Silver triflate-catalyzed tandem reaction of N′-(2- alkynylbenzylidene)hydrazide with pyridyne

Article abstract of DOI:10.1039/c2ob26379c

A silver triflate-catalyzed tandem reaction of N′-(2- alkynylbenzylidene)hydrazide with pyridyne is presented. Different outcomes are obtained, depending on the pyridynes utilized in the transformation.

Full text of DOI:10.1039/c2ob26379c

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PAPER
Silver triflate-catalyzed tandem reaction of N′-(2-alkynylbenzylidene)-
hydrazide with pyridyne†
Lingyong Jiang,a Xingxin Yu,b Bing Fang*a and Jie Wu*b
Received 17th July 2012, Accepted 14th August 2012
DOI: 10.1039/c2ob26379c
A silver triflate-catalyzed tandem reaction of N′-(2-alkynylbenzylidene)hydrazide with pyridyne is
presented. Different outcomes are obtained, depending on the pyridynes utilized in the transformation.
1. Introduction
For the process of drug development, libraries of natural
product-like compounds are in great demand.1 Therefore, it is
highly important to develop efficient and facile approaches for
the generation of small molecules with privileged scaffolds.2
During the transformations, diversity and complexity should be
easily incorporated. Concerning efficiency, tandem reaction is
the choice for parallel synthesis in combinatorial chemistry.3
Recently, we developed several routes for the preparation of
H-pyrazolo[5,1-a]isoquinoline derivatives using tandem reac-
tions.4 Several hits exhibited promising biological activities for
Scheme 1 A possible route for the generation of diverse H-pyrazolo-
anti-bacterial and inhibition of CDC25B, TC-PTP, and PTP1B
[5,1-a]isoquinolines 3.
during the preliminary biological evaluations.4h The discovery of
more active compounds prompted us to consider their library
construction. Although there are reported procedures for the con-
struction of the scaffold of H-pyrazolo[5,1-a]isoquinoline,4,5
efficient methods for the concise synthesis of diverse H-pyrazolo-
[5,1-a]isoquinolines with complexity are highly desirable.
It is well known that pyridynes are analogues of arynes con-
taining a nitrogen in the ring. Their reactivity has been demon-
strated in cycloaddition and nucleophilic substitution reactions
for the construction of complex molecules.6–8 The pyridine
skeleton, which is important in pharmaceutical chemistry, could
be incorporated when pyridynes were used as the substrates in
organic reactions. Recently, we recognized that N′-(2-alkynyl-
benzylidene)hydrazide was a useful building block for the
formation of N-heterocycles.4 Inspired by the advancement of
pyridine chemistry, we envisioned that diverse H-pyrazolo[5,1-a]-
isoquinolines would be generated by the reaction of N′-(2-alkynyl-
benzylidene)hydrazides with pyridynes under proper con-
ditions (Scheme 1). The transformation would proceed through
6-endo cyclization, [3 + 2] cycloaddition, and intramolecular
rearrangement. In connection of our recent efforts for the
N′-(2-alkynylbenzylidene)hydrazide chemistry and to expand
the utility of pyridines, we started to explore the feasibility of the
proposed synthetic route as described in Scheme 1.
2. Results and discussion
The reaction of N′-(2-alkynylbenzylidene)hydrazide 1a with
pyridyne precursor 2a was initially studied in the presence of
10 mol% of silver triflate and a fluoro anion at room temperature
(Table 1). Interestingly, the corresponding products 3a and 3a′
were obtained in 31% total yield when the reaction occurred in
DCE in the presence of cesium fluoride (Table 1, entry 1). These
two products could be separated and isolated. Treatment of the
reaction with Et3NBnCl (0.25 equiv) as the additive provided
products 3a (26%) and 3a′ (16%) in 42% total yield (Table 1,
entry 2). A lower yield was obtained by switching the solvent to
toluene (Table 1, entry 3). Only a trace amount of product was
detected when the reaction took place in ethanol (Table 1, entry 4).
aDepartment of Oral and Maxillofacial Surgery, Ninth People’s
Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai
Key Laboratory of Stomatology, Shanghai 200011, China.
E-mail: braces_dr@hotmail.com
bDepartment of Chemistry, Fudan University, 220 Handan Road,
Shanghai 200433, China. E-mail: jie_wu@fudan.edu.cn;
Fax: +86 21 6564 1740; Tel: +86 21 6510 2412
†Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, 1H and 13C NMR spectra of com-
pounds 3 and 4, CIF of compound 4a. CCDC reference number 892699.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2ob26379c
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Table 1 Initial studies for the silver triflate-catalyzed tandem reaction
of N′-(2-alkynylbenzylidene)hydrazide 1a with pyridyne 2aa
cyclization of N′-(2-alkynylbenzylidene)hydrazide 1, isoquinoli-
nium-2-yl amide A would be formed. Then 2-chloropyridyne
would be involved and the following [3 + 2] cycloaddition
would occur to produce an intermediate C. We reasoned that the
presence of a chloro group in the intermediate C would promote
the cleavage of N–N bond to generate a radical D, which would
undergo an intramolecular addition to provide compound 4.
3. Conclusion
In summary, we have developed an efficient silver triflate-cata-
lyzed tandem reaction of N′-(2-alkynylbenzylidene)hydrazide
with pyridyne. Different outcomes are obtained, depending on
the pyridynes utilized in the transformation. The scaffold diver-
sity and complexity are easily introduced under mild conditions.
