Copper(II)-Mediated ortho-Selective C(sp2)-H Tandem Alkynylation/Annulation and ortho-Hydroxylation of Anilides with 2-Aminophenyl-1H-pyrazole as a Directing Group

Article abstract of DOI:10.1021/acs.joc.7b02893

2-Aminophenyl-1H-pyrazole has been identified as a viable directing group to promote copper(II)-mediated ortho-selective sp² C-H bond tandem alkynylation/annulation of anilides with terminal alkynes to offer arylmethylene isoindolinones. Meanwhile, copper(II)-mediated ortho-selective sp² C-H hydroxylation of anilides has also been optimized as the major reaction pathway by using Cu(OAc)₂ as the promoter and 1,1,3,3-tetramethylguanidine as an organic base. Recovery of the directing group was achieved by hydrazinolysis for arylmethylene isoindolinones and basic hydrolysis for the hydroxylation products.

Full text of DOI:10.1021/acs.joc.7b02893

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Note
Copper(II)-Mediated ortho-Selective C(sp2)–H Tandem
Alkynylation/Annulation and ortho-Hydroxylation of Anilides
with 2-Aminophenyl-1H-pyrazole as A Directing Group
Wan-Chen Cindy Lee, Wei Wang, and Jie Jack Li
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 15 Jan 2018
Downloaded from http://pubs.acs.org on January 15, 2018
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Copper(II)-Mediated ortho-Selective C(sp2)–H Tandem Alkynylation/Annulation and
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ortho-Hydroxylation of Anilides with 2-Aminophenyl-1H-pyrazole as A Directing Group
*
WanꢀChen Cindy Lee,† Wei Wang,‡ and Jie Jack Li†
†Department of Chemistry, University of San Francisco, 2130 Fulton Street, San Francisco, CA
94117, USA; ‡Pfizer La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA.
*Email: lijiejackli@hotmail.com
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Abstract:
2ꢀAminophenylꢀ1Hꢀpyrazole has been identified as a viable directing group to promote
copper(II)ꢀmediated orthoꢀselective sp2 C–H bond tandem alkynylation/annulation of anilides
with terminal alkynes to offer arylmethylene isoindolinones. Meanwhile, copper(II)ꢀmediated
orthoꢀselective sp2 C–H hydroxylation of anilides has also been optimized as the major reaction
pathway by using Cu(OAc)2 as the promoter and 1,1,3,3ꢀtetramethylguanidine as an organic
base. Recovery of the directing group was achieved by hydrazinolysis for arylmethylene
isoindolinones and basic hydrolysis for the hydroxylation products, respectively.
____________________________________________________________________________
Isoindolinones are present in natural products such as fumaridine (1 in Fig. 1),1 an
arylmethylene isoindolinone alkaloid.1 They are also important pharmacophores. For instance,
lenalidomide (Revlimid, 2),2 a thalidomide derivative, is a potent tumor necrosis factor (TNF)ꢀ
α inhibitor for the treatment of multiple myeloma. On the other hand, phthalazinꢀ1(2H)ꢀones
are present in several drugs as represented by olaparib (Lynparza, 3), as a polyꢀadenosine
diphosphate (ADP) ribose polymerase (PARP) inhibitor for the treatment of ovarian cancer.3
Herein, we report a synthesis of isoindolinone derivatives employing a copper(II)ꢀmediated sp2
C–H bond alkynylation/annulation of anilides with terminal alkynes, employing 2ꢀ
aminophenylꢀ1Hꢀpyrazole (2ꢀAPP) as a new directing group, to furnish arylmethylene
isoindolinones, which may be conveniently converted to phthalazinꢀ1(2H)ꢀones via
hydrazinolysis (vide infra).
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Fig. 1. Bioactive isoindolinones and phthalazinꢀ1(2H)ꢀone
In 2014, You4 first described a copperꢀmediated tandem oxidative sp2 C–H
alkynylation/annulation with terminal alkynes to afford the 3ꢀmethyleneisoindolinone scaffold
although removal of the 2ꢀaminoquinoline (Q) directing group was not successful [eq (1)].
Similar methodology on copperꢀmediated C(sp2)–H/C(sp)–H couplings was reported by
Huang5 in 2014 and Liu6 in 2015, respectively. The two latter papers described the removal of
the directing group via hydrazinolysis to prepare phthalazinꢀ1(2H)ꢀones. Subsequently, Zhang
extended the substrate scope to aliphatic amides to produce pyrrolidones.7 Meanwhile, Niu and
Song’s group employed Co(II)ꢀ and Ni(II)ꢀcatalysts and pyridine oxide (PyO) as an auxiliary to
realize an sp2 C–H tandem alkynylation/annulation using silver acetate as an oxidant to gain
access to 3ꢀmethylene isoindolinꢀ1ꢀone structures [eq (2)].8 In 2016, we discovered that 2ꢀ
aminophenylꢀ1Hꢀpyrazole (2ꢀAPP) as a new removable directing group was efficient in
facilitating C–H carbon–nitrogen,9 carbon–chlorine,10 and carbon–carbon bond11 formations.
