5 H), 3.38
MS: m/z (%) = 335 (22), 334 (90) [M]+, 333 (100), 318 (8), 291 (9), (t, J = 6.2 Hz, 2 H), 3.18 (t, J = 6.0 Hz, 2 H), 2.30–2.23 (m, 2
77 (3).
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.3, 149.5, 141.1,
138.6, 137.9, 136.3, 131.4, 130.3, 130.0, 129.1, 128.2, 127.6, 127.1,
126.9, 124.8, 123.9, 123.6, 34.8, 30.8, 23.5 ppm. MS: m/z (%) = 321
(52) [M]+, 320 (100), 304 (7), 77 (2).
4-Methyl-6,7-diphenylthieno[3,2-c]pyridine (4ka): Flash chromatog-
raphy on a silica gel column (petroleum ether/ethyl acetate, 20:1)
afforded a white solid; m.p. 147–149 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.50 (d, J = 5.6 Hz, 1 H), 7.44 (d, J = 5.6 Hz, 1 H),
7.44–7.43 (m, 2 H), 7.39–7.38 (m, 5 H), 7.19 (s, 3 H), 2.93 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.6, 150.0, 149.6,
1-Ethyl-3,4-diphenylisoquinoline (4ra):[7g] Flash chromatography on
a silica gel column (petroleum ether/ethyl acetate, 20:1) afforded a
1
white solid. H NMR (400 MHz, CDCl3): δ = 8.23–8.21 (m, 1 H),
140.2, 138.6, 133.8, 130.4, 129.8, 128.7, 127.79, 127.76, 127.7, 7.66–7.65 (m, 1 H), 7.56–7.55 (m, 2 H), 7.38–7.32 (m, 5 H), 7.23–
127.6, 127.3, 122.6, 22.9 ppm. IR: ν = 2921, 2853, 1669, 1548, 1416, 7.16 (m, 5 H), 3.43 (q, J = 7.2 Hz, 2 H), 1.53 (t, J = 7.2 Hz, 3
˜
1079, 1048, 968, 898, 699 cm–1. MS: m/z (%) = 302 (17), 301 (60) H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.3, 149.3, 141.2,
[M]+, 300 (100), 285 (4), 77 (7). HRMS (EI-TOF): calcd. for
C20H15NS [M]+ 301.0925; found 301.0924.
137.8, 136.4, 131.5, 130.4, 129.8, 129.0, 128.3, 127.6, 127.2, 126.9,
126.5, 126.5, 125.4, 125.2, 28.8, 14.0 ppm. MS: m/z (%) = 309 (62)
[M]+, 308 (100), 293 (10), 280 (10), 77 (14).
7-Methyl-4,5-diphenylthieno[2,3-c]pyridine
(4la):[7e]
Flash
chromatography on a silica gel column (petroleum ether/ethyl acet-
3,4-Diphenyl-1-propylisoquinoline (4sa):[7g] Flash chromatography
on a silica gel column (petroleum ether/ethyl acetate, 20:1) afforded
ate, 20:1) afforded a white solid. 1H NMR (400 MHz, CDCl3): δ =
7.60 (d, J = 5.2 Hz, 1 H), 7.36–7.34 (m, 2 H), 7.31–7.28 (m, 3 H), a white solid. 1H NMR (400 MHz, CDCl3): δ = 8.25–8.23 (m, 1
7.25–7.19 (m, 6 H), 2.90 (s, 3 H) ppm. 13C NMR (100 MHz, H), 7.67–7.65 (m, 1 H), 7.58–7.55 (m, 2 H), 7.38–7.32 (m, 5 H),
CDCl3): δ = 151.4, 151.0, 145.7, 140.5, 138.3, 134.3, 131.0, 130.6,
130.3, 128.3, 127.7, 127.2, 127.1, 124.3, 23.7 ppm. MS: m/z (%) =
302 (12), 301 (50) [M]+, 300 (100), 258 (11), 149 (10), 77 (12).
7.23–7.17 (m, 5 H), 3.39 (t, J = 7.6 Hz, 2 H), 2.06–1.96 (m, 2 H),
1.14 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
161.3, 149.3, 141.3, 137.8, 136.4, 131.4, 130.4, 129.7, 129.0, 128.2,
127.9, 127.6, 127.1, 126.9, 126.4, 125.6, 125.3, 37.7, 23.2, 14.5 ppm.
