Direct synthesis of pyrazolo[5,1-a]isoindoles via intramolecular palladium-catalyzed C-H bond activation

Article abstract of DOI:10.1002/adsc.201000260

An efficient, direct synthesis of pyrazolo-[5,1-a]isoindoles employing a palladium-catalyzed intramolecular C-H bond activation of 1-(2-halobenzyl) pyrazoles has been developed. The use of lithium chloride (LiCl) was found to be essential in these reactions, to suppress further C-H bond activation at the C-3 position of pyrazolo[5,1-a]isoindole, when C-3 is unsubstituted. This protocol can be applied to the synthesis of a pyrazolo[5,1-a]isoquinoline possessing a six-membered central ring system and a fully substituted pyrazolo[5,1-a]isoindole using sequential intra- and intermolecular C-H bond activation.

Full text of DOI:10.1002/adsc.201000260

FULL PAPERS
DOI: 10.1002/adsc.201000260
Direct Synthesis of Pyrazolo
[5,1-a]isoindoles via Intramolecular
À
Young Lok Choi,a,b Hyuk Lee,a Bum Tae Kim,a Kihang Choi,b
and Jung-Nyoung Heoa,*
a
Medicinal Chemistry Research Center, Korea Research Institute of Chemical Technology, 100 Jang-dong, Daejeon
305-600, Republic of Korea
Fax : (+82)-42-861-0307; e-mail: heojn@krict.re.kr
Department of Chemistry, Korea University, Anam-dong, Seoul 105-600, Republic of Korea
b
Received: April 4, 2010; Revised: June 15, 2010; Published online: August 16, 2010
Dedicated to Professor Bong Young Chung on the occasion of his honorable retirement.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000260.
Abstract: An efficient, direct synthesis of pyrazolo- the synthesis of a pyrazolo
ACHTUNGERTN[NUNG 5,1-a]isoquinoline pos-
ACHTUNGTRENNUNG[5,1-a]isoindoles employing a palladium-catalyzed in- sessing a six-membered central ring system and a
À
tramolecular C H bond activation of 1-(2-haloben- fully substituted pyrazoloACTHUNRTGNEUNG[5,1-a]isoindole using se-
zyl)pyrazoles has been developed. The use of lithium quential intra- and intermolecular C H bond activa-
chloride (LiCl) was found to be essential in these re- tion.
À
À
actions, to suppress further C H bond activation at
the C-3 position of pyrazolo
C-3 is unsubstituted. This protocol can be applied to um; pyrazoles
À
N
Introduction
(Scheme 1).[11] In this example, the metal-catalyzed in-
tramolecular cyclization of 1-(2-iodobenzyl)pyrazole
À
One of the most attractive methods for forming C C (1a) was difficult owing to the formation of the
À
bonds with a catalytic system is through C H bond
functionalization.[1] Transition metal-catalyzed trans-
formations represent a central strategy in this respect,
and Pd-catalyzed reactions in particular play a pivotal
role.[2,3] In connection with our ongoing studies on the
synthesis of biologically important heterocyclic com-
pounds containing a pyrazole motif,[4] we became in-
À
terested in exploring the intramolecular C H bond
activation of pyrazole scaffolds. Pyrazoles display a
wide variety of pharmacological and agrochemical ef-
fects, including anti-inflammatory (celecoxib),[5] anti-
ACHTUNGTRENNUNG
obesity (rimonabant),[6] phosphodiesterase inhibitory
(sildenafil),[7] and insecticidal (chloantraniliprole)[8]
activities (Figure 1).
À
Although elegant approaches towards C H bond
activation in these systems have been developed by
the groups of Sames[9] and the Lautens,[10] intramolec-
À
ular C H bond activation of pyrazole motifs remains
somewhat limited. For example, an unsuccessful at-
tempt at the intramolecular cyclization of pyrazole 1a
Figure 1. Biologically active compounds possessing a pyra-
has been reported by Mori and co-workers zole motif.
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Young Lok Choi et al.
FULL PAPERS
Scheme 1. Catalytic poisoning of the Pd-pyrazole complex.
strongly chelating complex 2 with a basic pyrazole ni- proved the reaction yield while suppressing the for-
trogen atom.[12] In addition, Grigg and co-workers re- mation of heterodimer 8 (entry 3).[16]
ported that pyrazole 4 failed to cyclize probably due
We were pleased to find that the combination of
to formation of a stable intermediate 5 (Scheme 1).[13] PivOH and LiCl significantly enhanced the reaction,
Despite these formidable challenges, the need re- achieving a 71% isolated yield (entry 4). Additionally,
mains for the development of novel catalytic systems we found that decreasing the amount of LiCl
À
that probe intramolecular C H bond activation of (1 equiv.) slightly decreased the yield, while increasing
pyrazoles.[14]
the amount of LiCl (5 equiv.) significantly lowered
Recently, studies in our laboratory have concentrat- the yields (entries 5 and 6). Other additives that were
ed on routes for the synthesis of novel polycyclic sub- tested, including Ag2CO3 and Ag(OAc), also proved
AHCTUNGTRENNUNG
stances that are based on a Pd-catalyzed coupling and inferior to our previous experiments using LiCl (en-
intramolecular cyclization strategy.[15] Herein, we tries 7 and 8). The addition of AcOH in place of the
report the first direct, one-step synthesis of pyrazolo- PivOH resulted in comparable results, affording 3a in
À
ACHTUNGTRENNUNG[5,1-a]isoindoles via Pd-catalyzed intramolecular C H 67% yield (entry 9). When the reaction temperature
bond activation of 1-(2-halobenzyl)pyrazoles.
was lowered to 1008C, only 14% and 6% of the de-
sired product were observed with respect to bromo-
and chloroarene (entry 10 and entry 13).