The transformation provides a facile route to pyridinyl-fused
H-pyrazolo[5,1-a]isoquinolines. Additionally, 6,11-dihydro-5H-
Entry “F”
Additive
Solvent
DCE
Yielda (%)
1
2
3
4
5
6
7
8
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
KF
—
31 (3a/3a′: 20/11)
42 (3a/3a′: 26/16)
18 (3a/3a′: 10/8)
Trace
60 (3a/3a′: 36/24)
62 (3a/3a′: 40/22)
61 (3a/3a′: 38/23)
60 (3a/3a′: 35/25)
Et3NBnCl DCE
Et3NBnCl Toluene
Et3NBnCl EtOH
Et3NBnCl MeCN
Et3NBnCl THF
Et3NBnCl 1,4-Dioxane
Et3NBnCl THF/MeCN
Table 2 Silver triflate-catalyzed tandem reaction of N′-(2-
alkynylbenzylidene)hydrazides 1 with pyridyne 2aa
9
Et3NBnCl 1,4-Dioxane/MeCN 73 (3a/3a′: 46/27)
10
11
12
13
14b
Et3NBnCl 1,4-Dioxane/DCM
Et3NBnCl 1,4-Dioxane/DMF
Et3NBnCl 1,4-Dioxane/DMF
40 (3a/3a′: 26/14)
54 (3a/3a′: 34/20)
48 (3a/3a′: 28/20)
65 (3a/3a′: 41/24)
TBAF Et3NBnCl 1,4-Dioxane/DMF
CsF
Et3NBnCl 1,4-Dioxane/MeCN 62 (3a/3a′: 40/22)
a Isolated yield based on N′-(2-alkynylbenzylidene)hydrazide 1a. b In the
presence of 10 mol% of additive.
The result could be dramatically improved when the solvent was
changed to MeCN, THF, or 1,4-dioxane (Table 1, entries 5–7).
A mixed solvent of 1,4-dioxane/MeCN gave rise to the
desired products 3a (46%) and 3a′ (27%) in 73% total yield
(Table 1, entry 9). No better results were observed when other
combinations of solvents were examined.
We next explored the scope of this silver triflate-catalyzed
tandem reaction of N′-(2-alkynylbenzylidene)hydrazide 1 with
pyridyne precursor 2a under the optimized conditions (10 mol%
of AgOTf, CsF, Et3NBnCl, 1,4-dioxane/MeCN, rt). The results
are summarized in Table 2. Various N′-(2-alkynylbenzylidene)
hydrazides 1 with substitutions on the aromatic ring were evalu-
ated. All the reactions produced the expected pyridinyl-fused
H-pyrazolo[5,1-a]isoquinolines in good yields. Additionally,
reactions of N′-(2-alkynylbenzylidene)hydrazides
1 bearing
either aryl or alkyl substituents on the triple bond (R2 position)
worked well. Although the transformation was not regioselective
and two regioisomers were isolated, the total yield demonstrated
the efficiency of the conversion.
To our surprise, an unexpected result was generated for the
silver triflate-catalyzed tandem reaction of N′-(2-alkynylbenzyli-
dene)hydrazide 1 with 2-chloropyridyne precursor 2b. 6,11-
Dihydro-5H-11,6-(azenometheno)benzo[e]pyrido[4,3-b]azepines
4 were isolated and obtained (Table 3). The structure of com-
pound 4a was confirmed by X-ray diffraction analysis (Fig. 1,
see the ESI†). Again, different functional groups were compati-
ble under the standard conditions. According to the previous
report,4g we proposed a possible mechanism which was pre-
sented in Scheme 2. After the silver(I)-mediated 6-endo
a Isolated yield based on N′-(2-alkynylbenzylidene)hydrazide 1.
Org. Biomol. Chem., 2012, 10, 8102–8107 | 8103
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Table 3 Silver triflate-catalyzed tandem reaction of N′-(2-
alkynylbenzylidene)hydrazide 1 with 2-chloropyridyne 2ba
Scheme 2 A possible mechanism for the silver triflate-catalyzed reac-
tion of N′-(2-alkynylbenzylidene)hydrazide with 2-chloropyridyne.
6-Phenylpyrido[3′,4′:3,4]pyrazolo[5,1-a]isoquinoline 3a
1H NMR (400 MHz, CDCl3) δ 7.57–7.61 (m, 4H), 7.66 (t, J =
7.6 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H),
7.98 (d, J = 6.4 Hz, 2H), 8.26 (d, J = 6.0 Hz, 1H), 8.43 (d, J =
6.0 Hz, 1H), 8.64 (d, J = 7.8 Hz, 1H), 9.50 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 114.5, 118.9, 119.0, 122.7, 125.8, 127.9,
128.0, 128.6, 128.8, 129.8, 129.9, 131.4, 133.3, 137.8, 138.7,
144.3, 144.8; HRMS calcd for C20H14N3 (M+ + H): 296.1188,
found: 296.1180.
a Isolated yield based on N′-(2-alkynylbenzylidene)hydrazide 1.