MS: m/z (%) = 324 (52), 323 (100) [M]+, 295 (10), 308 (44), 280
(20), 77 (8).
1,3,4-Triphenylisoquinoline (4ma):[7g] Flash chromatography on a
silica gel column (petroleum ether/ethyl acetate, 20:1) afforded a
1
white solid. H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 8.4 Hz,
1 H), 7.82 (d, J = 7.2 Hz, 2 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.59–
1-Methyl-3,4-di-p-tolylisoquinoline (4ab):[7g] Flash chromatography
7.47 (m, 5 H), 7.44–7.41 (m, 2 H), 7.39–7.34 (m, 3 H), 7.30–7.28
on a silica gel column (petroleum ether/ethyl acetate, 20:1) afforded
(m, 2 H), 7.19–7.15 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): a white solid. 1H NMR (400 MHz, CDCl3): δ = 8.16 (dd, J =
δ = 159.9, 149.7, 141.0, 139.9, 137.6, 137.0, 131.4, 130.5, 130.3,
130.0, 129.8, 128.6, 128.4, 127.6, 127.5, 127.4, 127.1, 126.7, 126.1,
125.5 ppm. MS: m/z (%) = 358 (25), 357 (88) [M]+, 356 (100), 277
(21), 182 (19), 77 (31).
6.4 Hz, J = 3.2 Hz, 1 H), 7.66–7.64 (m, 1 H), 7.57–7.53 (m, 2 H),
7.28 (d, J = 8.0 Hz, 2 H), 7.17–7.10 (m, 4 H), 7.00 (d, J = 7.6 Hz,
2 H), 3.05 (s, 3 H), 2.38 (s, 3 H), 2.27 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 157.4, 149.4, 138.2, 136.6, 136.5, 136.3,
134.7, 131.2, 130.2, 129.8, 129.0, 128.9, 128.4, 126.3, 126.1, 125.5,
114.0, 22.7, 21.3, 21.2 ppm. MS: m/z (%) = 324 (22), 323 (91)
[M]+, 322 (100), 308 (5), 91 (3).
2-(3,4-Diphenylisoquinolin-1-yl)aniline (4na): Flash chromatography
on a silica gel column (petroleum ether/ethyl acetate, 20:1) afforded
1
a white solid; m.p. 196–198 °C. H NMR (400 MHz, CDCl3): δ =
8.12 (d, J = 8.2 Hz, 1 H), 7.71 (d, J = 8.2 Hz, 2 H), 7.59–7.55 (m, 3,4-Bis(4-methoxyphenyl)-1-methylisoquinoline
1 H), 7.51–7.47 (m, 1 H), 7.41–7.34 (m, 6 H), 7.30–7.22 (m, 3 H), chromatography on a silica gel column (petroleum ether/ethyl acet-
7.19–7.13 (m, 2 H), 6.91–6.86 (m, 2 H), 4.39 (s, 2 H) ppm. 13C ate, 5:1) afforded a white solid. H NMR (400 MHz, CDCl3): δ =
(4ac):[7g]
Flash
1
NMR (100 MHz, CDCl3): δ = 158.8, 149.4, 145.8, 140.8, 137.5,
137.4, 132.0, 131.4, 130.4, 130.3, 129.9, 129.7, 128.4, 127.8, 127.6,
8.18–8.15 (m, 1 H), 7.68–7.66 (m, 1 H), 7.59–7.52 (m, 2 H), 7.34–
7.31 (m, 2 H), 7.15–7.12 (m, 2 H), 6.92–6.89 (m, 2 H), 6.77–6.73
(m, 2 H), 3.84 (s, 3 H), 3.76 (s, 3 H), 3.06 (s, 3 H) ppm. 13C NMR
127.4, 127.1, 126.7, 126.0, 124.0, 117.9, 117.1 ppm. IR: ν = 3372,
˜
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7

Job/Unit: O43085
/KAP1
Date: 29-10-14 17:25:56
Pages: 10
J. Zhang, H. Qian, Z. Liu, C. Xiong, Y. Zhang
FULL PAPER
106, 4644; e) K. Godula, D. Sames, Science 2006, 312, 67; f) T.