Results and Discussion
We next investigated the scope of different halogen
substituents on the aryl ring by replacing the bro-
To explore this approach, we began with a model moarene that we had previously been using with a
À
system studying the Pd-catalyzed intramolecular C H chloro- or iodoarene. Interestingly, chloroarene 1c, in
bond activation of 1-(2-bromobenzyl)pyrazole (1b) the presence of PivOH, proved effective and reduced
for the synthesis of pyrazoloACTHNUTRGNEUNG[5,1-a]isoindole (3a). The heterodimer formation (entry 11). In contrast, the use
results are illustrated in Table 1. We initially em- of PivOH and LiCl significantly retarded the reaction
ployed common catalytic conditions in the presence process (entry 12). Furthermore, iodoarene 1a result-
of PdACHTUNGTRENNUNG(OAc)2 (10 mol%) and K2CO3 (2 equiv.), using ed in a similar product ratio as that of bromoarene 1b
N,N-dimethylacetamide (DMA) as the solvent at (entries 14 and 15). Based on these observations, we
1508C for 24 h. Using these conditions, we could hypothesized that the salt effect of LiCl could control
obtain the desired cyclized product 3a in moderate the formation of heterodimeric compound 8. Using
yield, along with the debrominated product 7a sulfonate-based ring substituents, such as tosylate, me-
(entry 1). Surprisingly, the heterodimeric product 8 sylate, and triflate, provided unsatisfactory results (en-
À
was also observed, presumably due to further C H tries 16–18).
bond activation of 3a with 1b. Although we screened
The use of a wide range of phosphine-based ligands
several different solvents and various reaction tem- (Figure 2) did not exert any notable influence on the
peratures employing this Pd catalyst, the results re- reaction yield, as illustrated in Table 2. Neither mono-
mained unsatisfactory. The use of pivalic acid phosphine biaryl ligands[17] L1–L5 (entries 1–5) nor bi-
(PivOH, 30 mol%) did not provide any benefit dentate ligands L6–L8 (entries 6–8) gave satisfactory
(entry 2). However, the addition of LiCl (3 equiv.) im- results. Pyrrole- and indole-based ligands[18] L9–L11
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Adv. Synth. Catal. 2010, 352, 2041 – 2049

À
Direct Synthesis of PyrazoloACHTNUGTRENNUNG
Table 1. Formation of pyrazoloACHTNUGTRENNUNG
Entry
X
Additives
Yield [%][b]
3a
7a
8
1
2
3
4
5
6
7
8
Br (1b)
Br (1b)
Br (1b)
Br (1b)
Br (1b)
Br (1b)
Br (1b)
Br (1b)
Br (1b)
Br (1b)
Cl (1c)
Cl (1c)
Cl (1c)
I (1a)
none
PivOH (30 mol%)
LiCl (3 equiv.)
PivOH (30 mol%)+LiCl (3 equiv.)
PivOH (30 mol%)+LiCl (1 equiv.)
PivOH (30 mol%)+LiCl (5 equiv.)
PivOH (30 mol%)+Ag2CO3 (1 equiv.)
53
55
6
5
41
40
10
10
26
0
0
0
20
4
10
5
65
20
15
7
10
20
15
13
4
3
13
0
4
25
2
75 (71)[c]
67
10
0
26
67
14
69
45
6
60
65
2
PivOH (30 mol%)+Ag
(OAc) (1 equiv.)
9
AcOH (30 mol%)+LiCl (3 equiv.)
PivOH (30 mol%)+LiCl (3 equiv.)
PivOH (30 mol%)
PivOH (30 mol%)+LiCl (3 equiv.)
PivOH (30 mol%)+LiCl (3 equiv.)
PivOH (30 mol%)
PivOH (30 mol%)+LiCl (3 equiv.)
PivOH (30 mol%)+LiCl (3 equiv.)
PivOH (30 mol%)+LiCl (3 equiv.)
PivOH (30 mol%)+LiCl (3 equiv.)
10[d]
11
12
13[d]
14
15
16[e]
17[e]
18[e]
2
36
10
–
–
–
I (1a)
OTs (1d)
OMs (1e)
OTf (1f)
4
4
9
13 (14)[c]
[a]
Conditions: 1 (1 mmol), PdACHTNURGTNEG(UN OAc)2 (10 mol%), K2CO3 (2 equiv.), additives, DMA (0.14M), 1508C, 24 h.
Yields determined by H NMR.
Isolated yields in parenthesis.
The reaction was performed at 1008C.
Starting sulfonates were decomposed to the corresponding phenol.
[b]
[c]
[d]
[e]
1
(entries 9–11) proved inferior in circumventing the the formation of the heterodimeric by-product, we
formation of heterodimer 8. Consequently, the reac- used 4-methylpyrazole 1g, in which the C-3 position
À
tion under phosphine ligand-free conditions was used of the product 3b is blocked for the further C H
as the optimized catalytic system.
bond activation, as a precursor. As shown in Table 3,
Next, we wanted to investigate the influence of the reaction was found to be dependent on the
LiCl in these reactions with greater detail. To prevent amount of LiCl used. When the LiCl was used in
Figure 2. Structure of phosphine ligands.
