Cu-Catalyzed alkynylation-cyclization cascade for the construction of the pyrazolo[5,1-a]isoquinoline skeleton

Article abstract of DOI:10.1039/c3ra40270c

A Cu-catalyzed Sonogashira-type coupling of 3-(2-bromophenyl)pyrazoles with terminal alkynes combined with a subsequent electrophilic cyclization in the same pot was developed to afford pyrazolo[5,1-a]isoquinolines. The transformation proceeds without the necessity of using Pd or ligands, while an Ag additive is beneficial. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra40270c

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Cu-Catalyzed alkynylation–cyclization cascade for the
construction of the pyrazolo[5,1-a]isoquinoline
skeleton3
Cite this: RSC Advances, 2013, 3,
10434
Yanfang Yang, Hailong Ren, Dongyang Wang, Feng Shi* and Chunrui Wu*
Received 17th January 2013,
Accepted 10th April 2013
A Cu-catalyzed Sonogashira-type coupling of 3-(2-bromophenyl)pyrazoles with terminal alkynes combined
with a subsequent electrophilic cyclization in the same pot was developed to afford pyrazolo[5,1-
a]isoquinolines. The transformation proceeds without the necessity of using Pd or ligands, while an Ag
additive is beneficial.
DOI: 10.1039/c3ra40270c
www.rsc.org/advances
Despite the success above, this strategy has limitations.
Most existing protocols have to work with aryl/vinyl iodides
Introduction
The Sonogashira coupling1,2 has been recognized as one of the
most effective methods to construct C(sp2)–C(sp) bonds.
Traditionally, the Sonogashira coupling was co-catalyzed both
by Pd and Cu species, and was performed with excesses of
amines typically used as co-solvents. Recently, both Pd3 and
Cu4,5 have proved effective as the sole catalyst for this
transformation. The Pd-independent Sonogashira coupling
has certain advantages, including lowered cost, no Pd residue,
and the avoidance of environmentally hazardous amines,
which make it an attractive alternative to the conventional
protocol.
Since its discovery,4a several attempts have been made to
strategically combine this Cu-catalyzed alkynylation with a
subsequent cyclization to construct an additional ring in a
single operation, providing that there is an internal nucleo-
phile at a suitable position in the substrate. Such a method
exploits the ability of the same Cu catalyst to act as a soft Lewis
acid during the cyclization step.6 In this regard,
Venkatarman,7 Ma,8 Cacchi,9 and their co-workers have
developed Cu-catalyzed alkynylation–cyclization cascades to
synthesize indoles and benzofurans. Ma10 and co-workers have
additionally developed tandem reactions to synthesize iso-
coumarins, furans, and 3-alkylideneisoindolinones. The
Thibonnet–Abarbri group11 has also been successful in the
construction of several other heterocyclic scaffolds. To date,
the scope of the internal nucleophiles that can be employed in
this cascade covers alcohols, phenols, amides, and acids.
and perform unsatisfactorily for the corresponding bromide-
s4a,7a which are cheaper, more accessible, and easier to store.
In addition, the scope of the internal nucleophile is yet to be
broadened. Herein, we wish to report a one-pot Cu-catalyzed
alkynylation–cyclization reaction of 3-(2-bromophenyl)pyra-
zoles (1) with terminal alkynes to afford pyrazolo[5,1-a]iso-
quinolines (3)12 under Pd- and ligand-free conditions
(Scheme 1). We are using a heterocyclic nitrogen as the
nucleophile for the subsequent cyclization, which not only
broadens the scope of nucleophiles, but may also serve as a
potential coordinator for activating the C–Br bond during the
alkynylation stage, thus allowing for the chemistry to operate
on bromides in addition to iodides.
Results and discussion
Development of reaction conditions
We commenced our work optimizing the model reaction of
substrate 1a with phenylacetylene 2a (Table 1). Under the
Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province,
Henan University, Jinming Campus, Kaifeng, Henan 475004, China PR.
E-mail: fshi@henu.edu.cn; cwu@henu.edu.cn; Fax: +(86)-378-2864665;
Tel: +(86)-378-2864665
Electronic supplementary information (ESI) available: additional experimental
3
Scheme 1 Cu-catalyzed alkynylation–cyclization cascade for the construction of
pyrazolo[5,1-a]isoquinolines.
procedures and characterization data, as well as copies of NMR spectra for all
products. See DOI: 10.1039/c3ra40270c
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Table 1 Optimization of reaction conditionsa,b
entry
cat.
base
solvent/mL
yieldc (%)
entry
cat.
base
solvent/mL
yieldc (%)
1
2
3
4
5
6
7
8
9
10
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
KOAc
DMF/2.0
DMF/2.0
DMF/2.0
DMF/2.0
DMF/2.0
Tol/2.0
Dioxane/2.0
DMSO/2.0
DMSO/0.6
DMAc/0.6
trace
63
25
trace
21
trace
trace
66
11
12
13
14
15
16
17
18
19
20
CuI
CuBr
CuBr2
CuCl
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NMP/0.6
NMP/0.6
NMP/0.6
NMP/0.6
NMP/0.6
NMP/0.6
NMP/0.6
NMP/0.6
NMP/0.6
NMP/0.6
75
78
80
84
68
61
61
73
46
56
K2CO3
Cs2CO3
2,6-lutidine
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
CuCl2
CuOTf
Cu(OTf)2
Cu(OAc)2
CuBr-phen
CuBr-dtbpy
67
74
a
The reaction was carried out on a 0.3 mmol scale in a sealed vial under N2. DMAc = N,N-dimethylacetamide; NMP = N-methylpyrrolidinone;
phen = 1,10-phenanthroline; dtbpy = 4,49-di-tert-butyl-2,29-bipyridyl. Under all successful conditions a small quantity of another isomeric
product was observed. Isolated yield.
b
c
catalysis of 5 mol% of CuI, K2CO3 appeared to be the optimal
base for the transformation in DMF (entries 1–5). Among
different solvents, non-coordinating ones such as toluene and
dioxane did not effect the reaction (entries 6 and 7). DMSO
proved comparable to DMF (entries 8 and 9), and the best
yields were obtained in DMAc or NMP (entries 10 and 11).