Uto, M. Shimizu, K. Ueura, H. Tsurugi, T. Satoh, M. Miura, J.
Org. Chem. 2008, 73, 298; g) X. Chen, K. M. Engle, D.-H.
Wang, J.-Q. Yu, Angew. Chem. Int. Ed. 2009, 48, 5094; Angew.
Chem. 2009, 121, 5196; h) L. Ackermann, R. Vicente, A. R.
Kapdi, Angew. Chem. Int. Ed. 2009, 48, 9792; Angew. Chem.
2009, 121, 9976; i) D. A. Colby, R. G. Bergman, J. A. Ellman,
Chem. Rev. 2010, 110, 624; j) C.-L. Sun, B.-J. Li, Z.-J. Shi,
Chem. Commun. 2010, 110, 1147; k) G.-Y. Song, X. Gong, X.-
W. Li, J. Org. Chem. 2011, 76, 7583; l) C. S. Yeung, V. M.
Dong, Chem. Rev. 2011, 111, 1215; m) D. P. Curran, A. Solov-
yev, M. Makhlouf, L. Fensterbank, M. Malacria, E. Lacôte,
Angew. Chem. Int. Ed. 2011, 50, 10294; n) X.-F. Wu, H. Neum-
ann, M. Beller, Chem. Rev. 2012, 113, 1.
(100 MHz, CDCl3): δ = 158.7, 158.6, 157.6, 149.1, 136.5, 133.6,
132.4, 131.5, 129.9, 129.8, 128.4, 126.3, 126.2, 126.0, 125.5, 113.8,
113.2, 55.3, 55.2, 22.7 ppm. MS: m/z (%) = 356 (15), 355 (68)
[M]+, 354 (100), 268 (13).
3,4-Bis(4-chlorophenyl)-1-methylisoquinoline
(4ad):[7g]
Flash
chromatography on a silica gel column (petroleum ether/ethyl acet-
ate, 20:1) afforded a white solid. 1H NMR (400 MHz, CDCl3): δ =
8.20–8.17 (m, 1 H), 7.62–7.58 (m, 3 H), 7.36–7.28 (m, 4 H), 7.20–
7.13 (m, 4 H), 3.05 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 158.4, 148.2, 139.2, 135.8, 135.7, 133.3, 133.3, 132.7, 131.6, 130.4,
128.8, 128.1, 128.0, 127.0, 126.3, 125.9, 125.7, 22.7 ppm. MS: m/z
(%) = 365 (45), 364 (85), 363 (62) [M]+, 362 (100), 327 (16), 291
(12), 277 (8), 111 (26).
[2]
a) M. Croisy-Delcey, A. Croisy, D. Carrez, C. Huel, A. Chia-
roni, P. Ducrot, E. Bisagni, L. Jin, G. Leclercq, Bioorg. Med.
Chem. 2000, 8, 2629; b) J. E. van Muilwijk-Koezen, H. Timm-
3,4-Bis(4-fluorophenyl)-1-methylisoquinoline
(4ae):[7g]
Flash
chromatography on a silica gel column (petroleum ether/ethyl acet-
ate, 20:1) afforded a white solid. 1H NMR (400 MHz, CDCl3): δ =
8.21–8.19 (m, 1 H), 7.62–7.59 (m, 3 H), 7.34–7.30 (m, 2 H), 7.19–
7.16 (m, 2 H), 7.08–7.04 (m, 2 H), 6.93–6.88 (m, 2 H), 3.06 (s, 3
erman,
H.
van der Goot,
W. M. P. B.
Menge,
J.
Frijtag von Drabbe Künzel, M. de Groote, A. P. IJzerman, J.
Med. Chem. 2000, 43, 2227; c) T. Eicher, S. Hauptmann, A.
Speicher, The Chemistry of Heterocycles: Structure, Reactions,
Syntheses, and Applications, 2nd ed., Wiley-VCH, Weinheim,
Germany, 2003; d) B. Reux, T. Nevalainen, K. H. Raitio,
A. M. P. Koskinen, Bioorg. Med. Chem. 2009, 17, 4441; e) J. A.
Joule, K. Mills, Heterocyclic Chemistry, 5th ed., Wiley, Chiches-
ter, UK, 2010; f) Y. Chen, M. Sajjad, Y. Wang, C. Batt, H. A.