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Young Lok Choi et al.
Table 3. Formation of 3-methylpyrazoloACTHUNGRTENNUGN
[5,1-a]isoindole.[a]
FULL PAPERS
Table 2. Ligand screening.[a]
Entry
Ligand
Yield [%][b]
3a
7a
8
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
49
69
61
74
69
69
62
56
61
63
67
7
5
6
7
4
6
6
25
7
5
7
14
24
28
19
27
25
26
18
26
26
26
Entry
LiCl (equiv.)
Yield [%][b]
3b
7b
1
2
3
4
5
6
none
100 (87)[c]
100
0
0
0
1
29
48
9
10
11
1
2
3
4
5
100
99 (86)[c]
71
[a]
Conditions: 1b (1 mmol), PdACHTNUGTRENUNG(OAc)2 (10 mol%), ligand
(20 mol%), PivOH (30 mol%), LiCl (3 equiv.), K2CO3
52
[a]
(2 equiv.), DMA (0.14M), 1508C, 24 h.
Conditions: 1g (1 mmol), PdACHTNUGTRENUNG(OAc)2 (10 mol%), PivOH
(30 mol%), LiCl (0–5 equiv.), K2CO3 (2 equiv.), DMA
[b]
1
Yields determined by H NMR.
(0.14M), 1508C, 24 h.
Yields determined by H NMR.
Isolated yields in parenthesis.
[b]
[c]
1
equivalents greater than 3, the reaction became slug-
gish and resulted in a lower yield (entries 4 and 5). In
contrast, with the absence of LiCl, the reaction pro-
ceeded smoothly to provide the cyclised product 3b [PdACTHNUGTRNEUNG(dppf)2Cl2·DCM, PPh3, Ag2CO3, H2O, 50 8C,
with 100% conversion (entry 1). We believe that 16 h].[19] Both electron-donating and electron-with-
these results illustrate that the primary purpose of drawing substituents on the bromoarene were tolerat-
LiCl addition is to minimize the formation of the by- ed, providing the desired products in good yields (en-
product.
We subsequently adopted these optimized condi- a good substrate for cyclization and provided 3,4-di-
tions, including Pd(OAc)2 (10 mol%), PivOH methyl-substituted pyrazoloisoindole 3k in 97% yield
tries 7–9). Sterically hindered bromoarene 1p was also
AHCTUNGTRENNUNG
(30 mol%), LiCl (none or 3 equiv.), and K2CO3 (entry 10). In addition, heteroarenes, such as naph-
(2 equiv.) in DMA at 1508C for 6 h, for the synthesis thyl, thienyl, and pyridinyl moieties, afforded the cor-
of various pyrazoloACTHNUTRGNE[UNG 5,1-a]isoindoles using a wide responding products, albeit reaction yields were only
range of substituted pyrazole-benzyl halides as pre- moderate (entries 11–13). Interestingly, when the re-
cursors (Table 4). The use of LiCl was mainly depen- action of bromothiophene 1r was carried out in the
dent on the substitution pattern of pyrazole. For ex- absence of LiCl, the further C-5 dimerization of 3m
ample, in the absence of LiCl, 4-methylpyrazole 1g with 1r occurred significantly to afford compound
provided the desired product 3b in 87% yield. How- 12[21] along with the desired product 3m in only 17%
ever, in the case of compound 1h, which was bearing yield (entry 12).
a 3-methylpyrazole group, LiCl was required to bring
the reaction to completion to produce the correspond- reacted 2-bromophenethylpyrazole 9 under standard
ing pyrazoloisoindole 3c in 99% yield (entry 2). Aryl- conditions to provide 5,6-dihydropyrazolo[5,1-a]iso-
To expand the utility of this reaction protocol, we
AHCTUNGTRENNUNG
substituted pyrazoles 1i and 1j also resulted in the quinoline 10 possessing a six-membered central ring
corresponding cyclized products 3d and 3e in 84% system in 63% yield (Scheme 2). Furthermore, the
À
and 85% yield, respectively (entries 3 and 4). The last available C H bond activation at the C-3 position
structure of 3e was confirmed by X-ray crystallogra- of 3e was achieved in the presence of P
A
phy (see ORTEP representation in Figure 3). It provide the fully substituted pyrazolo
should be noted that in cases using C-3-substituted 11 in 65% yield.[22]
pyrazoles, little to no heterodimeric side product was
ACHTUNGTRENNUNG
observed. In case of the disubstituted pyrazole 1k, the
reaction provided solely 3f in good yield (entry 5).
In the case of the N-2 substituted indazole 1l, we
Conclusions
successfully prepared isoindoloACTHNUTRGNEU[GN 2,1-b]indazole 3g in In summary, we have established a novel, direct, one-
moderate yield. Greaney and co-workers had previ- step synthesis of pyrazolo
ously reported that this type of intramolecular cycliza- lyzed intramolecular C H bond activation. The use of
tion was ineffective under their optimized conditions LiCl is essential in these reactions to suppress further
[5,1-a]isoindoles via Pd-cata-
À
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À
Direct Synthesis of PyrazoloACHTNUGTRENNUNG
[a]
À
Table 4. Scope of intramolecular Pd-catalyzed C H bond activation.