Besides CuI, many other Cu salts were also catalytically active
(entries 12–18). CuCl, CuBr, and CuBr2 were the best among
them (entries 12–14),13 but CuO and Cu2O were inactive (not
shown). A control experiment using a Pd catalyst without Cu
under otherwise identical conditions afforded no more than
trace amounts of product, and standard Sonogashira condi-
tions (cat. Pd(PPh3)2–CuI, Et3N–DMF at 100 uC) resulted in a
suppressed cyclization (ca. 10% yield of 3aa) despite a
successful cross-coupling (ca. 40% yield of the simple
alkynylated intermediate). Although we may not completely
rule out the possible synergistic effects of trace quantities of
Pd,14 side-by-side reactions suggest that the yield of 3aa does
not change upon artificial addition of ppm levels of Pd.
Under all conditions, no ligand or amine was needed for the
transformation, and somewhat surprisingly, the addition of
1,10-phenanthroline or bipyridyl ligand decreased the yield
(entries 19 and 20). Last but not least, the 6-endo-dig
cyclization was the preferred mode of cyclization under all
conditions described above, and only small quantities (,10%)
of what appeared to be the 5-exo-dig cyclization product were
obtained.
could not be utilized in this reaction (entry 7), but use of a
silylacetylene delivered a high yield with in situ desilylation
(entry 8). The preparation of this type of product may not be
straightforward using existing methods,12 which makes our
chemistry complementary in this respect.
The scope of 3-(2-bromoaryl)pyrazoles (1) was studied next
(Table 3). A variety of substitutions on the benzene ring (R1)
could be tolerated (entries 1–4). While the yields remained
high for most substitutions, a methoxy group in the para
position to the bromide (substrate 1c, entry 2) lowered the
yield, indicative of a modest detrimental effect of electron-
donating groups. For this type of substrate, CuBr proved to be
a better catalyst. A pyridine-based substrate 1f was also
transformed smoothly (entry 5). The 5-position of the pyrazole
(R3) could accommodate a variety of substitutions, including
aryl (entries 6 and 7), heteroaryl (entry 8), alkyl (entry 9), and
ester (entry 10) groups. Specifically, a remote bromide in
substrate 1h remained intact (entry 7), highlighting a potential
chemoselectivity.
Unfortunately, substitution at the 4-position of the pyrazole
(R2) caused a lower yield together with another isomeric
fraction, presumably a 5-exo cyclization product (entry 11).15
This problem was not as significant when the R2 and R3
groups were tethered into a ring (entry 12). Further optimiza-
tion of these reactions revealed that these low yields could be
improved by the addition of an Ag salt. Thus, the yield of 3la
was improved from 24% to 46% (entry 11) by adding 1 equiv.
of AgOTf, and the yield of 1m was increased from 43% to 56%
(entry 12). This Ag effect was more pronounced in the reaction
of the indazole derivative 1n (Scheme 2). Thus, compared to
the failure using a Cu catalyst alone (,5% yield for CuBr,
,10% yield for CuCl), addition of AgOTf, preferably in
substoichiometric or stoichiometric quantities, significantly
increased the yield. Although AgOTf has been known to
catalyze Sonogashira-type coupling reactions,16 it was inactive
Scope and limitation
The scope of the reaction was first tested against a range of
alkynes (Table 2). As expected, the reaction worked well with
aryl- and heteroarylacetylenes (entries 1–3). Pleasingly, a vinyl
acetylene (2e, entry 4) and two alkylacetylenes (2f and 2g,
entries 5 and 6) could also be employed. Even the presence of a
free hydroxyl group (entry 6) did not lower the yield. Propiolate
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Table 2 Scope of alkynesa
Entry
1
R4
3
yieldb (%)
81
entry
5
R4
3
yieldb (%)
59
4-MeC6H4
(2b)
n-pentyl
(2f)
2
4-BrC6H4
(2c)
61
6
CH2CH2OH
(2g)
73
3
4
3-thiophenyl
(2d)
80
7
8
CO2Et
(2h)
not observed
cyclohexenyl
(2e)
46c
TIPS
(2i)
92d
a
b
c
The reaction was carried out on a 0.3–0.5 mmol scale in 0.6–1.2 mL of NMP in a sealed vial under N2. Isolated yield. Reaction for 2 d.
Reaction was performed with CuBr instead of CuCl for 30 h.
d
in our transformation in the absence of Cu. For this reason, Ag
(Scheme 4). These data indicate that the cyclization described
in our chemistry is rather a base-promoted process. The
involvement of Cu as a soft Lewis acid was not required (let
alone Ag). The presumed carbanion resulting from the
cyclization might be much more easily protonated than
iodinated. Thus, going back to Ag as an additive, it appears
clear that its beneficial role lies at the cross-coupling stage, not
the cyclization stage. Surely, studying this Ag effect in a
broader picture of Cu-catalyzed alkynylation should be
encouraged, which may help to widen the scope of the current
protocols.
appears to have an enhancing role in the catalytic effect of Cu.
The mechanistic rationale, particularly the reason for the need
for stoichiometric quantities, remains unclear.
In a vain attempt to incorporate an iodine atom at the
6-position of the pyrazolo[5,1-a]isoquinolines,17 we performed
the reaction in the presence of stoichiometric amounts of NIS
(Scheme 3) or I2. The failure of these reactions under various
conditions lead us to the hypothesis that the cyclization step
after the alkynylation might be so facile that the assumed ‘‘I+’’
could not get involved. To probe this possibility, we prepared
the presumed intermediate 5a and observed that the cycliza-
tion of 5a to 3aa was very facile. Even at 80 uC, conversion of 5a
to 3aa was complete within 20 min without Cu. In sharp
contrast, only a trace amount of 3aa was observed in the
absence of K2CO3, whether or not a Cu catalyst was present.
Similarly, despite a lower yield, the cyclization of 5b to 3na
could be effected without Cu as well, but not without K2CO3
Conclusions
In summary, we presented
a Cu-catalyzed alkynylation–
cyclization approach that transforms 3-(2-bromophenyl)pyra-
zoles to pyrazolo[5,1-a]isoquinolines. The reaction expands the
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Table 3 Scope of 3-(2-bromoaryl)pyrazolesa
entry
1
1
3
yieldb (%)
86
entry
7
1
3
yieldb (%)
78
2
3
66c
8
9
72
77
45c
4
5
88
59
10
11
63cd
24ce (46c)
6
75
12
43c (56c)
a
b
The reaction was carried out on a 0.2–0.5 mmol scale in 0.5–1.2 mL of NMP in a sealed vial under N2. Isolated yield. Yields in parentheses
c
d
were obtained with 1 equiv. of AgOTf. The reaction was performed with CuBr instead of CuCl. The reaction was carried out for 30 h.
e
Another 15% of what appeared to be the 5-exo cyclization product (32% with the addition of 1 equiv. of AgOTf) was also isolated. For its
characterization, see ESI .