6-Phenylpyrido[4′,3′:3,4]pyrazolo[5,1-a]isoquinoline 3a′
1H NMR (400 MHz, CDCl3) δ 7.58–7.64 (m, 4H), 7.73–7.77
(m, 2H), 7.85 (t, J = 7.6 Hz, 1H), 7.95–8.00 (m, 3H), 8.47 (d,
J = 6.4 Hz, 1H), 8.76 (d, J = 8.2 Hz, 1H), 9.97 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 111.3, 114.9, 118.7, 123.6,
124.6, 128.0, 128.7, 129.1, 129.2, 129.6, 129.8, 130.0, 133.2,
138.7, 142.1, 146.1, 150.1; HRMS calcd for C20H14N3
(M+ + H): 296.1188, found: 296.1181.
Fig. 1 X-ray ORTEP illustration of 6,11-dihydro-5H-11,6-(azeno-
metheno)benzo[e]pyrido[4,3-b]azepines 4a (30% probability ellipsoids).
6-Cyclopropylpyrido[3′,4′:3,4]pyrazolo[5,1-a]isoquinoline 3b
11,6-(azenometheno)benzo[e]pyrido[4,3-b]azepines are gener-
ated as a different outcome when 2-chloropyridyne is used as the
substrate. Employing pyridynes for the construction of other
N-heterocycles is ongoing in our laboratory.
1H NMR (400 MHz, CDCl3) δ 0.99–1.03 (m, 2H), 1.32–1.36
(m, 2H), 2.87–2.95 (m, 1H), 7.17 (s, 1H), 7.61 (t, J = 7.3 Hz,
1H), 7.71 (t, J = 7.3 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 8.22 (d,
J = 6.0 Hz, 1H), 8.42 (d, J = 5.5 Hz, 1H), 8.55 (d, J = 7.8 Hz,
1H), 9.58 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 7.6, 11.9,
113.1, 114.6, 119.2, 122.6, 124.9, 127.2, 127.8, 128.0, 128.5,
130.9, 137.6, 141.2, 143.9, 144.9; HRMS calcd for C17H13N3
(M+ + H): 260.1188, found: 260.1181.
Experimental section
General experimental procedure for the silver triflate-catalyzed
tandem reaction of N′-(2-alkynylbenzylidene)hydrazide with
pyridyne. A mixture of N′-(2-alkynylbenzylidene)hydrazide 1
(0.3 mmol) and AgOTf (10 mol%) in 1,4-dioxane (2.0 mL) was
heated at 70 °C with vigorous stirring for 1 hour. Then, pyridyne
precursor 2 (0.45 mmol, 1.5 equiv), CsF (0.9 mmol, 3.0 equiv),
TEBAC (0.075 mmol, 0.25 equiv), and MeCN (2.0 mL) were
added. The reaction mixture was stirred at room temperature or
50 °C until completion of the reaction. The reaction mixture was
diluted with ethyl acetate (5.0 mL), and quenched with water
(5.0 mL). The organic layer was washed with brine, dried over
Na2SO4 and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel to provide
the desired product.
6-Cyclopropylpyrido[4′,3′:3,4]pyrazolo[5,1-a]isoquinoline 3b′
1H NMR (400 MHz, CDCl3) δ 0.99–1.04 (m, 2H), 1.32–1.36
(m, 2H), 2.90–2.97 (m, 1H), 7.18 (s, 1H), 7.67 (t, J = 7.3 Hz,
1H), 7.75 (t, J = 7.3 Hz, 1H), 7.81–7.85 (m, 2H), 8.51 (d, J =
6.0 Hz, 1H), 8.66 (d, J = 7.8 Hz, 1H), 9.88 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 7.8, 12.0, 110.8, 112.6, 115.1, 123.4,
123.9, 127.3, 128.2, 128.6, 129.4, 132.5, 141.2, 143.1, 146.6,
150.1; HRMS calcd for C17H13N3 (M+ + H): 260.1188, found:
260.1170.
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6-Butylpyrido[3′,4′:3,4]pyrazolo[5,1-a]isoquinoline 3c
6-Cyclopropyl-3-fluoropyrido[4′,3′:3,4]pyrazolo[5,1-a]-
isoquinoline 3e′
1H NMR (400 MHz, CDCl3) δ 1.04 (t, J = 7.3 Hz, 3H),
1.56–1.60 (m, 2H), 1.91–1.99 (m, 2H), 3.32–3.36 (m, 2H), 7.32
(s, 1H), 7.61 (t, J = 7.3 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.83
(d, J = 7.8 Hz, 1H), 8.17 (d, J = 5.5 Hz, 1H), 8.40 (d, J =
5.5 Hz, 1H), 8.51 (d, J = 7.8 Hz, 1H), 9.52 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 14.0, 22.6, 28.8, 31.0, 114.6, 115.7, 119.0,
122.5, 125.1, 127.2, 127.7, 127.9, 128.4, 130.8, 137.6, 139.8,
143.9, 144.8; HRMS calcd for C18H18N3 (M+ + H): 276.1501,
found: 276.1485.
1H NMR (400 MHz, CDCl3) δ 1.01–1.05 (m, 2H), 1.34–1.39
(m, 2H), 2.93–3.00 (m, 1H), 7.13 (s, 1H), 7.50–7.52 (m, 2H),
7.82 (d, J = 6.0 Hz, 1H), 8.51–8.53 (m, 1H), 8.66–8.70 (m, 1H),
9.86 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 8.0, 12.0, 110.9,
111.7, 111.9 (d, JCF = 22 Hz), 114.8, 117.6 (d, JCF = 25 Hz),
120.7, 125.9 (d, JCF = 10 Hz), 131.3 (d, JCF = 10 Hz), 132.4,
2
2
3
3
1
142.5, 143.2, 146.5, 150.2, 162.2 (d, JCF = 249 Hz); HRMS
calcd for C17H13FN3 (M+ + H): 278.1094, found: 278.1085.