Entry
Substrate
LiCl (equiv.)
Product
Yield [%][b]
87
1
1g
1h
1i
none
3b
3c
3d
2
3
3.0
99
84
none
4
1j
3.0
3e
85
5
6
1k
1l
none
none
3f
3g
78
53
7
8
9
1m
1n
1o
none
none
none
3h
3i
79
85
85
3j
10
11
12
1p
1q
1r
none
3.0
3k
3l
97
50
3.0
3m
51 (17)[c]
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Young Lok Choi et al.
Yield [%][b]
FULL PAPERS
Table 4. (Continued)
Entry
Substrate
LiCl (equiv.)
none
Product
13
1s
3n
55
[a]
Reaction conditions: substrate (1 mmol), PdACHTNUTRGNE(UNG OAc)2 (10 mol%), PivOH (30 mol%), LiCl (0 or 3 equiv.), K2CO3 (2 equiv.),
DMA (0.14M), 1508C, 6 h.
Isolated yields.
Isolated yield when the reaction was performed in the absence of LiCl.
[b]
[c]
Figure 3. ORTEP representation of pyrazoloACHTNUTRGNEUNG[5,1-a]isoindole
3e. Thermal ellipsoids are set at 50% probability.[20]
Scheme 2. Synthesis of pyrazolo
ACHTUNGTNER[NUNG 5,1-a]isoquinoline 10 and
fully substituted pyrazolo[5,1-a]isoindole 11.
AHCTUNGTRENNUNG
À
C H bond activation at the C-3 position of pyrazolo-
A
7.65 (d, 1H, J=1.8 Hz), 7.59 (d, 1H, J=7.5 Hz), 7.47 (d,
1H, J=7.4 Hz), 7.41 (d, 1H, J=7.2 Hz), 7.33 (t, 1H, J=
7.3 Hz), 6.38 (d, 1H, J=1.8 Hz), 5.12 (s, 2H); 13C NMR
(75 MHz, CDCl3): d=146.3, 143.6, 140.5, 131.0, 128.2, 127.2,
123.5, 120.5, 96.4, 52.1; IR (neat): n=1474, 1452, 1401, 1316,
932, 749 cmÀ1; MS (EI): m/z=156 (M+, 100), 129 (99), 102
(35), 77 (21), 63(27); HR-MS (EI): m/z=156.0678, calcd. for
C10H8N2 [M+]: 156.0687.
Furthermore, we have applied this protocol to the
synthesis of pyrazolo[5,1-a]isoquinolines possessing a
six-membered central ring system. Fully substituted
pyrazolo[5,1-a]isoindole was also synthesized by using
sequential intra- and intermolecular C H bond acti-
vation. Further studies towards the synthesis of bio-
logically important compounds will be discussed in
following reports.
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
À
3-{2-[(1H-Pyrazol-1-yl)methyl]phenyl}-8H-pyrazoloACHTUNGTRENNUNG[5,1-
a]isoindole (8): colorless liquid; 1H NMR (500 MHz,
CDCl3): d=7.52 (s, 1H), 7.50 (d, 1H, J=1.6 Hz), 7.50–7.46
(m, 2H), 7.39 (td, 1H, J=7.5, 1.4 Hz), 7.37–7.30 (m, 4H),
7.19 (d, 1H, J=2.2 Hz), 7.12 (d, 1H, J=7.5 Hz), 6.19 (t, 1H,
J=2.1 Hz), 5.40 (s, 2H), 5.18 (s, 2H); 13C NMR (75 MHz,
CDCl3): d=143.8, 143.3, 140.6, 139.5, 135.1, 131.7, 130.7,
129.4, 128.8, 128.3, 128.11, 128.06, 127.6, 123.6, 120.2, 112.4,
105.8, 53.7, 52.3, 29.7; IR (neat): n=1605, 1585, 1402, 1394,
1087, 1047, 753, 726 cmÀ1; MS (EI): m/z=312 (M+, 1), 244
(1), 111 (8), 97 (14), 57 (100); HR-MS (EI): m/z=312.1364,
calcd. for C20H16N4 [M+]: 312.1375.
Experimental Section
Typical Procedure for the Synthesis of 8H-
Pyrazolo
ACHTUNGTRENNUNG
A
vial was charged with 1-(2-halobenzyl)-1H-pyrazole
(0.50 mmol), PdACHTUNGTRENNUNG(OAc)2 (11 mg, 10 mol%), K2CO3 (138 mg,
1.0 mmol), and LiCl (64 mg, 1.5 mmol). A solution of
PivOH (15 mg, 30 mol%) in DMA (3.6 mL, 0.14M) was
added. The resulting mixture was vigorously stirred at
1508C for 6 h. The reaction mixture was cooled to room
temperature and directly purified by silica gel column chro-
matography (10% EtOAc/hexanes) to provide the corre-
sponding isoindoles 3a–3n.