3
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Scheme 2 Reaction with an indazole-derived substrate.
scope of the current Cu-catalyzed alkynylation reactions. In
addition, an Ag effect was observed that appears to facilitate
the Cu-catalyzed alkynylation protocol.
Scheme 4 Testing the involvement of Cu in the cyclization step.
Experimental section
Materials and methods
The aqueous phase was extracted with EtOAc, and the
combined extracts were dried over MgSO4, filtered, and
evaporated. The residue was purified by column chromato-
graphy (PE/DCM = 3/1) to afford 81 mg (84%) of the desired
product 3aa as a slightly yellow solid; mp 95–96 uC (lit20,21 142–
143 uC). 1H NMR (CDCl3, 400 MHz) d 8.19–8.14 (m, 1 H), 8.08–
7.99 (m, 4 H), 7.78–7.73 (m, 1 H), 7.62–7.49 (m, 5 H), 7.44 (t, J =
All materials supplied from commercial sources were used as
received unless otherwise noted. DMF, DMAc, and NMP were
dried first over K2CO3 followed by 4 Å molecular sieves. Silica
gel for column chromatography was supplied as 300–400 mesh
from Haiyang Chemicals (Qingdao, China, which gives a
different retardation compared with silica gel typically used in
western countries). All melting points were uncorrected. The
1H and 13C NMR spectra were referenced to the residual
solvent signals (7.26 ppm for 1H and 77.0 ppm for 13C in
CDCl3). HRMS (ESI) spectra were recorded using a Fourier
transformed ion cyclotron resonance analyzer, and HRMS (EI)
spectra were recorded using a double focusing magnetic sector
analyzer.
7.7 Hz, 2 H), 7.41 (s, 1 H), 7.38–7.32 (m, 1 H), 7.08 (s, 1 H); 13
C
NMR (100 MHz, CDCl3) d 152.2, 140.7, 138.4, 133.7, 133.4,
129.6, 129.24, 129.18, 128.6, 128.2, 128.1, 127.9, 127.3, 127.2,
126.4, 123.9, 123.5, 112.5, 94.8; HRMS (ESI) calcd for C23H17N2
[M + H] 321.1392, found 321.1384.
2-Phenyl-5-p-tolylpyrazolo[5,1-a]isoquinoline (3ab). The gen-
eral procedure was applied to 90 mg of 1a, 1.5 mg of CuCl, 83
mg of K2CO3, and 70 mg of alkyne 2b to afford 81 mg (81%) of
Substrates 1a through 1k and 1m were prepared according
to literature procedures.18 Substrate 1n was prepared accord-
ing to our own protocol.19 Procedures for the synthesis of 1l
1
the desired product 3ab as a white solid; mp 109–110 uC. H
NMR (CDCl3, 400 MHz) d 8.18–8.14 (m, 1 H), 8.02 (d, J = 7.7 Hz,
2 H), 7.96 (d, J = 8.0 Hz, 2 H), 7.77–7.71 (m, 1 H), 7.60–7.51 (m,
2 H), 7.44 (t, J = 7.7 Hz, 2 H), 7.40 (s, 1 H), 7.39–7.32 (m, 3 H),
7.06 (s, 1 H), 2.48 (s, 3 H); 13C NMR (CDCl3, 100 MHz) d 152.1,
140.7, 139.2, 138.4, 133.4, 130.8, 129.5, 129.3, 128.8, 128.6,
128.1, 127.8, 127.1 (overlapped signal), 126.4, 123.8, 123.4,
112.0, 94.7, 21.4; IR (KBr): 1632, 1549, 1458, 816, 741, 681
cm21; HRMS (ESI) calcd for C24H19N2 [M + H] 335.1548, found
335.1537.
are listed in the ESI .
3
Representative procedure and characterization of the products
2,5-Diphenylpyrazolo[5,1-a]isoquinoline (3aa). To an oven-
dried 1-dram vial equipped with a stirrer were added CuCl (1.5
mg, 0.015 mmol, 5 mol%), 1a (90 mg, 0.3 mmol), and K2CO3
(83 mg, 0.6 mmol, 2 equiv.). NMP (0.6 mL) was added via
syringe, followed by the addition of alkyne 2a (61 mg, 0.6
mmol, 2 equiv.). The vial was flushed with nitrogen and
sealed. The mixture was heated in an oil bath at 120 uC for 24
h. After being cooled to room temperature, the reaction
mixture was filtered, and the filtrate was diluted with brine.
5-(4-Bromophenyl)-2-phenylpyrazolo[5,1-a]isoquinoline
(3ac). The general procedure was applied to 90 mg of 1a, 1.5
mg of CuCl, 83 mg of K2CO3, and 109 mg of alkyne 2c to afford
73 mg (61%) of the desired product 3ac as a bright yellow
1
solid; mp 162–163 uC. H NMR (CDCl3, 400 MHz) d 8.18–8.14
(m, 1 H), 8.02–7.97 (m, 2 H), 7.96–7.91 (m, 2 H), 7.77–7.73 (m,
1 H), 7.71–7.65 (m, 2 H), 7.62–7.53 (m, 2 H), 7.45 (t, J = 7.5 Hz,
2 H), 7.40 (s, 1 H), 7.38–7.33 (m, 1 H), 7.06 (s, 1 H); 13C NMR
(CDCl3, 100 MHz) d 152.3, 140.7, 137.2, 133.2, 132.6, 131.3,
131.2, 129.0, 128.6, 128.3, 128.0, 127.5, 127.2, 126.3, 123.9,
123.5, 123.4, 112.5, 94.9; IR (KBr): 1634, 1549, 1489, 1458,
1437, 814, 739, 681 cm21; HRMS (EI) calcd for C23H1581BrN2
[M] 400.0398, found 400.0393.
Scheme 3 An unsuccessful iodination attempt.
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NMP for 30 h to afford 117 mg (contaminated by a petroleum
ether residue at 1.25 and 0.87 ppm respectively, H NMR ratio
2-Phenyl-5-(thiophen-3-yl)pyrazolo[5,1-a]isoquinoline (3ad).