We then proceeded to explore 2ꢀAPP’s utility as a directing group for promoting the C(sp2)–
H/C(sp)–H couplings to produce 3ꢀmethyleneisoindolinꢀ1ꢀones [eq (3), PP = 1ꢀphenylꢀ1Hꢀ
pyrazole]. In comparison to existing directing groups such as 8ꢀaminoquinoline and 2ꢀ
aminophenyloxazoline, 2ꢀAPP is less expensive, especially in comparison to the latter.9
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You, 2014:
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O
R
O
Cu
(1)
(2)
(3)
N
Q
N
H
N
H
H
R
9
Niu & Song, 2015:
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O
R
Co, Ni
N
O
N PyO
R
N
H
O
H
H
This work:
O
O
R
Cu
N PP
R
N
H
N
H
N
H
After experimentations employing anilide 4 as the substrate with 2ꢀAPP as the directing
group, we discovered that Cu(OAc)2 was the promoter of choice and DMSO the optimal
solvent for facilitating the sp2 C–H bond cascade alkynylation/annulation. As shown in Table 1,
when anilide 4 in DMSO was heated with 2 equiv of Cu(OAc)2, along with Cs2CO3 as the base
in open air, arylmethylene isoindolinone 6 was formed in 62% yield, along with 18% of the
hydroxylation product 7a (entry 1). Formation of phenol 7 is consistent with our previous
observations for Cu(OAc)2ꢀmediated C(sp2)–H amidation.9 As far as the base is concerned,
both 1,1,3,3ꢀtetramethylguanidine (TMG, entry 2) and CsOAc (entry 3) proved to be inferior to
Cs2CO3 for the production of 6 although the latter seemed to promote the hydroxylation
product 7 with higher efficiency. A few additives that accelerated other C–H bond
functionalizations in the literature were tested for our method, but pyridine,
tetrabutylammonium iodide (TBAI), and Nꢀmethylmorpholine Nꢀoxide (NMO) did not show
much advantages (entries 4–6). With regard to reaction temperature, when the reaction was run
at 120 oC, the yield dropped (entry 7), and 100 oC was found to be optimal (entry 8). When the
reaction was run under nitrogen (entry 9), the yields for 6 and 7 were both suppressed,
indicating the reaction is indeed an aerobic oxidation process. Not surprisingly, the reaction run
under an oxygen atmosphere favors the hydroxylation, producing 70% of the hydroxylation
product 7 (entry 10) as the major product.
Table 1. Optimization of Cu(OAc)2ꢀMediated Oxidative C(sp2–H) Bond
Alkynylation/Annulationa
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Entry
Base
Additive
Temp. (ºC)
6, Yield (%)b
7, Yield (%)b
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1
2
Cs2CO3
TMG
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80
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36
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25
32
65
45
78
38
25
18
10
74
6
−
−
−
3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
80
4
pyridine
TBAI
NMO
−
80
5
80
6
6
80
24
0
7
120
100
80
8
−
18
5
9
N2
10
O2
80
70
aThe reactions were run with 2 equiv of Cu(OAc)2, base, and additive in DMSO in open air
for 12 h. bThe yield determined by 1H NMR analysis of crude reaction product using CH2Br2 as
an internal standard.
After securing the optimal reaction conditions, we probed the scope of substrates. As
shown in Table 2, this methodology accommodates substrates with both electronꢀdonating
substituents (6a–6d) and electronꢀwithdrawing substituent (6e). In addition, the naphthalenyl
substrate offered the isoindolinone derivative 6f in moderate yield. Gratifyingly, this method
also worked for heterocyclic substrates, giving rise to the corresponding furanꢀ and thiopheneꢀ
derivatives 6g and 6h in 41% and 63% yield, respectively.
Table 2. Substrate Scope for Cu(OAc)2ꢀMediated Oxidative Alkynylation/Annulationa
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aReaction conditions: Substrate 4 (0.19 mmol), phenylacetylene (5a, 3 equiv), Cu(OAc)2, (2
equiv), Cs2CO3 (2 equiv) in DMSO at 100 °C overnight in open air. bIsolated yield.; cA mixture
of 1:1 regioisomers onto the methylenedioxybenzene ring.