6-Butyl-3-fluoropyrido[3′,4′:3,4]pyrazolo[5,1-a]isoquinoline 3f
6-Butylpyrido[4′,3′:3,4]pyrazolo[5,1-a]isoquinoline 3c′
1H NMR (400 MHz, CDCl3) δ 1.04 (t, J = 7.3 Hz, 3H),
1.53–1.60 (m, 2H), 1.92–2.00 (m, 2H), 3.35–3.39 (m, 2H), 7.30
(s, 1H), 7.46–7.52 (m, 2H), 8.15 (d, J = 5.5 Hz, 1H), 8.42 (d,
1H NMR (400 MHz, CDCl3) δ 1.03 (t, J = 6.8 Hz, 3H),
1.53–1.58 (m, 2H), 1.91–1.95 (m, 2H), 3.30–3.34 (m, 2H), 7.31
(s, 1H), 7.64–7.76 (m, 3H), 7.83 (d, J = 7.8 Hz, 1H), 8.49 (d,
J = 6.0 Hz, 1H), 8.57 (d, J = 7.8 Hz, 1H), 9.81 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 14.0, 22.6, 28.8, 31.1, 110.8, 114.9,
115.3, 123.3, 123.9, 127.2, 128.1, 128.6, 129.3, 132.4, 139.8,
142.8, 146.4, 149.9; HRMS calcd for C18H18N3 (M+ + H):
276.1501, found: 276.1483.
J = 5.5 Hz, 1H), 8.53–8.56 (m, 1H), 9.54 (s, 1H); 13C NMR
2
(100 MHz, CDCl3) δ 14.0, 22.6, 28.7, 31.1, 111.9 (d, JCF
=
2
22 Hz), 114.3, 114.9, 117.1 (d, JCF = 24 Hz), 118.6, 121.9,
124.9 (d, JCF = 9 Hz), 130.2 (d, JCF = 10 Hz), 130.6, 137.7,
141.1, 144.1, 144.9, 161.6 (d, JCF = 248 Hz); HRMS calcd for
3
3
1
C18H17FN3 (M+ + H): 294.1407, found: 294.1379.
3-Fluoro-6-phenylpyrido[3′,4′:3,4]pyrazolo[5,1-a]isoquinoline 3d
6-Butyl-3-fluoropyrido[4′,3′:3,4]pyrazolo[5,1-a]isoquinoline 3f′
1H NMR (400 MHz, CDCl3) δ 7.51–7.60 (m, 6H), 7.95–7.97
(m, 2H), 8.19 (d, J = 5.5 Hz, 1H), 8.42 (d, J = 5.5 Hz, 1H),
8.60–8.64 (m, 1H), 9.49 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ 112.6 (d, 2JCF = 22 Hz), 114.2, 117.8 (d, 2JCF = 24 Hz), 117.9,
1H NMR (400 MHz, CDCl3) δ 1.04 (t, J = 7.3 Hz, 3H),
1.54–1.59 (m, 2H), 1.92–1.96 (m, 2H), 3.33–3.37 (m, 2H), 7.29
(s, 1H), 7.48–7.52 (m, 2H), 7.76 (d, J = 4.2 Hz, 1H), 8.51 (s,
1H), 8.61–8.64 (m, 1H), 9.81 (s, 1H); 13C NMR (100 MHz,
118.5, 122.5, 125.1 (d, 3JCF = 9 Hz), 128.7, 129.7, 130.2, 130.3,
2
CDCl3) δ 14.0, 22.6, 28.8, 31.2, 110.7, 111.9 (d, JCF = 22 Hz),
1
131.2, 132.9, 137.9, 139.8, 144.4, 144.9, 161.8 (d, JCF
=
2
3
114.4, 117.5 (d, JCF = 23 Hz), 120.8, 125.8 (d, JCF = 9 Hz),
248 Hz); HRMS calcd for C20H13FN3 (M+ + H): 314.1094,
found: 314.1071.
131.1 (d, 3JCF = 9 Hz), 132.1, 141.0, 143.4, 146.5, 150.0, 162.1
(d, JCF = 249 Hz); HRMS calcd for C18H17FN3 (M+ + H):
1
294.1407, found: 294.1428.