The general procedure was applied to 90 mg of 1a, 1.5 mg of
CuCl, 83 mg of K2CO3, and 65 mg of alkyne 2d to afford 78 mg
(80%) of the desired product 3ad as a slightly yellow solid; mp
1
100 : 2.5 (product/PE as dodecane), corresponding to 112 mg
of pure product, 92%) of the desired product 3ai as a white
solid; mp 115–116 uC. 1H NMR (CDCl3, 400 MHz) d 8.27 (d, J =
7.4 Hz, 1 H), 8.13 (d, J = 7.6 Hz, 1 H), 8.01 (d, J = 7.6 Hz, 2 H),
7.72 (d, J = 7.3 Hz, 1 H), 7.62–7.52 (m, 2 H), 7.48 (t, J = 7.5 Hz, 2
H), 7.40–7.36 (m, 1 H), 7.29 (s, 1 H), 6.99 (d, J = 7.4 Hz, 1 H);
13C NMR (CDCl3, 100 MHz) d 153.0, 139.8, 133.2, 128.81,
128.76, 128.3, 127.9, 127.6, 127.2, 126.33, 126.31, 124.5, 123.7,
112.0, 94.6; IR (KBr): 1634, 1537, 1462, 1362, 793, 758, 696
cm21; HRMS (ESI) calcd for C17H13N2 [M + H] 245.1079, found
245.1079.
1
111–112 uC. H NMR (CDCl3, 400 MHz) d 8.72 (d, J = 3.0 Hz, 1
H), 8.17–8.11 (m, 1 H), 8.08 (d, J = 8.1 Hz, 2 H), 7.85 (d, J = 5.1
Hz, 1 H), 7.77–7.71 (m, 1 H), 7.59–7.45 (m, 5 H), 7.43–7.37 (m,
1 H), 7.40 (s, 1 H), 7.30 (s, 1 H); 13C NMR (CDCl3, 100 MHz) d
152.1, 140.9, 133.44, 133.36, 133.3, 129.1, 128.7, 128.3, 127.92,
127.89, 127.23, 127.18, 127.1, 126.4, 124.9, 123.5, 123.4, 111.1,
94.7; IR (KBr): 1626, 1547, 1458, 1356, 837, 795, 750, 683 cm21
;
HRMS (ESI) calcd. for C21H15N2S [M + H] 327.0956, found
327.0950.
9-Chloro-2,5-diphenylpyrazolo[5,1-a]isoquinoline (3ba). The
general procedure was applied to 100 mg of 1b, 1.5 mg of
CuCl, 83 mg of K2CO3, and 61 mg of alkyne 2a to afford 92 mg
(86%) of the desired product 3ba as a white solid; mp 158–159
uC. 1H NMR (CDCl3, 400 MHz) d 8.13 (d, J = 2.1 Hz, 1 H), 8.05–
7.97 (m, 4 H), 7.67 (d, J = 8.5 Hz, 1 H), 7.58–7.51 (m, 3 H), 7.49
(dd, J = 8.5, 2.1 Hz, 1 H), 7.47–7.42 (m, 2 H), 7.39–7.33 (m, 1 H),
7.38 (s, 1 H), 7.03 (s, 1 H); 13C NMR (CDCl3, 100 MHz) d 152.4,
139.6, 138.6, 133.3, 133.0, 132.9, 129.6, 129.3, 128.62, 128.57,
128.31, 128.30, 128.2, 127.5, 126.4, 124.8, 122.9, 111.6, 95.2; IR
(KBr): 1636, 1597, 1549, 1450, 1398, 858, 764, 691 cm21; HRMS
(ESI) calcd for C23H1635ClN2 [M + H] 355.1002, found 355.0994.
9-Methoxy-2,5-diphenylpyrazolo[5,1-a]isoquinoline (3ca).
The general procedure was applied to 165 mg of 1c (0.5 mmol
scale), 3.6 mg of CuBr, 140 mg of K2CO3, and 102 mg of alkyne
2a in 1.2 mL of NMP to afford 115 mg (66%) of the desired
5-Cyclohexenyl-2-phenylpyrazolo[5,1-a]isoquinoline (3ae).
The general procedure was applied to 90 mg of 1a, 1.5 mg of
CuCl, 83 mg of K2CO3, and 64 mg of alkyne 2e for 2 days to
afford 46 mg (contaminated by a petroleum ether residue at
1.25 and 0.87 ppm respectively, 1H NMR ratio 100 : 4 (product/
PE as dodecane), corresponding to 45 mg of pure product,
46%) of the desired product 3ae as a yellow glass. 1H NMR
(CDCl3, 400 MHz) d 8.14–8.09 (m, 1 H), 8.07–8.02 (m, 2 H),
7.72–7.67 (m, 1 H), 7.56–7.43 (m, 4 H), 7.39–7.33 (m, 1 H), 7.33
(s, 1 H), 6.89 (s, 1 H), 6.44–6.40 (m, 1 H), 2.81–2.74 (m, 2 H),
2.37–2.30 (m, 2 H), 1.93–1.79 (m, 4 H); 13C NMR (100 MHz,
CDCl3) d 152.0, 141.3, 140.4, 133.8, 133.5, 130.6, 129.5, 128.6,
128.1, 127.7, 126.9, 126.8, 126.3, 123.7, 123.4, 110.2, 94.2, 27.4,
25.7, 22.6, 22.1; IR (film): 1632, 1545, 1458, 835, 752, 692 cm21
;
HRMS (ESI) calcd for C23H21N2 [M + H] 325.1705, found
325.1700.
1
product 3ca as a slightly yellow solid; mp 97–98 uC. H NMR
5-Pentyl-2-phenylpyrazolo[5,1-a]isoquinoline (3af). The gen-
eral procedure was applied to 90 mg of 1a, 1.5 mg of CuCl, 83
mg of K2CO3, and 58 mg of alkyne 2f to afford 56 mg (59%) of
the desired product 3af as a slightly yellow solid; mp 57–58 uC.