Nabi, R. K. Pandey, ACS Med. Chem. Lett. 2011, 2, 136.
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.1 (JC,F
245.0 Hz), 162.0 (JC,F = 246.0 Hz), 158.1, 148.6, 136.9 (JC,F
=
=
4.1 Hz), 136.0, 133.3 (JC,F = 3.9 Hz), 132.9 (JC,F = 8.1 Hz), 132.0
(JC,F = 8.2 Hz), 130.2, 128.2, 126.8, 126.2, 125.9, 125.7, 115.5 (JC,F
= 20.4 Hz), 114.7 (JC,F = 20.0 Hz), 22.7 ppm. MS: m/z (%) = 332
(29), 331 (100) [M]+, 330 (100), 288 (35), 97 (7).
[3]
[4]
a) N. W. Alcock, J. M. Brown, G. I. Hulmes, Tetrahedron:
Asymmetry 1993, 4, 743; b) C. W. Lim, O. Tissot, A. Mattison,
M. W. Hooper, J. M. Brown, A. R. Cowley, D. I. Hulmes, A. J.
Blacker, Org. Process Res. Dev. 2003, 7, 379; c) B. A. Sweet-
man, H. Muller-Bunz, P. J. Guiry, Tetrahedron Lett. 2005, 46,
4643; d) F. Durola, J.-P. Sauvage, O. S. Wenger, Chem. Com-
mun. 2006, 171.
a) A. Bischler, B. Napieralski, Ber. Dtsch. Chem. Ges. 1893, 26,
1903; b) A. Pictet, T. Spengler, Ber. Dtsch. Chem. Ges. 1911,
44, 2030; c) C. Pomeranz, Monatsh. Chem. 1893, 14, 116; d) P.
Fritsch, Ber. Dtsch. Chem. Ges. 1893, 26, 419; e) G. M.
Coppola, H. F. Schuster (Eds.), The Chemistry of Hetrocyclic
Compounds: Isoquinolines, John Wiley & Sons, New York,
1981, vol. 38, part 3; f) A. R. Katritzky, O. M. Cohn, C. W.
Rees (Eds.), Comprehensive Organic Functional Group Transfor-
mations, 1st ed., Pergamon, Chichester, UK, 1991, vol. 2, p.
328.
a) K. R. Roesch, R. C. Larock, J. Org. Chem. 1998, 63, 5306;
b) K. R. Roesch, R. C. Larock, Org. Lett. 1999, 1, 553; c) G. X.
Dai, R. C. Larock, Org. Lett. 2001, 3, 4035; d) R. P. Korivi,
C.-H. Cheng, Org. Lett. 2005, 7, 5179; e) R. P. Korivi, Y. C.
Wu, C. H. Cheng, Chem. Eur. J. 2009, 15, 10727; f) W.-C. Shih,
C. C. Teng, K. Parthasarathy, C.-H. Cheng, Chem. Asian J.
2012, 7, 306; g) Y. N. Niu, Z. Y. Yan, G. L. Gao, H. L. Wang,
X. Z. Shu, K. G. Ji, Y. M. Liang, J. Org. Chem. 2009, 74, 2893.
For selected papers, see: a) T. W. Lyons, M. S. Sanford, Chem.
Rev. 2010, 110, 1147; b) T. Satoh, M. Miura, Chem. Eur. J.
2010, 16, 11212; c) J. Wencel-Delord, T. Droge, F. Glorius,
Chem. Soc. Rev. 2011, 40, 4740; d) K. M. Engle, T.-S. Mei, M.
Wasa, J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788; e) C. Zhu, R.
Wang, J. R. Falck, Chem. Asian J. 2012, 7, 1502; f) D. A. Colby,
A. S. Tsai, R. G. Bergman, J. A. Ellman, Acc. Chem. Res. 2012,
45, 814; g) B.-J. Li, H.-Y. Wang, Q.-L. Zhu, Z.-J. Shi, Angew.
Chem. Int. Ed. 2012, 51, 3948; h) G.-Y. Song, F. Wang, X.-W.