3-Fluoro-6-phenylpyrido[4′,3′:3,4]pyrazolo[5,1-a]isoquinoline
3d′
6-Cyclopropyl-2-fluoropyrido[3′,4′:3,4]pyrazolo[5,1-a]-
isoquinoline 3g
1H NMR (400 MHz, CDCl3) δ 7.55–7.63 (m, 6H), 7.74 (d, J =
6.0 Hz, 1H), 7.95–7.97 (m, 2H), 8.48–8.49 (m, 1H), 8.75–8.77
(m, 1H), 9.92 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 111.2,
1H NMR (400 MHz, CDCl3) δ 1.01–1.05 (m, 2H), 1.34–1.39
(m, 2H), 2.94–2.96 (m, 1H), 7.13 (s, 1H), 7.46–7.50 (m, 2H),
8.19 (d, J = 6.0 Hz, 1H), 8.42 (d, J = 5.5 Hz, 1H), 8.56–8.60
(m, 1H), 9.58 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 7.9, 11.9,
2
2
112.6 (d, JCF = 21 Hz), 114.6, 117.6, 117.7, 118.4 (d, JCF
=
3
24 Hz), 121.5, 126.1 (d, JCF = 9 Hz), 128.7, 129.8, 130.2,
131.3 (d, 3JCF = 9 Hz), 133.0, 139.7, 143.0, 146.4, 150.2, 162.3
2
2
112.0 (d, JCF = 22 Hz), 112.2, 114.4, 117.1 (d, JCF = 24 Hz),
1
(d, JCF = 251 Hz); HRMS calcd for C20H13FN3 (M+ + H):
3
3
118.8, 121.7, 125.0 (d, JCF = 9 Hz), 130.3 (d, JCF = 9 Hz),
1
314.1094, found: 314.1097.
130.7, 137.6, 142.6, 144.1, 144.9, 161.7 (d, JCF = 248 Hz);
HRMS calcd for C17H13FN3 (M+ + H): 278.1094, found:
278.1107.
6-Cyclopropyl-3-fluoropyrido[3′,4′:3,4]pyrazolo[5,1-a]-
isoquinoline 3e
6-Cyclopropyl-2-fluoropyrido[4′,3′:3,4]pyrazolo[5,1-a]-
isoquinoline 3g′
1H NMR (400 MHz, CDCl3) δ 1.01–1.05 (m, 2H), 1.34–1.39
(m, 2H), 2.91–2.98 (m, 1H), 7.13 (s, 1H), 7.46–7.50 (m, 2H),
8.19 (d, J = 6.0 Hz, 1H), 8.41–8.43 (m, 1H), 8.56–8.59 (m, 1H),
9.57 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 7.9, 11.9, 112.0 (d,
1H NMR (400 MHz, CDCl3) δ 1.01–1.05 (m, 2H), 1.33–1.39
(m, 2H), 2.94–2.99 (m, 1H), 7.14 (s, 1H), 7.45–7.54 (m, 2H),
7.81 (d, J = 6.0 Hz, 1H), 8.52 (d, J = 6.0 Hz, 1H), 8.67–8.71
(m, 1H), 9.87 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 8.1, 12.0,
2
2JCF = 22 Hz), 112.2, 114.5, 117.1 (d, JCF = 24 Hz), 118.8,
3
3
121.7, 125.0 (d, JCF = 9 Hz), 126.5, 129.7, 130.3 (d, JCF
=
1
2
2
9 Hz), 137.4, 142.5, 143.9, 161.7 (d, JCF = 248 Hz); HRMS
110.9, 111.6, 111.9 (d, JCF = 22 Hz), 114.7, 117.6 (d, JCF =
calcd for C17H13FN3 (M+ + H): 278.1094, found: 278.1088.
24 Hz), 120.7, 125.9 (d, 3JCF = 10 Hz), 131.3 (d, 3JCF = 10 Hz),
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1
132.4, 142.5, 143.2, 146.5, 150.2, 162.2 (d, JCF = 249 Hz);
127.4, 127.5, 127.6, 128.6, 129.1, 129.3, 129.9, 131.6, 131.9,
134.5, 135.5, 141.9, 145.1, 145.5, 147.9, 150.9, 167.0; HRMS
HRMS calcd for C17H13FN3 (M+ + H): 278.1094, found:
278.1102.
calcd for C27H21ClN3O2S (M+
486.1043.
+ H): 486.1043, found:
6-Butyl-2-fluoropyrido[3′,4′:3,4]pyrazolo[5,1-a]isoquinoline 3h
1H NMR (400 MHz, CDCl3) δ 1.04 (t, J = 7.3 Hz, 3H),
1.54–1.60 (m, 2H), 1.90–1.98 (m, 2H), 3.31–3.34 (m, 2H),
7.30–7.37 (m, 2H), 7.80–7.84 (m, 1H), 8.09–8.10 (m, 2H),
8.42–8.43 (m, 1H), 9.53 (s, 1H); 13C NMR (100 MHz, CDCl3)
13-Butyl-1-chloro-5-tosyl-6,11-dihydro-5H-11,6-(azenometheno)-
benzo[e]pyrido[4,3-b]azepine 4b
1H NMR (400 MHz, CDCl3) δ 0.91 (t, J = 7.2 Hz, 3H),
1.28–1.37 (m, 2H), 1.65–1.72 (m, 2H), 2.29 (s, 3H), 2.61–2.79
(m, 2H), 6.19 (s, 1H), 6.49 (s, 1H), 7.07 (d, J = 7.8 Hz, 2H),
7.21 (t, J = 7.3 Hz, 3H), 7.37–7.45 (m, 2H), 7.49 (d, J = 6.9 Hz,
1H), 7.62 (d, J = 7.3 Hz, 1H), 7.81 (d, J = 5.5 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 13.8, 21.5, 22.4, 27.7, 37.9, 55.6,
61.4, 114.7, 121.0, 124.9, 127.3, 127.5, 128.4, 129.2, 129.9,
131.7, 134.7, 142.3, 145.1, 145.4, 147.8, 150.7, 172.7; HRMS
2
δ 14.0, 22.6, 28.7, 30.9, 107.7 (d, JCF = 24 Hz), 114.1, 115.1,
2
3
116.7 (d, JCF = 24 Hz), 119.2, 124.9, 126.1 (d, JCF = 10 Hz),
129.5 (d, 3JCF = 9 Hz), 129.9, 138.0, 139.2, 143.9, 144.7, 161.9
(d, JCF = 247 Hz); HRMS calcd for C18H17FN3 (M+ + H):
1
294.1407, found: 294.1410.