1H NMR (CDCl3, 400 MHz) d 8.15–8.09 (m, 1 H), 8.06 (d, J = 7.9
Hz, 2 H), 7.71–7.65 (m, 1 H), 7.55–7.44 (m, 4 H), 7.40–7.35 (m,
1 H), 7.34 (s, 1 H), 6.83 (s, 1 H), 3.24 (t, J = 7.7 Hz, 2 H), 2.02–
1.90 (m, 2 H), 1.55–1.40 (m, 4 H), 0.96 (t, J = 7.0 Hz, 3 H); 13C
NMR (CDCl3, 100 MHz) d 152.0, 140.1, 139.8, 133.7, 129.3,
128.7, 128.1, 127.6, 126.5, 126.41, 126.35, 123.4 (overlapped
signal), 109.3, 94.6, 31.6, 30.8, 26.5, 22.5, 14.1; IR (KBr): 1645,
1547, 1460, 1437, 818, 745, 681 cm21; HRMS (ESI) calcd for
C22H23N2 [M + H] 315.1861, found 315.1850.
(CDCl3, 400 MHz) d 8.08–8.00 (m, 4 H), 7.65 (d, J = 8.7 Hz, 1 H),
7.58–7.43 (m, 6 H), 7.39–7.34 (m, 1 H), 7.36 (s, 1 H), 7.17 (dd, J
= 8.7, 2.5 Hz, 1 H), 7.03 (s, 1 H), 3.99 (s, 3 H); 13C NMR (CDCl3,
100 MHz) d 158.9, 151.9, 140.4, 136.3, 133.9, 133.4, 129.5,
128.9, 128.8, 128.6, 128.1 (overlapped signal), 126.3, 125.0,
123.4, 117.8, 112.3, 104.6, 94.6, 55.6; IR (KBr): 1612, 1547,
1499, 1450, 1259, 1209, 1022, 860, 764, 735, 692 cm1; HRMS
(ESI) calcd for C24H19N2O [M + H] 351.1497, found 351.1489.
8-Methyl-2,5-diphenylpyrazolo[5,1-a]isoquinoline (3da). The
general procedure was applied to 94 mg of 1d, 1.5 mg of CuCl,
83 mg of K2CO3, and 61 mg of alkyne 2a to afford 77 mg (77%)
of the desired product 3da as a white solid; mp 114–115 uC. 1H
NMR (CDCl3, 400 MHz) d 8.07–7.98 (m, 5 H), 7.58–7.49 (m, 4
H), 7.46–7.38 (m, 3 H), 7.37–7.32 (m, 1 H), 7.35 (s, 1 H), 7.01 (s,
1 H), 2.53 (s, 3 H); 13C NMR (CDCl3, 100 MHz) d 152.1, 140.8,
138.3, 137.9, 133.8, 133.5, 129.6, 129.4, 129.1, 128.9, 128.6,
128.09, 128.07, 126.9, 126.4, 123.3, 121.7, 112.3, 94.2, 21.6; IR
(KBr): 1634, 1549, 1481, 1460, 762, 739, 692 cm21; HRMS (ESI)
calcd for C24H19N2 [M + H] 335.1548, found 335.1540.
2-(2-Phenylpyrazolo[5,1-a]isoquinolin-5-yl)ethanol (3ag). The
general procedure was applied to 90 mg of 1a, 1.5 mg of CuCl,
83 mg of K2CO3, and 42 mg of alkyne 2g to afford 63 mg (73%)
1
of the desired product 3ag as a white solid; mp 87–88 uC. H
NMR (CDCl3, 400 MHz) d 8.14–8.09 (m, 1 H), 8.01–7.96 (m, 2
H), 7.70–7.64 (m, 1 H), 7.59–7.51 (m, 2 H), 7.47 (t, J = 7.5 Hz, 2
H), 7.41–7.36 (m, 1 H), 7.34 (s, 1 H), 6.88 (s, 1 H), 4.58 (brs, 1
H), 4.14 (t, J = 5.4 Hz, 2 H), 3.50 (t, J = 5.3 Hz, 2 H); 13C NMR
(CDCl3, 100 MHz) d 152.3, 140.5, 137.6, 132.8, 129.3, 128.8,
128.5, 128.2, 127.1, 126.7, 126.4, 123.6 (overlapped signal),
111.8, 95.1, 61.9, 35.7; IR (KBr): 3100–3500(br), 1643, 1547,
1460, 1327, 1051, 829, 754, 687 cm21; HRMS (ESI) calcd for
C19H17N2O [M + H] 289.1341, found 289.1335.
8-Fluoro-2,5-diphenylpyrazolo[5,1-a]isoquinoline (3ea). The
general procedure was applied to 95 mg of 1e, 1.5 mg of CuCl,
83 mg of K2CO3, and 61 mg of alkyne 2a to afford 89 mg (88%)
of the desired product 3ea as a slightly yellow solid; mp 106–
107 uC (lit20 121–122 uC). 1H NMR (CDCl3, 400 MHz) d 8.13 (dd,
J = 8.8, 5.3 Hz, 1 H), 8.05–7.97 (m, 4 H), 7.59–7.50 (m, 3 H), 7.44
(t, J = 7.5 Hz, 2 H), 7.41–7.28 (m, 3 H), 7.34 (s, 1 H), 7.01 (s, 1
2-Phenylpyrazolo[5,1-a]isoquinoline (3ai). The general pro-
cedure was applied to 150 mg of 1a (0.5 mmol scale), 3.6 mg of
CuBr, 140 mg of K2CO3, and 182 mg of alkyne 2i in 1.2 mL of
1
H); 13C NMR (CDCl3, 100 MHz) d 162.0 (d, JCF = 247.6 Hz),
152.5, 140.4, 139.4, 133.4, 133.2, 130.9 (d, 3JCF = 9.3 Hz), 129.6,
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129.4, 128.6, 128.3, 128.2, 126.4, 125.7 (d, 3JCF = 9.0 Hz), 120.5
(d, 4JCF = 1.7 Hz), 115.9 (d, 2JCF = 24.0 Hz), 111.9 (d, 2JCF = 21.8
Hz), 111.6 (d, JCF = 3.4 Hz), 94.5; HRMS (ESI) calcd for
C23H16FN2 [M + H] 339.1298, found 339.1291.