3-Methyl-8H-pyrazoloACTHNUGRTENUNG[5,1-a]isoindole (3b): The reaction
was run without LiCl. Yield: 87%, white solid, mp 96–978C;
1H NMR (300 MHz, CDCl3): d=7.59 (d, 1H, J=7.6 Hz),
7.45–7.38 (m, 3H), 7.31 (d, 1H, 7.5 Hz), 5.07 (s, 2H), 2.31 (s,
3H); 13C NMR (75 MHz, CDCl3): d=144.0, 143.6, 140.2,
131.7, 128.1, 126.6, 123.5, 119.8, 107.9, 52.0, 8.8; IR (neat):
8H-Pyrazolo
A
n=1477, 1546, 1402, 1382, 1321, 1160, 1004, 761, 717 cmÀ1
;
1
yellow solid, mp 43–458C; H NMR (300 MHz, CDCl3): d=
MS (EI): m/z=170 (M+, 100), 155 (16), 143 (27), 115 (29),
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À
Direct Synthesis of PyrazoloACTHNUTRGNE[NUG 5,1-a]isoindoles via Intramolecular Palladium-Catalyzed C H Bond Activation
89 (11); HR-MS (EI): m/z=170.0840, calcd. for C11H10N2
n=1595, 1475, 1447, 1430, 1400, 1246, 1206, 1161, 1126,
808 cmÀ1; MS (EI): m/z=188 (M+, 100), 173 (11), 161 (25),
133 (31), 107 (11); HR-MS (EI): m/z=188.0747, calcd. for
C14H10N2 [M+]: 206.0844.
[M+]: 170.0844.
2-Methyl-8H-pyrazoloACHTUNGTERNNU[NG 5,1-a]isoindole (3c): Yield: 99%,
1
white solid, mp 67–688C; H NMR (300 MHz, CDCl3): d=
7.54 (d, 1H, J=7.5 Hz), 7.45–7.26 (m, 4H), 6.16 (s, 2H),
5.05 (s, 3H); 13C NMR (75 MHz, CDCl3): d=153.3, 147.0,
140.4, 131.3, 128.1, 127.0, 123.4, 120.4, 95.9, 52.0, 14.4; IR
(neat): n=1730, 1562, 1469, 1004, 754, 717 cmÀ1; MS (EI):
m/z=170 (M+, 100), 155(26), 129 (77), 115 (35), 63 (25);
HR-MS (EI): m/z=170.0840, calcd. for C11H10N2 [M+]:
170.0844.
5-Fluoro-3-methyl-8H-pyrazoloACTHNUGTRNEUNG[5,1-a]isoindole (3i): The
reaction was run without LiCl. Yield: 85%, yellow solid, mp
119–1208C; 1H NMR (300 MHz, CDCl3): d=7.44 (s, 1H),
7.38 (dd, 1H, J=8.1, 4.7 Hz), 7.28–7.25 (m, 1H), 7.02–6.96
(m ,1H), 5.04 (s, 2H), 2.30 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=163.0 (d, J=245.2 Hz), 144.1, 142.8 (d, J=
3.5 Hz), 135.4 (d, J=2.8 Hz), 133.3 (d, J=10.0 Hz), 124.6 (d,
J=9.1 Hz), 113.3 (d, J=23.1 Hz), 107.3 (d, J=24.8 Hz),
51.7, 8.72; IR (neat): n=1595, 1476, 1431, 1400, 1276, 1247,
1206, 1090, 809 cmÀ1; MS (EI): m/z=188 (M+, 1), 129 (18),
97 (23), 73 (100); HR-MS (EI): m/z=188.0747, calcd. for
C11H9FN2 [M+]: 188.0750.
3-Phenyl-8H-pyrazoloACTHNUGRTENUNG[5,1-a]isoindole (3d): The reaction
was run without LiCl. Yield: 84%, white solid, mp 98–998C;
1H NMR (300 MHz, CDCl3): d=7.82 (d, 1H, J=6.7 Hz),
7.77 (s, 1H), 7.63 (d, 2H, J=7.1 Hz), 7.47 (t, 3H, J=
7.7 Hz), 7.41–7.30 (m, 3H), 5.17 (s, 2H); 13C NMR (75 MHz,
CDCl3): d=159.3, 156.0, 147.5, 140.3, 131.1, 128.2, 127.3,
126.9, 126.7, 123.5, 120.5, 114.1, 92.9, 55.3, 52.3; IR (neat):
6-Methoxy-3-methyl-8H-pyrazolo
G
(3j):
The reaction was run without LiCl. Yield: 85%, white solid,
n=1606, 1473, 1454, 1353, 1236, 1170, 965, 755, 697 cmÀ1
;
mp 90–928C; H NMR (300 MHz, CDCl3): d=7.47 (d, 1H,
1
MS (EI): m/z=232 (M+, 100), 204 (51), 176 (20), 88 (12);
HR-MS (EI): m/z=232.0995, calcd. for C16H12N2 [M+]:
232.1000.