6-Butyl-2-fluoropyrido[4′,3′:3,4]pyrazolo[5,1-a]isoquinoline 3h′
calcd for C25H25ClN3O2S (M+
466.1345.
+ H): 466.1356, found:
1H NMR (400 MHz, CDCl3) δ 1.04 (t, J = 7.3 Hz, 3H),
1.53–1.60 (m, 2H), 1.94–2.01 (m, 2H), 3.38–3.42 (m, 2H), 7.41
(s, 1H), 7.44–7.48 (m, 1H), 7.81 (d, J = 6.0 Hz, 1H), 7.91–7.94
(m, 1H), 8.31 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 5.0 Hz, 1H), 9.86
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.0, 22.6, 28.8, 31.1,
1-Chloro-9-methyl-13-phenyl-5-tosyl-6,11-dihydro-5H-11,6-
(azenometheno)benzo[e]pyrido[4,3-b]azepine 4c
2
2
1H NMR (400 MHz, CDCl3) δ 2.28 (s, 3H), 2.42 (s, 3H), 6.70
(s, 1H), 7.02–7.05 (m, 3H), 7.22–7.26 (m, 4H), 7.37 (s, 1H),
7.48–7.50 (m, 3H), 7.59 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 6.0
Hz, 1H), 8.07–8.09 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 21.5, 53.1, 62.0, 114.6, 120.6, 125.6, 127.4, 127.6, 128.8,
129.0, 129.1, 129.9, 131.5, 134.6, 135.6, 139.5, 142.0, 145.0,
145.5, 147.8, 150.9, 167.3; HRMS calcd for C28H23ClN3O2S
(M+ + H): 500.1200, found: 500.1218.
108.5 (d, JCF = 24 Hz), 110.9, 114.8, 117.9 (d, JCF = 24 Hz),
3
3
125.1 (d, JCF = 9 Hz), 126.1, 129.8 (d, JCF = 9 Hz), 131.7,
1
139.4, 143.4, 145.1, 146.2, 150.1, 162.0 (d, JCF = 247 Hz);
HRMS calcd for C18H17FN3 (M+ + H): 294.1407, found:
294.1412.
2-Chloro-6-phenylpyrido[3′,4′:3,4]pyrazolo[5,1-a]isoquinoline 3i
1H NMR (400 MHz, CDCl3) δ 7.54–7.62 (m, 5H), 7.86 (d, J =
8.7 Hz, 1H), 7.96–7.97 (m, 2H), 8.23 (d, J = 5.5 Hz, 1H), 8.46
(s, 1H), 8.57 (s, 1H), 9.51 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ 114.1, 118.1, 119.0, 122.1, 126.6, 126.8, 128.5, 128.7, 129.3,
129.7, 130.1, 130.3, 133.0, 134.8, 138.3, 139.0, 144.5, 145.1;
HRMS calcd for C20H13ClN3 (M+ + H): 330.0798, found:
330.0796.
1-Chloro-8-fluoro-13-phenyl-5-tosyl-6,11-dihydro-5H-11,6-
(azenometheno)benzo[e]pyrido[4,3-b]azepine 4d
1H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H), 6.75 (s, 1H),
7.03–7.13 (m, 4H), 7.23–7.26 (m, 3H), 7.42–7.54 (m, 5H), 7.83
(d, J = 5.5 Hz, 1H), 8.06 (d, J = 6.4 Hz, 2H); 13C NMR
2
(100 MHz, CDCl3) δ 21.5, 52.9, 61.4, 114.8 (d, JCF = 23 Hz),
2
3
2-Chloro-6-phenylpyrido[4′,3′:3,4]pyrazolo[5,1-a]isoquinoline
3i′
114.9, 116.0 (d, JCF = 22 Hz), 120.5, 126.7 (d, JCF = 8 Hz),
127.4, 127.5, 129.1, 130.0, 131.7, 133.9 (d, 3JCF = 8 Hz), 134.5,
1
135.3, 137.7, 145.3, 145.5, 148.0, 150.8, 162.8 (d, JCF = 247
1H NMR (400 MHz, CDCl3) δ 7.32–7.35 (m, 1H), 7.59–7.62
(m, 3H), 7.69 (d, J = 8.3 Hz, 1H), 7.73–7.77 (m, 1H), 7.84 (d,
J = 7.3 Hz, 1H), 7.92–7.97 (m, 2H), 8.53 (s, 1H), 8.72 (s, 1H),
9.94 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 117.7, 120.5,
122.9, 127.9, 128.2, 128.7, 129.4, 129.8, 130.1, 130.2, 130.3,
133.1, 135.1, 139.0, 143.4, 146.3, 151.2; HRMS calcd for
C20H13ClN3 (M+ + H): 330.0798, found: 330.0792.
Hz), 166.4; HRMS calcd for C27H20ClFN3O2S (M+ + H):
504.0949, found: 504.0968.