alkyne 2a in 0.5 mL of NMP to afford 32.2 mg (contaminated
by petroleum ether residue at 1.25 and 0.87 ppm respectively,
1H NMR ratio 100 : 8.5 (product/PE as dodecane), correspond-
ing to 30.9 mg of pure product, 45%) of the desired product 3ja
4
1
as a light yellow glass. H NMR (400 MHz, CDCl3) d 7.97–7.93
2,5-Diphenylpyrazolo[5,1-f][1,6]naphthyridine (3fa). The
general procedure was applied to 90 mg of 1f, 1.5 mg of
CuCl, 83 mg of K2CO3, and 61 mg of alkyne 2a to afford 57 mg
(59%) of the desired product 3fa as a yellow solid; mp 126–127
uC. 1H NMR (CDCl3, 400 MHz) d 8.87 (dd, J = 4.5, 1.6 Hz, 1 H),
8.42 (dd, J = 8.1, 1.0 Hz, 1 H), 8.12–8.05 (m, 2 H), 8.02–7.96 (m,
2 H), 7.62–7.53 (m, 3 H), 7.50–7.40 (m, 4 H), 7.40–7.33 (m, 2 H);
13C NMR (CDCl3, 100 MHz) d 153.0, 150.7, 146.4, 142.1, 139.9,
133.0, 132.9, 131.1, 129.70, 129.66, 128.6, 128.5, 128.2, 126.4,
121.7, 119.4, 113.6, 96.0; IR (KBr): 1630, 1558, 1456, 1433,
1383, 845, 758, 745, 683 cm21; HRMS (ESI) calcd for C22H16N3
[M + H] 322.1344, found 322.1337.
(m, 2 H), 7.63 (d, J = 8.7 Hz, 1 H), 7.54–7.42 (m, 4 H), 7.14 (dd, J
= 8.7, 2.5 Hz, 1 H), 6.93 (s, 1 H), 6.86 (s, 1 H), 3.97 (s, 3 H), 2.86
(t, J = 7.8 Hz, 2 H), 1.84–1.75 (m, 2 H), 1.47–1.36 (m, 4 H), 0.93
(t, J = 7.0 Hz, 3 H); 13C NMR (100 MHz, CDCl3) d 158.7, 155.0,
139.7, 136.2, 134.1, 129.3, 128.9, 128.6, 128.2, 124.9, 123.4,
117.5, 111.4, 104.5, 96.1, 55.5, 31.7, 29.6, 28.7, 22.5, 14.1; IR
(film): 1616, 1547, 1501, 1466, 1261, 1234, 1034, 854, 741, 694
cm21; HRMS (ESI) calcd for C23H25N2O [M + H] 345.1967,
found 345.1958.
Ethyl 9-methoxy-5-phenylpyrazolo[5,1-a]isoquinoline-2-car-
boxylate (3ka). The general procedure was applied to 98 mg
of 1k, 2.2 mg of CuBr, 83 mg of K2CO3, and 61 mg of alkyne 2a
for 30 h to afford 66 mg (63%) of the desired product 3ka as a
white solid; mp 137–138 uC. 1H NMR (CDCl3, 400 MHz) d 7.97–
7.92 (m, 2 H), 7.69 (d, J = 8.7 Hz, 1 H), 7.60 (s, 1 H), 7.54–7.44
(m, 4 H), 7.20 (dd, J = 8.7, 2.5 Hz, 1 H), 7.16 (s, 1 H), 4.45 (q, J =
7.1 Hz, 2 H), 3.99 (s, 3 H), 1.44 (t, J = 7.1 Hz, 3 H); 13C NMR
(CDCl3, 100 MHz) d 162.8, 159.3, 143.8, 139.9, 136.3, 133.1,
129.4, 129.2, 128.9, 128.3, 125.2, 123.1, 118.4, 114.7, 104.6,
100.7, 61.2, 55.6, 14.3; IR (KBr): 1740, 1616, 1501, 1350, 1258,
1205, 1184, 1036, 1016, 854, 764, 692 cm21; HRMS (ESI) calcd
for C21H19N2O3 [M + H] 347.1396, found 347.1384.
1-(4-Methoxyphenyl)-2-methyl-5-phenylpyrazolo[5,1-a]iso-
quinoline (3la). The general procedure was applied to 117 mg
of 1l (0.34 mmol scale), 2.5 mg of CuBr, 95 mg of K2CO3, and
70 mg of alkyne 2a in 0.7 mL of NMP to afford 30 mg (24%) of
the desired product 3la (the low running spot on TLC) as a
yellow solid; mp 153–154 uC. 1H NMR (CDCl3, 400 MHz) d
7.98–7.92 (m, 2 H), 7.77 (d, J = 8.2 Hz, 1 H), 7.68 (d, J = 7.8 Hz, 1
H), 7.57–7.36 (m, 6 H), 7.29–7.23 (m, 1 H), 7.10–7.05 (m, 2 H),
6.96 (s, 1 H), 3.93 (s, 3 H), 2.33 (s, 3 H); 13C NMR (CDCl3, 100
MHz) d 158.9, 149.5, 138.1, 135.6, 134.1, 131.8, 129.8, 129.5,
129.2, 128.3, 127.4, 127.0, 126.6, 126.5, 124.4, 123.0, 114.8,
114.3, 111.8, 55.3, 12.6; IR (KBr): 1566, 1472, 1244, 1171, 1024,
835, 768, 698 cm21; HRMS (ESI) calcd for C25H21N2O [M + H]
365.1654 found 365.1643. For the other product (the high
2-(3-Methoxyphenyl)-5-phenylpyrazolo[5,1-a]isoquinoline
(3ga). The general procedure was applied to 99 mg of 1g, 1.5
mg of CuCl, 83 mg of K2CO3, and 61 mg of alkyne 2a to afford
79 mg (75%) of the desired product 3ga as a white solid; mp
1
123–124 uC. H NMR (CDCl3, 400 MHz) d 8.17–8.15 (m, 1 H),
8.07–8.02 (m, 2 H), 7.77–7.73 (m, 1 H), 7.62–7.48 (m, 7 H), 7.39
(s, 1 H), 7.36 (t, J = 7.9 Hz, 1 H), 7.08 (s, 1 H), 6.91 (ddd, J = 8.2,
2.6, 0.8 Hz, 1 H), 3.89 (s, 3 H); 13C NMR (CDCl3, 100 MHz) d
159.8, 152.0, 140.7, 138.4, 134.8, 133.7, 129.61, 129.60, 129.23,
129.16, 128.1, 127.9, 127.3, 127.2, 123.9, 123.4, 119.0, 113.7,
112.5, 111.9, 94.9, 55.3; IR (KBr): 1610, 1549, 1474, 1283, 1045,
768, 748, 692 cm21; HRMS (ESI) calcd for C24H19N2O [M + H]
351.1497, found 351.1491.