Li, Chem. Soc. Rev. 2012, 41, 3651; i) L. Wan, N. Dastbaravar-
deh, G. Li, J. Q. Yu, J. Am. Chem. Soc. 2013, 135, 18056; j)
P. S. Thuy-Boun, G. Villa, D. Dang, P. Richardson, S. Su, J. Q.
Yu, J. Am. Chem. Soc. 2013, 135, 17508; k) Z. Dong, G. Dong,
J. Am. Chem. Soc. 2013, 135, 18350; l) S. Lee, H. Lee, K. L.
Tan, J. Am. Chem. Soc. 2013, 135, 18778; m) W. Dong, L.
Wang, K. Parthasarathy, F. Pan, C. Bolm, Angew. Chem. Int.
Ed. 2013, 52, 11573; n) J. R. Huckins, E. A. Bercot, O. R. Thiel,
T. L. Hwang, M. M. Bio, J. Am. Chem. Soc. 2013, 135, 14492;
1-Methyl-3,4-dipropylisoquinoline (4af):[7g] Flash chromatography
on a silica gel column (petroleum ether/ethyl acetate, 20:1) afforded
a white solid. 1H NMR (400 MHz, CDCl3): δ = 8.09–8.07 (m, 1
H), 7.96 (d, J = 8.8 Hz, 1 H), 7.67–7.63 (m, 1 H), 7.51–7.47 (m, 1
H), 2.99–2.90 (m, 7 H), 1.82–1.73 (m, 2 H), 1.71–1.62 (m, 2 H),
1.09 (t, J = 7.2 Hz, 3 H), 1.04 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 155.7, 151.3, 135.5, 129.7, 126.6, 126.2,
126.1, 125.4, 123.6, 37.0, 27.3, 24.2, 23.9, 21.7, 14.6, 14.4 ppm. MS:
m/z (%) = 227 (40) [M]+, 226 (38), 213 (18), 212 (100), 199 (31),
198 (80), 184 (39), 43 (11).
4-Ethyl-1-methyl-3-phenylisoquinoline (4ag):[7g] Flash chromatog-
raphy on a silica gel column (petroleum ether/ethyl acetate, 20:1)
1
afforded a white solid. H NMR (400 MHz, CDCl3): δ = 8.16 (d,
J = 8.4 Hz, 1 H), 8.07 (d, J = 8.4 Hz, 1 H), 7.73 (t, J = 7.6 Hz, 1
H), 7.59 (t, J = 8.0 Hz, 1 H), 7.52–7.44 (m, 4 H), 7.41–7.37 (m, 1
H), 3.03–2.97 (m, 5 H), 1.26 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 155.9, 150.7, 141.9, 135.2, 129.9, 129.2,
128.6, 128.2, 127.4, 126.7, 126.4, 126.2, 124.2, 22.6, 21.7, 15.8 ppm.
MS: m/z (%) = 248 (11), 247 (56) [M]+, 246 (100), 232 (17), 231
(18), 115 (14), 77 (15).
[5]
[6]
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra for the isolated prod-
ucts and X-ray structure of 4da.
Acknowledgments
The authors gratefully acknowledge the National Basic Research
Program of China (grant number 2011CB936003), the National
Natural Science Foundation of China (NSFC) (grant number
21272205), and the Program for Zhejiang Leading Team of S&T
Innovation for their financial support.
[1] For selected examples, see: a) K. R. Roesch, R. C. Larock, J.
Org. Chem. 2002, 67, 86; b) A. Deiters, S. F. Martin, Chem.
Rev. 2004, 104, 2199; c) S. Bräse, C. Gil, K. Knepper, V. Zim-
mermann, Angew. Chem. Int. Ed. 2005, 44, 5188; Angew. Chem.
2005, 117, 5320; d) G. Zeni, R. C. Larock, Chem. Rev. 2006,
8
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Access to Isoquinolines in Aqueous Medium
o) L. Zhou, W. Lu, Org. Lett. 2014, 16, 508; p) B. Wang, C.
Shen, J. Yao, H. Yin, Y. Zhang, Org. Lett. 2014, 16, 46.
[7] a) N. Guimond, K. Fagnou, J. Am. Chem. Soc. 2009, 131,
12050; b) T. Fukutani, N. Umeda, K. Hirano, T. Satoh, M.