1-Chloro-9-fluoro-13-phenyl-5-tosyl-6,11-dihydro-5H-11,6-
(azenometheno)benzo[e]pyrido[4,3-b]azepine 4e
1H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H), 6.75 (s, 1H),
7.03–7.13 (m, 4H), 7.23–7.26 (m, 3H), 7.42–7.54 (m, 5H), 7.83
(d, J = 6.0 Hz, 1H), 8.06 (d, J = 7.3 Hz, 2H); 13C NMR
1-Chloro-13-phenyl-5-tosyl-6,11-dihydro-5H-11,6-
(azenometheno)benzo[e]pyrido[4,3-b]azepine 4a
2
(100 MHz, CDCl3) δ 21.5, 52.9, 61.4, 114.8 (d, JCF = 23 Hz),
2
3
1H NMR (400 MHz, CDCl3) δ 2.27 (s, 3H), 6.76 (s, 1H), 7.01
(d, J = 8.3 Hz, 2H), 7.08 (s, 1H), 7.19 (d, J = 8.2 Hz, 2H), 7.24
(d, J = 6.0 Hz, 1H), 7.40–7.57 (m, 6H), 7.72 (d, J = 6.9 Hz,
1H), 7.80 (d, J = 6.0 Hz, 1H), 8.08–8.10 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 21.5, 53.2, 62.0, 114.7, 120.5, 125.0,
114.9, 116.0 (d, JCF = 21 Hz), 126.7 (d, JCF = 8 Hz), 127.4,
127.5, 129.0, 129.1, 130.0, 131.7, 133.9 (d, 3JCF = 8 Hz), 134.5,
1
135.3, 137.7, 145.3, 145.5, 148.0, 150.8, 162.8 (d, JCF = 247
Hz), 166.4; HRMS calcd for C27H20ClFN3O2S (M+ + H):
504.0949, found: 504.0974.
8106 | Org. Biomol. Chem., 2012, 10, 8102–8107
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Ed., 2006, 45, 7134; (i) D. Enders, C. Grondal and M. R. M. Hüttl,
Angew. Chem., Int. Ed., 2007, 46, 1570; ( j) L. F. Tietze, G. Brasche and
K. Gericke, Domino Reactions in Organic Synthesis, Wiley-VCH, Wein-
heim, Germany, 2006; (k) L. F. Tietze, M. A. Düfert, T. Hungerland,
K. Oum and T. Lenzer, Chem.–Eur. J., 2011, 17, 8452; (l) J. Panteleev,
L. Zhang and M. Lautens, Angew. Chem., Int. Ed., 2011, 50, 9089;
(m) S. H. Kim, S. H. Park, J. H. Choi and S. Chang, Chem.–Asian J.,
2011, 6, 2618.
4 For selected examples: (a) S. Li and J. Wu, Org. Lett., 2011, 13, 712;
(b) S. Ye, X. Yang and J. Wu, Chem. Commun., 2010, 46, 5238; (c) X. Yu,
S. Ye and J. Wu, Adv. Synth. Catal., 2010, 352, 2050; (d) X. Yu, Z. Chen,
X. Yang and J. Wu, J. Comb. Chem., 2010, 12, 374; (e) Z. Chen, L. Gao,
S. Ye, Q. Ding and J. Wu, Chem. Commun., 2012, 48, 3975; (f) S. Li,
Y. Luo and J. Wu, Org. Lett., 2011, 13, 4312; (g) G. Liu, H. Liu, G. Qiu,
S. Pu and J. Wu, Chem. Commun., 2012, 48, 7049; (h) Z. Chen and J. Wu,
Org. Lett., 2010, 12, 4856.
13-Butyl-1-chloro-9-fluoro-5-tosyl-6,11-dihydro-5H-11,6-
(azenometheno)benzo[e]pyrido[4,3-b]azepine 4f
1H NMR (400 MHz, CDCl3) δ 0.91 (t, J = 7.3 Hz, 3H),
1.28–1.37 (m, 2H), 1.64–1.71 (m, 2H), 2.32 (s, 3H), 2.61–2.79
(m, 2H), 6.17 (s, 1H), 6.46 (s, 1H), 7.11–7.13 (m, 3H),
7.20–7.28 (m, 4H), 7.57–7.60 (m, 1H), 7.83 (d, J = 6.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 13.8, 21.5, 22.3, 27.6, 37.8,
2
2
54.9, 61.2, 112.5 (d, JCF = 22 Hz), 114.7, 115.3 (d, JCF
=
3
22 Hz), 120.4, 127.4, 129.1 (d, JCF = 8 Hz), 130.1, 134.7,
3
144.6 (d, JCF = 8 Hz), 145.3, 145.4, 148.0, 150.8, 162.9 (d,
1JCF = 250 Hz), 172.9; HRMS calcd for C25H24ClFN3O2S
(M+ + H): 484.1262, found: 484.1252.
5 (a) S. Hernández, R. SanMartin, I. Tellitu and E. Domínguez, Org. Lett.,
2003, 5, 1095; (b) J. J. Mousseau, A. Fortier and A. Charette, Org. Lett.,
2010, 12, 516; (c) E. E. Schweizer, M. Nelson and W. Stallings, J. Org.
Chem., 1980, 45, 4795; (d) X. Li and M. Zhao, J. Org. Chem., 2011, 76,
8530; (e) D. B. Huple, C.-H. Chen, A. Das and R.-S. Liu, Adv. Synth.