2-(4-Bromophenyl)-5-phenylpyrazolo[5,1-a]isoquinoline
(3ha). The general procedure was applied to 113 mg of 1h, 1.5
mg of CuCl, 83 mg of K2CO3, and 61 mg of alkyne 2a to afford
93 mg (78%) of the desired product 3ha as a white solid; mp
1
160–161 uC. H NMR (CDCl3, 400 MHz) d 8.16–8.09 (m, 1 H),
8.05–7.98 (m, 2 H), 7.86 (d, J = 8.5 Hz, 2 H), 7.77–7.70 (m, 1 H),
7.62–7.49 (m, 7 H), 7.34 (s, 1 H), 7.08 (s, 1 H); 13C NMR (CDCl3,
100 MHz) d 151.0, 140.8, 138.3, 133.6, 132.3, 131.7, 129.6,
129.3, 129.2, 128.2, 128.0, 127.9, 127.4, 127.2, 123.8, 123.4,
122.1, 112.7, 94.7; IR (KBr): 1634, 1547, 1460, 1437, 1395, 831,
752, 689 cm21; HRMS (ESI) calcd for C23H16N279Br [M + H]
399.0497, found 399.0489.
running spot on TLC) see the ESI .
5-Phenyl-2-(thiophen-3-yl)pyrazolo[5,1-a]isoquinoline (3ia).
The general procedure was applied to 153 mg of 1i (0.5 mmol
scale), 2.5 mg of CuCl, 140 mg of K2CO3, and 102 mg of alkyne
2a in 1.2 mL of NMP to afford 117 mg (72%) of the desired
product 3ia as a slightly yellow solid; mp 137–138 uC. 1H NMR
(CDCl3, 400 MHz) d 8.17–8.11 (m, 1 H), 8.05–8.00 (m, 2 H), 7.77
(dd, J = 2.9, 1.1 Hz, 1 H), 7.76–7.72 (m, 1 H), 7.64 (dd, J = 5.0,
1.0 Hz, 1 H), 7.60–7.48 (m, 5 H), 7.38 (dd, J = 5.0, 3.0 Hz, 1 H),
7.28 (s, 1 H), 7.07 (s, 1 H); 13C NMR (CDCl3, 100 MHz) d 148.6,
140.5, 138.4, 135.3, 133.7, 129.6, 129.3, 129.2, 128.1, 128.0,
127.3, 127.2, 126.6, 125.8, 123.8, 123.5, 121.8, 112.4, 95.1; IR
3
6-Phenyl-9,10,11,12-tetrahydroindazolo[3,2-a]isoquinoline
(3ma). The general procedure was applied to 55 mg of 1m (0.2
mmol scale), ca. 1.5 mg of CuBr, 56 mg of K2CO3, and 41 mg of
alkyne 2a in 0.5 mL of NMP to afford 26 mg (43%) of the
desired product 3ma as a yellow solid; mp 117–118 uC. 1H
NMR (CDCl3, 400 MHz) d 8.18 (d, J = 7.7 Hz, 1 H), 7.92–7.88 (m,
2 H), 7.73–7.69 (m, 1 H), 7.57–7.44 (m, 5 H), 6.91 (s, 1 H), 3.15
(t, J = 6.1 Hz, 2 H), 2.92 (t, J = 6.0 Hz, 2 H), 2.02–1.89 (m, 4 H);
13C NMR (CDCl3, 100 MHz) d 151.0, 138.4, 134.8, 134.3, 129.5,
129.4, 129.1, 128.3, 126.89, 126.87, 126.8, 125.3, 123.2, 111.4,
109.8, 24.2, 23.6, 23.0, 22.9; IR (KBr): 1568, 1485, 1398, 1352,
764, 692 cm21; HRMS (ESI) calcd for C21H19N2 [M + H]
299.1548, found 299.1547.
(KBr): 1634, 1568, 1539, 1470, 1369, 854, 783, 760, 694 cm21
;
HRMS (ESI) calcd for C21H15N2S [M + H] 327.0956, found
327.0947.
9-Methoxy-2-pentyl-5-phenylpyrazolo[5,1-a]isoquinoline
(3ja). The general procedure was applied to 65 mg of 1j (0.2
mmol scale), ca. 1.5 mg of CuBr, 56 mg of K2CO3, and 41 mg of
6-Phenylindazolo[3,2-a]isoquinoline (3na). The general pro-
cedure was applied to 82 mg of 1n, 2.2 mg of CuBr, 83 mg of
K2CO3, and 61 mg of alkyne 2a in the presence of 77 mg of
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P. Saejueng, J. M. Murphy and D. Venkataraman, Org. Lett.,
2002, 4, 4727.
8 (a) F. Liu and D. Ma, J. Org. Chem., 2007, 72, 4844; (b) D. Ma
and F. Liu, Chem. Commun., 2004, 1934.
9 S. Cacchi, G. Fabrizi and L. M. Parisi, Org. Lett., 2003, 5,
3843.
10 (a) L. Li, M. Wang, X. Zhang, Y. Jiang and D. Ma, Org. Lett.,
2009, 11, 1309; (b) L. Wang, X. Zhang, Y. Jiang and D. Ma,
Sci. China, Ser. B: Chem., 2009, 52, 1616; (c) Y. Wang, L. Xu
and D. Ma, Chem.–Asian J., 2010, 5, 74.
AgOTf for 30 h to afford 38 mg (43%) of the desired product
3na as a yellow solid; mp 129–130 uC (lit22 134–135 uC). 1H
NMR (CDCl3, 400 MHz) d 8.76 (d, J = 8.1 Hz, 1 H), 8.53 (d, J =
8.5 Hz, 1 H), 8.05–7.99 (m, 2 H), 7.97 (d, J = 8.7 Hz, 1 H), 7.92
(d, J = 7.9 Hz, 1 H), 7.80–7.75 (m, 1 H), 7.67–7.51 (m, 5 H), 7.46
(s, 1 H), 7.39–7.33 (m, 1 H); 13C NMR (CDCl3, 100 MHz) d
148.8, 138.4, 133.9, 131.4, 129.7, 129.5, 128.6, 128.5, 128.2,
127.6, 127.2, 127.1, 125.7, 122.7, 121.4, 121.1, 117.7, 116.9,
116.7; HRMS (ESI) calcd for C21H15N2 [M + H] 295.1235, found
295.1233.