Miura, Chem. Commun. 2009, 5141; c) K. Morimoto, K. Hir-
ano, T. Satoh, M. Miura, Chem. Lett. 2011, 40, 600; d) X.
Zhang, D. Chen, M. Zhao, A. Jia, X. Li, Adv. Synth. Catal.
2011, 353, 719; e) L. Zheng, J. Ju, Y. Bin, R. Hua, J. Org. Chem.
2012, 77, 5794; f) D.-S. Kim, J.-W. Park, C.-H. Jun, Adv. Synth.
Catal. 2013, 355, 2667; g) S.-C. Chuang, P. Gandeepan, C.-H.
Cheng, Org. Lett. 2013, 15, 5750; h) H. Lee, Y.-K. Sim, J.-W.
Park, C.-H. Jun, Chem. Eur. J. 2014, 20, 323.
[8] P. C. Too, Y.-F. Wang, S. Chiba, Org. Lett. 2010, 12, 5688.
[9] a) K. Parthasarathy, M. Jeganmohan, C.-H. Cheng, Org. Lett.
2008, 10, 325; b) X. Zhang, D. Chen, M. Zhao, J. Zhao, A.
Jia, X. Li, Adv. Synth. Catal. 2011, 353, 719.
[10] Q.-R. Zhang, J.-R. Huang, W. Zhang, L. Dong, Org. Lett.
2014, DOI: 10.1021/ol500345n.
[11] a) S. S. Stahl, Angew. Chem. Int. Ed. 2004, 43, 3400; Angew.
Chem. 2004, 116, 3480; b) T. Punniyamurthy, S. Velusamy, J.
Iqbal, Chem. Rev. 2005, 105, 2329; c) J. Piera, J.-E. Bäckvall,
Angew. Chem. Int. Ed. 2008, 47, 3506; Angew. Chem. 2008, 120,
3558; d) K. M. Gligorich, M. S. Sigman, Chem. Commun.
2009, 3854; e) A. N. Campbell, S. S. Stahl, Acc. Chem. Res.
2012, 45, 851; f) W. Wu, H. Jiang, Acc. Chem. Res. 2012, 45,
1736; g) Z. Shi, C. Zhang, C. Tang, N. Jiao, Chem. Soc. Rev.
2012, 41, 3381.
P. Xie, H. Huang, Adv. Synth. Catal. 2013, 355, 1315; p) Y. H.
Xu, T. He, Q. C. Zhang, T. P. Loh, Chem. Commun. 2014, 50,
2784.
[13]
[14]
a) G. Zhang, L. Yang, Y. Wang, Y. Xie, H. Huang, J. Am.
Chem. Soc. 2013, 135, 8850; b) G. Zhang, H. Yu, G. Qin, H.
Huang, Chem. Commun. 2014, 50, 4331.
For a general introduction to organic reactions in water, see:
a) C. J. Li, Chem. Rev. 2005, 105, 3095; b) P. A. Grieco (Ed.),
Organic Synthesis in: Water, Blackie Academic and Profes-
sional, London, 1998; c) C. J. Li, T. H. Chan, Organic Reac-
tions in Aqueous Media, Wiley, New York, 1997; d) C. J. Li,
Chem. Rev. 1993, 93, 2023; e) J.-P. Genet, M. Savignac, J. Or-
ganomet. Chem. 1999, 576, 305.
a) C. I. Herreias, X. Yao, Z. Li, C.-J. Li, Chem. Rev. 2007, 107,
2546; b) C.-J. Li, Acc. Chem. Res. 2009, 42, 335; c) C.-J. Li,
Acc. Chem. Res. 2010, 43, 581; d) N. Uhlig, C.-J. Li, Chem.
Sci. 2011, 2, 1241.
a) L. Adrio, A. J. Gimeno, C. Vicent, Chem. Commun. 2013,
49, 8320; b) X.-Y. Shi, C.-J. Li, Org. Lett. 2013, 15, 1476.
[15]
[16]
[17]
a) P. B. Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev.
2012, 112, 5879; b) B. Li, P. H. Dixneuf, Chem. Soc. Rev. 2013,
42, 5744.
[18] a) R. Shintani, K. Okamoto, T. Hayashi, J. Am. Chem. Soc.
2005, 127, 2872; b) R. Shintani, K. Yashio, T. Nakamura, K.