J=8.3 Hz), 7.39 (s, 1H), 7.00 (d, 1H, J=2.1 Hz), 6.92 (dd,
1H, J=8.3, 2.3 Hz), 5.02 (s, 2H), 3.85 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=158.9, 143.9, 143.6, 142.1, 124.6, 120.5,
113.4, 110.0, 106.7, 55.6, 52.0, 8.8; IR (neat): n=1712, 1400,
2-(4-Methoxyphenyl)-8H-pyrazolo
G
(3e):
Yield: 85%, white solid, mp 171–1728C; 1H NMR
(300 MHz, CDCl3): d=7.79 (d, 2H, J=8.9 Hz), 7.61 (d, 1H ,
J=7.4 Hz), 7.48 (d, 1H, J=7.4 Hz), 7.42 (td, 1H, J=7.5,
1.2 Hz), 7.34 (td, 1H, J=7.5, 1.2 Hz), 6.96 (d, 2H, J=
8.9 Hz), 5.15 (s, 2H), 3.85 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=159.4, 156.0, 147.5, 140.3, 131.1, 128.3, 127.3,
126.9, 126.8, 123.5, 120.5, 114.1, 92.9, 55.3, 52.3; IR (neat):
n=2111, 1610, 1527, 1453, 1432, 1298, 1245, 1182, 1029, 837,
758 cmÀ1; MS (EI): m/z=262 (M+, 100), 247 (42), 189 (23),
129 (22), 63 (21); HR-MS (EI): m/z=262.1104, calcd. for
C17H14N2O [M+]: 262.1106.
1481, 1289, 1265, 1253, 1216, 1141, 1038, 1000, 807, 675 cmÀ1
;
MS (EI): m/z=200 (M+, 100), 185 (41), 130 (32), 103 (26),
77 (27); HR-MS (EI): m/z=200.0948, calcd. for C12H12N2O
[M+]: 200.0950.
3,4-Dimethyl-8H-pyrazoloACHTNUTRGNE[NUG 5,1-a]isoindole (3k): The reac-
tion was run without LiCl. Yield: 97%, yellow solid, mp 87–
1
898C; H NMR (300 MHz, CDCl3): d=7.43 (s, 1H), 7.26–
7.14 (m, 4H), 5.02 (s, 2H), 2.66 (s, 3H), 2.41 (s, 3H);
13C NMR (75 MHz, CDCl3): d=145.0, 143.9, 140.3, 131.6,
130.5, 129.9, 127.0, 120.7, 107.7, 51.8, 21.8, 11.3; IR (neat):
n=1760, 1484, 1450, 1394, 1347, 1321, 1275, 1156, 836, 806,
763, 673 cmÀ1; MS (EI): m/z=184 (M+, 100), 169 (71), 157
(14), 142 (14), 128 (14), 115 (15); HR-MS (EI): m/z=
184.1027, calcd. for C12H12N2 [M+]: 184.1000.
Methyl 2-methyl-8H-pyrazoloACTHNUTRGENUGN[5,1-a]isoindole-3-carboxyl-
ate (3f): The reaction was run without LiCl. Yield: 78%,
1
white solid, mp 58–608C; H NMR (300 MHz, CDCl3): d=
8.27 (d, 1H, J=7.1 Hz), 7.51–7.41 (m, 3H), 5.07 (s, 2H),
3.96 (s, 3H), 2.57 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
164.6, 155.8, 149.5, 141.0, 130.4, 128.5, 123.7, 123.1, 104.3,
52.3, 51.1, 14.6; IR (neat): n=1693, 1556, 1472, 1443, 1278,
1198, 1164, 1111, 1086, 768, 722 cmÀ1; MS (EI): m/z=228
(M+, 68), 213 (24), 197 (100), 115 (24); HR-MS (EI): m/z=
228.0895, calcd. for C13H12N2O2 [M+]: 228.0899.
10H-Pyrazolo[1’,5’:1,2]pyrrolo
[3,4-b]naphthalene
(3l):
Yield: 50%, yellow solid, mp 102–1038C; 1H NMR
(300 MHz, CDCl3): d=8.21 (d, 1H, J=8.3 Hz), 7.95 (d, 1H,
J=8.2 Hz), 7.87 (d, 1H, J=8.5 Hz), 7.68–7.57 (m, 3H),
6.678 (s, 1H), 5.26 (s, 2H); 13C NMR (75 MHz, CDCl3): d=
146.1, 143.8, 138.3, 133.2, 128.7, 127.9, 127.6, 127.1, 126.6,
126.3, 124.1, 121.0, 97.8, 52.7; IR (neat): n=1553, 1378,
1522, 1369, 1173, 956, 805, 779 cmÀ1; MS (EI): m/z=206
(M+, 100), 179 (38), 152 (34); HR-MS (EI): m/z=206.0847,
calcd. for C14H10N2 [M+]. 206.0844.
3H-IsoindoloACHTUNGTRENNUNG[2,1-b]indazole (3g): The reaction was run
without LiCl. Yield: 53%, white solid, mp 118–2008C;
1H NMR (300 MHz, CDCl3): d=7.94 (d, 1H, J=8.4 Hz),
7.83–7.75 (m, 2H), 7.36 (t, 2H, J=7.7 Hz), 7.19 (t, 1H, J=
7.5 Hz), 5.38 (s, 2H); 13C NMR (75 MHz, CDCl3): d=153.4,
139.5, 139.2, 131.6, 128.6, 126.8, 126.1, 123.4, 121.6, 119.8,
119.7, 118.0, 114.7, 53.3; IR (neat): n=1737, 1689, 1476,
1399, 1379, 1318, 1280, 1011, 752, 715 cmÀ1; MS (EI): m/z=
206 (M+, 100), 179 (19), 151 (24), 103 (15), 89 (16); HR-MS
(EI): m/z=206.0835, calcd. for C14H10N2 [M+]: 206.0844.