´
11 (a) S. Inack-Ngi, K. Cherry, V. Heran, L. Commeiras, J.-
ˆ
L. Parrain, A. Duchene, M. Abarbri and J. Thibonnet,
Chem.–Eur. J., 2011, 17, 13692; (b) S. Inack-Ngi,
R. Rahmani, L. Commeiras, G. Chouraqui, J. Thibonnet,
Acknowledgements
ˆ
A. Duchene, M. Abarbri and J.-L. Parrain, Adv. Synth. Catal.,
This project is financially supported by the National Natural
Science Foundation of China (No. 21202035 to C.W.), Chinese
Ministry of Education (Scientific Research Foundation for the
Returned Overseas Chinese Scholars to C.W.), and the start-up
funds from Henan University (to F.S. and C.W.). We thank
Prof. Hua Fu (Tsinghua University) and Prof. Xiaodong Shi
(West Virginia University) for helpful discussions, and Dr Jiang
Zhou (Peking University) for the HRMS analysis.
ˆ
2009, 351, 779; (c) Z. Bahlaouan, M. Abarbri, A. Duchene,
J. Thibonnet, N. Henry, C. Enguehard-Gueiffier and
A. Gueiffier, Org. Biomol. Chem., 2011, 9, 1212.
12 (a) Z. Chen, X. Yang and J. Wu, Chem. Commun., 2009,
3469; (b) H. Wang, Y. Kuang and J. Wu, Asian J. Org. Chem.,
2012, 1, 302 and references therein; (c) P. Huang, Q. Yang,
Z. Chen, Q. Ding, J. Xu and Y. Peng, J. Org. Chem., 2012, 77,
8092; (d) P. Huang, Z. Chen, Q. Yang and Y. Peng, Org. Lett.,
2012, 14, 2790; (e) X. Li and M. Zhao, J. Org. Chem., 2011,
76, 8530; (f) X. Yang, Y. Luo, Y. Jin, H. Liu, Y. Jiang and
H. Fu, RSC Adv., 2012, 2, 8258.
13 Despite the possibly of higher yields obtained by using
CuBr2, we still elected to use CuBr or CuCl as the working
catalyst, as we preferred to handle a powdered catalyst as
opposed to larger crystals, which are harder to weigh on
smaller scales.
References
1 K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron
Lett., 1975, 16, 4467.
2 (a) E.-I. Negishi and L. Anastasia, Chem. Rev., 2003, 103,
1979; (b) R. R. Tykwinski, Angew. Chem., Int. Ed., 2003, 42,
´
1566; (c) R. Chinchilla and C. Najera, Chem. Rev., 2007, 107,
14 Z. Gonda, G. L. Tolnai and Z. Novak, Chem.–Eur. J., 2010,
16, 11822.
´
874; (d) R. Chinchilla and C. Najera, Chem. Soc. Rev., 2011,
40, 5084; (e) U. H. F. Bunz, Chem. Rev., 2000, 100, 1605.
15 Although it is still early to draw any conclusions, we
consider that the narrowing of the bite angle between the
pyrazole and the alkyne moiety caused by the large R2
group might be a reason for this low yield and formation of
two isomeric products.
´
´
´
3 M. Garcıa-Melchor, M. C. Pacheco, C. Najera, A. Lledoos
and G. Ujaque, ACS Catal., 2012, 2, 135 and references
therein.
4 For the seminal publication see: (a) K. Okuro, M. Furuune,
M. Enna, M. Miura and M. Nomura, J. Org. Chem., 1993, 58,
4716. For a comprehensive review see (b) G. Evano,
N. Blanchard and M. Toumi, Chem. Rev., 2008, 108, 3054.
5 (a) J.-H. Li, J.-L. Li, D.-P. Wang, S.-F. Pi, Y.-X. Xie, M.-
B. Zhang and X.-C. Hu, J. Org. Chem., 2007, 72, 2053. For
the use of Cu(II) as the catalyst see (b) C.-L. Deng, Y.-X. Xie,
D.-L. Yin and J.-H. Li, Synthesis, 2006, 3370.
6 (a) M. Zora and A. Kivrak, J. Org. Chem., 2011, 76, 9379; (b)
B. Montaignac, M. R. Vitale, V. Ratovelomanana-Vidal and
V. Michelet, Eur. J. Org. Chem., 2011, 3723; (c) Z. Li,
L. Hong, R. Liu, J. Shen and X. Zhou, Tetrahedron Lett.,
2011, 52, 1343; (d) J. Yang, C. Wang, X. Xie, H. Li, E. Li and
Y. Li, Org. Biomol. Chem., 2011, 9, 1342; (e) Z. Bahlaouan,
M. Abarbri, A. Duchene, J. Thibonnet, N. Henry,
C. Enguehard-Gueiffier and A. Gueiffier, Org. Biomol.
Chem., 2011, 9, 1212; (f) N. K. Swamy, A. Yazici and S.
G. Pyne, J. Org. Chem., 2010, 75, 3412.
16 P. Li and L. Wang, Synlett, 2006, 2261.
17 For a preparation of 6-substituted pyrazolo[5,1-a]isoquino-
lines see: W. Ma, K. Graczyk and L. Ackermann, Org. Lett.,
2012, 14, 6318.
18 (a) Substrates 1a to 1k were prepared using Aggarwal’s
method. See: V. K. Aggarwal, J. Vicente and R. V. Bonnert, J.
Org. Chem., 2003, 68, 5381; (b) Substrate 1m was prepared
by Yu’s method. See: J. Wen, Y. Fu, R.-Y. Zhang, J. Zhang,
S.-Y. Chen and X.-Q. Yu, Tetrahedron, 2011, 67, 9618.
19 P. Li, J. Zhao, C. Wu, R. C. Larock and F. Shi, Org. Lett.,
2011, 13, 3340.
20 P. Huang, Q. Yang, Z. Chen, Q. Ding, J. Xu and Y. Peng, J.
Org. Chem., 2012, 77, 8092.
21 Our compound is pure according to NMR analysis, and the
NMR data match those reported in the literature (ref. 12a).
The difference in melting points might be due to different
types of crystals.
7 (a) P. Saejung, C. G. Bates and D. Venkataraman, Synthesis,
2005, 1706; (b) C. G. Bates, P. Saejung and
D. Venkataraman, Org. Lett., 2004, 6, 1441; (c) C. G. Bates,
22 J. Zhao, P. Li, C. Wu, H. Chen, W. Ai, R. Sun, H. Ren, R.
C. Larock and F. Shi, Org. Biomol. Chem., 2012, 10, 1922.
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 10434–10441 | 10441