Okamoto, T. Shimada, T. Hayashi, J. Am. Chem. Soc. 2006,
128, 2772.
[12] a) B. A. Steinhoff, I. A. Guzei, S. S. Stahl, J. Am. Chem. Soc.
2004, 126, 11268; b) G. Liu, G. Yin, L. Wu, Angew. Chem. Int.
Ed. 2008, 47, 4733; Angew. Chem. 2008, 120, 4811; c) M. M.
[19] a) S. Ding, Z. Shi, Y. Cui, N. Jiao, Org. Lett. 2010, 12, 1540;
b) K. Morimoto, K. Hirano, T. Satoh, M. Miura, Org. Lett.
2010, 12, 2068.
Konnick, S. S. Stahl, J. Am. Chem. Soc. 2008, 130, 5753; d) S. [20] CCDC-981507 (for 4da) contains the supplementary crystallo-
Ueda, H. Nagasawa, Angew. Chem. Int. Ed. 2008, 47, 6411;
Angew. Chem. 2008, 120, 6511; e) O. Baslea, C. Li, Chem. Com-
mun. 2009, 4124; f) Y.-H. Zhang, J.-Q. Yu, J. Am. Chem. Soc.
2009, 131, 14654; g) H. Wang, Y. Wang, C. Peng, J. Zhang, Q.
Zhu, J. Am. Chem. Soc. 2010, 132, 13217; h) J.-S. Tian, T.-P.
Loh, Angew. Chem. Int. Ed. 2010, 49, 8417; i) K. M. Engle, D.-
H. Wang, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 14137; j)
A. N. Campbell, E. B. Meyer, S. S. Stahl, Chem. Commun.
2011, 47, 10257; k) S. Guo, B. Qian, Y. Xie, C. Xia, H. Huang,
Org. Lett. 2011, 13, 522; l) Y. Wei, I. Deb, N. Yoshikai, J. Am.
Chem. Soc. 2012, 134, 9098; m) X.-F. Xia, N. Wang, L.-L.
Zhang, X.-R. Song, X.-Y. Liu, Y.-M. Liang, J. Org. Chem.
2012, 77, 9163; n) G. Zhang, Y. Ma, S. Wang, Y. Zhang, R.
Wang, J. Am. Chem. Soc. 2012, 134, 12334; o) Y. Xie, B. Qian,
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[21] X. Tan, B. Liu, X. Li, B. Li, S. Xu, H. Song, B. Wang, J. Am.
Chem. Soc. 2012, 134, 16163.
[22] For C–H bond functionalizations that explore imine as a di-
recting group (DG), see: a) T. Katagiri, T. Mukai, T. Satoh, K.
Hirano, M. Miura, Chem. Lett. 2009, 38, 118; b) T. Fukutani,
N. Umeda, K. Hirano, T. Satoh, M. Miura, Chem. Commun.
2009, 34, 5141; c) Z. M. Sun, S. P. Chen, P. Zhao, Chem. Eur.
J. 2010, 16, 2619; d) D. N. Tran, N. Cramer, Angew. Chem. Int.
Ed. 2013, 52, 10630.
Received: August 15, 2014
Published Online: ᭿
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9

Job/Unit: O43085
/KAP1
Date: 29-10-14 17:25:56
Pages: 10
J. Zhang, H. Qian, Z. Liu, C. Xiong, Y. Zhang
FULL PAPER
Nitrogen Heterocycles
J. Zhang, H. Qian, Z. Liu, C. Xiong,*
Y. Zhang* ....................................... 1–10
Rhodium(III)-Catalyzed One-Pot Access
to Isoquinolines and Heterocycle-Fused
Pyridines in Aqueous Medium through C–
H Cleavage
An efficient RhIII-catalyzed ortho-C–H
bond activation for the synthesis of substi-
tuted isoquinolines and heterocycle-fused
pyridines in aqueous medium has been de-
veloped. This method involves the in situ
generation of ketimines from ketones and
ammonium acetate and subsequent oxidat-
ive C–H bond activation/annulation of the
ketimines with alkynes to form the C–C/C–
N bonds spontaneously.
Keywords: Synthetic methods / C–H acti-
vation / Nitrogen heterocycles / Annu-
lation / Rhodium / Ketones / Alkynes
10
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