3-Methyl-7H-thieno[2’,3’:3,4]pyrroloACTHNUTRGENUG[N 1,2-b]pyrazole (3m):
Yield: 51%, yellow solid, mp 114–1158C; 1H NMR
(300 MHz, CDCl3): d=7.37 (s, 1H), 7.34 (d, 1H, J=4.9 Hz),
7.07 (d, 1H, J=4.9 Hz), 4.95 (s, 3H), 2.21 (s, 4H); 13C NMR
(75 MHz, CDCl3): d=143.6, 143.2, 141.0, 131.5, 127.3, 121.5,
105.7, 51.4, 8.8; IR (neat): n=1727, 1602, 1444, 1395, 1383,
1326, 1263, 1085, 1008, 822, 708, 675 cmÀ1; MS (EI): m/z=
176 (M+, 100), 161 (12), 149 (20), 121 (13), 108 (9); HR-MS
(EI): m/z=176.0398, calcd. for C9H8N2S [M+]: 176.0408.
6-Fluoro-3-methyl-8H-pyrazoloACTHNUGTRNEUNG[5,1-a]isoindole (3h): The
reaction was run without LiCl. Yield: 79%, white solid, mp
1
115–1168C; H NMR (300 MHz, CDCl3): d=7.52 (dd, 1H,
3-Methyl-8H-pyrazolo[1’,5’:1,2]pyrroloACHTNGUTERNNU[G 3,4-b]pyridine
J=8.3, 4.9 Hz), 7.41 (s, 1H), 7.18–7.08 (m, 2H), 5.06 (s,
2H), 2.29 (s, 3H); 13C NMR (75 MHz, CDCl3): d=161.80
(d, J=246.0 Hz), 144.1, 142.9, 142.2 (d, J=8.9 Hz), 127.9 (d,
J=2.8 Hz), 120.8 (d, J=8.8 Hz), 115.2 (d, J=22.9 Hz), 111.6
(d, J=24.6 Hz), 107.6, 52.0 (d, J=2.8 Hz), 8.7; IR (neat):
(3n): The reaction was run without LiCl. Yield: 55%, yellow
solid, mp 152–1538C; H NMR (300 MHz, CDCl3): d=8.59
(d, 1H, J=5.1 Hz), 7.72 (d, 1H, J=7.7 Hz), 7.50 (s, 1H),
7.17 (dd, 1H, J=7.7, 5.1 Hz), 5.10 (s, 2H), 2.41 (s, 3H);
13C NMR (75 MHz, CDCl3): d=152.1, 149.4, 144.6, 142.4,
1
Adv. Synth. Catal. 2010, 352, 2041 – 2049
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2047

Young Lok Choi et al.
FULL PAPERS
134.5, 130.8, 120.6, 110.2, 50.6, 8.6; IR (neat): n=1599, 1574,
1390, 1175, 829, 791, 682 cmÀ1; MS (EI): m/z=171 (M+,
100), 143 (42), 117 (16), 89 (9); HR-MS (EI): m/z=
171.0798, calcd. for C10H9N3 [M+]: 171.0796.
A. R. Kapdi, Angew. Chem. 2009, 121, 9976–10011;
Angew. Chem. Int. Ed. 2009, 48, 9792–9826; c) O. Dau-
gulis, H.-Q. Do, D. Shabashov, Acc. Chem. Res. 2009,
42, 1074–1086; d) X. Chen, K. M. Engle, D.-H. Wang,
J.-Q. Yu, Angew. Chem. 2009, 121, 5196–5217; Angew.
Chem. Int. Ed. 2009, 48, 5094–5115; e) J. C. Lewis,
R. G. Bergman, J. A. Ellman, Acc. Chem. Res. 2008, 41,
1013–1025; f) B.-J. Li, S.-D. Yang, Z.-J. Shi, Synlett
2008, 949–957; g) R. Chinchilla, C. Nꢁjera, Chem. Rev.
2007, 107, 874–922; h) D. Alberico, M. E. Scott, M.
Lautens, Chem. Rev. 2007, 107, 174–238; i) L.-C. Cam-
peau, D. R. Stuart, K. Fagnou, Aldrichimica Acta 2007,
40, 35–41; j) K. Godula, D. Sames, Science 2006, 312,
67–72.
5,6-DihydropyrazoloACTHNUTRGNE[UNG 5,1-a]isoquinoline (10)
To a vial were added 1-(2-bromophenethyl)-1H-pyrazole 9
(126 mg, 0.5 mmol), Pd(OAc)2 (11 mg, 10 mol%), LiCl
AHCTUNGTRENNUNG
(64 mg, 1.5 mmol), and K2CO3 (138 mg, 1.0 mmol). A solu-
tion of PivOH (15 mg, 30 mol%) in DMA (3.6 mL, 0.14M)
was added and the reaction vial was tightly sealed. The re-
sulting mixture was vigorously stirred at 1508C for 24 h and
then cooled to room temperature. The reaction mixture was
purified by silica gel column chromatography (10% EtOAc/
hexanes) to provide isoquinoline 10 as a colorless liquid;
À
[2] For selected recent examples of Pd(0)-catalyzed C H
activation with aryl (peudo)halides, see: a) M. Wasa,
B. T. Worrell, J.-Q. Yu, Angew. Chem. 2010, 122, 1297–
1299; Angew. Chem. Int. Ed. 2010, 49, 1275–1277; b) T.
Nishikata, A. R. Abela, B. H. Lipshutz, Angew. Chem.