Catal., 2011, 353, 1877; (f) J. Zhao, C. Wu, P. Li, W. Ai, H. Chen,
C. Wang, R. C. Larock and F. Shi, J. Org. Chem., 2011, 76, 6837;
(g) M. Kobayashi, K. Kondo and T. Aoyama, Tetrahedron Lett., 2007, 48,
7019; (h) R. J. Sundberg and J. E. Ellis, J. Heterocycl. Chem., 1982, 19,
573; (i) 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.
6 For general reviews of hetarynes, see: (a) T. Kauffmann and R. Wirthwein,
Angew. Chem., Int. Ed. Engl., 1971, 10, 20; (b) M. G. Reinecke, Tetrahe-
dron, 1982, 38, 427.
7 (a) G. W. Fleet and I. Fleming, J. Chem. Soc. C, 1969, 1758;
(b) J. D. Cook and B. J. Wakefield, J. Chem. Soc. C, 1969, 1973;
(c) C. May and C. J. Moody, J. Chem. Soc., Perkin Trans. 1, 1988, 247;
(d) M. A. Walters and J. J. Shay, Synth. Commun., 1997, 27, 3573;
(e) S. J. Connon and A. F. Hegarty, Eur. J. Org. Chem., 2004, 3477;
(f) T. Iwayama and Y. Sato, Chem. Commun., 2009, 5245.
8 (a) T. Kauffmann and F.-P. Boettcher, Chem. Ber., 1962, 95, 949;
(b) G. W. Gribble, M. G. Saulnier, M. P. Sibi and J. A. Obaza-Nutaitis,
J. Org. Chem., 1984, 49, 4518; (c) B. Jamart-Gregoire, C. Leger and
P. Caubere, Tetrahedron Lett., 1990, 31, 7599; (d) G. W. Gribble and
M. G. Saulnier, Heterocycles, 1993, 35, 151; (e) S. J. Connon and
A. F. Hegarty, J. Chem. Soc., Perkin Trans. 1, 2000, 1245; (f) M. Díaz,
A. Cobas, E. Guitián and L. Castedo, Eur.J. Org. Chem., 2001, 4543;
(g) N. Mariet, M. Ibrahim-Ouali and M. Santelli, Tetrahedron Lett., 2002,
43, 5789; (h) W. Lin, L. Chen and P. Knochel, Tetrahedron, 2007, 63,
2787; (i) F. I. Carroll, T. P. Robinson, L. E. Brieaddy, R. N. Atkinson,
S. W. Mascarella, M. I. Damaj, B. R. Martin and H. A. Navarro, J. Med.
Chem., 2007, 50, 6383.
Financial support from the National Natural Science Foun-
dation of China (Nos. 21032007, 21172038) is gratefully
acknowledged.
Notes and references
1 (a) S. L. Schreiber, Proc. Natl. Acad. Sci. U. S. A., 2011, 108, 6699;
(b) K. Hübel, T. Leßmann and H. Waldmann, Chem. Soc. Rev., 2008, 37,
1361; (c) S. L. Schreiber, Chem. Eng. News, 2003, 81, 51;
(d) D. H. Drewry and R. Macarron, Curr. Opin. Chem. Biol., 2010, 14,
289; (e) K. H. Bleicher, H.-J. Böhm, K. Müller and A. I. Alanine, Nat.
Rev. Drug Discovery, 2003, 2, 369; (f) S. Dandapani and
L. A. Marcaurelle, Nat. Chem. Biol., 2010, 6, 861.
2 (a) D. P. Walsh and Y.-T. Chang, Chem. Rev., 2006, 106, 2476; (b) P. Arya,
D. T. H. Chou and M.-G. Baek, Angew. Chem., Int. Ed., 2001, 40, 339;
(c) S. L. Schreiber, Science, 2000, 287, 1964; (d) M. D. Burke and
S. L. Schreiber, Angew. Chem., Int. Ed., 2004, 43, 46; (e) S. L. Schreiber,
Nature, 2009, 457, 153; (f) D. S. Tan, Nat. Chem. Biol., 2005, 1, 74;
(g) C. Cordier, D. Morton, S. Murrison, A. Nelson and C. O’Leary-Steele,
Nat. Prod. Rep., 2008, 25, 719; (h) W. R. J. D. Galloway, A. I. Llobet and
D. R. Spring, Nat. Commun., 2010, 1, 80; (i) S. Oh and S. B. Park, Chem.
Commun., 2011, 47, 12754.
3 For reviews, see: (a) J. Montgomery, Angew. Chem., Int. Ed., 2004, 43,
3890; (b) E. Negishi, C. Coperet, S. Ma, S. Y. Liou and F. Liu, Chem.
Rev., 1996, 96, 365; (c) L. F. Tietze, Chem. Rev., 1996, 96, 115;
(d) R. Grigg and V. Sridharan, J. Organomet. Chem., 1999, 576, 65;
(e) T. Miura and M. Murakami, Chem. Commun., 2007, 217;
(f) M. Malacria, Chem. Rev., 1996, 96, 289; (g) K. C. Nicolaou,
T. Montagnon and S. A. Snyder, Chem. Commun., 2003, 551;
(h) K. C. Nicolaou, D. J. Edmonds and P. G. Bulger, Angew. Chem., Int.
This journal is © The Royal Society of Chemistry 2012
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