Int. Ed. 2010, 49, 781–784; c) L. Ackermann, A. Al-
thammer, S. Fenner, Angew. Chem. 2009, 121, 207–
210; Angew. Chem. Int. Ed. 2009, 48, 201–204; d) L.-C.
Campeau, D. R. Stuart, J.-P. Leclerc, M. Bertrand-La-
perle, E. Villemure, H.-Y. Sun, S. Lasserre, N. Gui-
mond, M. Lecavallier, K. Fagnou, J. Am. Chem. Soc.
2009, 131, 3291–3306; e) B. Liꢂgault, D. Lapointe, L.
Caron, A. Vlassova, K. Fagnou, J. Org. Chem. 2009, 74,
1826–1834; f) N. Lebrasseur, I. Larrosa, J. Am. Chem.
Soc. 2008, 130, 2926–2927; g) M. Iwasaki, H. Yorimitsu,
K. Oshima, Chem. Asian J. 2007, 2, 1430–1435;
h) H. A. Chiong, Q.-N. Pham, O. Daugulis, J. Am.
Chem. Soc. 2007, 129, 9879–9884; i) S. Chuprakov, N.
Chernyak, A. S. Dudnik, V. Gevorgyan, Org. Lett.
2007, 9, 2333–2336; j) D. Garcꢃa-Cuadrado, P. de Men-
doza, A. A. C. Braga, F. Maseras, A. M. Echavarren, J.
Am. Chem. Soc. 2007, 129, 6880–6886, and references
cited therein.
1
yield: 53 mg (63%). H NMR (300 MHz, CDCl3): d=7.55–
7.52 (m, 2H), 7.32–7.23 (m, 3H), 6.54 (d, 1H, J=1.9 Hz),
4.35 (t, 2H, J=6.9 Hz), 3.19 (t, 2H, J=6.9 Hz); 13C NMR
(75 MHz, CDCl3): d=139.2, 138.6, 131.7, 128.2, 128.0, 127.3,
127.0, 124.0, 100.5, 46.2, 29.2; IR (neat): n=1722, 1487,
1468, 1409, 1338, 1350, 1329, 753 cmÀ1; MS (EI): m/z=170
(M+, 100), 156 (23), 142 (55), 115 (97); HR-MS (EI): m/z=
170.0840, calcd. for C11H10N2 [M+]: 170.0844.
2-(4-Methoxyphenyl)-3-phenyl-8H-pyrazoloACTHNUTRGNEUG[N 5,1-a]-
isoindole (11)
To a vial (3 mL) were added 2-(4-methoxyphenyl)-8H-
pyrazolo[5,1-a]isoindole 3e (131 mg, 0.5 mmol), 1-bromo-
benzene (236 mg, 1.5 mmol), Pd(OAc)2 (11 mg, 10 mol%),
(n-Bu)Ad2 (36 mg, 20 mol%), and K2CO3 (138 mg,
1.0 mmol) sequentially. solution of PivOH (15 mg,
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
PACHTUNGTRENNUNG
A
30 mol%) in DMA (200 mL, 2.5M) was added and the reac-
tion vial was tightly sealed. The resulting mixture was vigo-
rously stirred at 1508C for 24 h and then cooled to room
temperature. The mixture was purified by silica gel column
chromatography (10% EtOAc/hexanes) to provide 11 as a
1
À
[3] For selected recent examples of intramolecular C H
white solid; yield: 110 mg (65%). mp 180–1818C; H NMR
activation, see: a) Y.-H. Zhang, B.-F. Shi, J.-Q. Yu,
Angew. Chem. 2009, 121, 6213–6216; Angew. Chem.
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Glorius, J. Am. Chem. Soc. 2009, 131, 4194–4195;
c) S. J. Hwang, S. H. Cho, S. Chang, J. Am. Chem. Soc.
2008, 130, 16158–16159; d) V. S. Thirunavukkarasu, K.
Parthasarathy, C.-H. Cheng, Angew. Chem. 2008, 120,
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2460–2468; g) P. Franck, S. Hostyn, B. Dajka-Halꢁsz,
ꢄ. Polonka-Bꢁlint, K. Monsieurs, P. Mꢁtyus, B. U. W.
Maes, Tetrahedron 2008, 64, 6030–6037.
(300 MHz, CDCl3): d=7.55–7.53 (m, 1H), 7.46–7.29 (m,
10H), 6.83 (d, 2H, J=8.8 Hz), 5.18 (s, 2H), 3.80 (s, 3H);
13C NMR (75 MHz, CDCl3): d=159.1, 153.1, 144.7, 140.4,
133.3, 131.3, 129.7, 129.4, 128.6, 128.1, 127.4, 126.8, 126.3,
123.5, 120.1, 113.7, 112.5, 55.2, 52.2; IR (neat): n=2928,
1608, 1524, 1427, 1244, 834, 758, 700 cmÀ1; MS (EI): m/z=
338 (M+, 100), 323 (14), 204 (12); HR-MS (EI): m/z=
338.1411, calcd. for C23H18N2O [M+]: 338.1419.
Acknowledgements
Financial support provided by the KRICT and Ministry of
Knowledge Economy (Korea) is gratefully acknowledged.
We thank Prof. Sukbok Chang (KAIST, Korea) for insightful
discussions.
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Adv. Synth. Catal. 2010, 352, 2041 – 2049
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2049