Interestingly, as shown in Scheme 1, when fluorineꢀsubstituted substrate 4i was
subjected to the standard reaction conditions, the hydroxylation product 7i was isolated in 42%
yield while the alkynylation/annulation product 6i in only 36% yield. Indeed, we observed in
the past that fluorineꢀsubstituted substrates are especially accommodating the aerobic oxidation
reaction. Furthermore, when chlorineꢀsubstituted substrate 4j was subjected to the standard
reaction conditions, the dechlorinated isoindolinone 6a was isolated as the predominant
product. We speculate that the ortho-C–Cl bond on 4j was much more readily activated
(Scheme 1) in comparison to the ortho-C–H bond under the standard reaction conditions.
Scheme 1. Anomalies of the Methodologya,b
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aReaction conditions: Substrate 4 (0.19 mmol), phenylacetylene (5, 3 equiv), Cu(OAc)2 (2
equiv), Cs2CO3 (2 equiv) in DMSO at 100 °C overnight in open air; bIsolated yield.
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We also set out to gauge the scope for the terminal acetylenes. As shown in Table 3, the
reaction works well for both aromatic acetylenes (6k and 6l) and aliphatic acetylenes such as
ethynylcyclohexane (6m). Intriguingly, when 3,3ꢀdimethylbutꢀ1ꢀyne was used as the coupling
partner, the alkynylation/annulation product 6n was isolated only in 30% yield while the
hydroxylation product 7a was isolated as the major product in 62% yield. This outcome did not
come as a complete surprise because the tertꢀbutyl is so bulky and the steric hindrance retarded
the annulation process thus allowing oxidation to proceed more rapidly.
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Table 3. Terminal Acetylene Scope for Cu(OAc)2ꢀMediated Alkynylation/Annulationa
aReaction conditions: Substrate 4 (0.19 mmol), phenylacetylene (5, 3 equiv), Cu(OAc)2 (2
equiv), Cs2CO3 (2 equiv) in DMSO at 100 °C overnight in open air; bIsolated yield.
Intrigued by the appearance of hydroxylation product 7, we set out to optimize its
production in the absence of terminal acetylenes. While Mother Nature can carry out chemoꢀ,
regioꢀ, and stereoselective C–H hydroxylation with stunning precision using chromosome
P450s,12 C–H hydroxylation in the laboratory remains in its infancy. In 2006, Yu’s group
revealed a Cu(II)ꢀcatalyzed aryl C–H bond hydroxylation.13 In 2014, Shi and coworkers
disclosed a copperꢀmediated hydroxylation of arenes and heteroarenes directed by a removable
bidentate auxiliary, 2ꢀ(pyridineꢀ2ꢀylꢀisopropylamine (PIPamine, see Fig. 2).14 In 2015, Yu’s
and Jiao’s groups accomplished a similar feat using 2ꢀ(4,5ꢀdihydrooxazolꢀ2ꢀyl)aniline (Oxa)15
and oxime ether,16 respectively, as the removable directing groups. More recently, chemists
from groups of Wang and Li produced 2ꢀ(phenylthio)phenols using disulfide to direct C–H
hydroxylation.17 Finally, Yu’s group described that monodentate oxazoline could serve as a
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ligand to promote copperꢀmediated ortho-C–H hydroxylation and amination.18 Intriguingly,
Baidya et al. disclosed a copperꢀmediated etherification of arenes with alkoxysilane employing
2ꢀAPP as the removable directing group19 shortly after our report on 2ꢀAPPꢀdirected ortho-C–
H amidation.9 Remarkably, with an exception of reference 17 where palladium was the catalyst,
all other metalꢀmediated ortho-C–H hydroxylation was carried out using copper salts.20
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Fig. 2. ortho-C(sp2)–H hydroxylation directed by a removable auxiliary
Optimization for ortho-C–H hydroxylation of substrate 4a was straightforward. As
shown in Table 4, it was rapidly established that Cu(OAc)2 and DMSO were the promoter and
solvent of choice, respectively. In contrast to what we observed for 4a’s C–H
alkynylation/annulation, TMG now delivered the highest yield of phenol 7a.
Table 4. Optimization of Cu(OAc)2ꢀMediated Oxidative C(sp2–H) Bond Hydroxylationa,b
Entry
Equiv Cu(OAc)2
Base (2 equiv)
Cs2CO3
TMG
Additive
6, Yield (%)
1
2
3
4
5
6
1
1
1
1
2
2
7
−
−
37
65
52
90
97
TMG
NMO
O2
−
TMG
CsOAc
TMG
−
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aThe yield determined by H NMR analysis of crude reaction product using CH2Br2 as an
b
internal standard. The reactions were run with 2 equiv of Cu(OAc)2 and base in DMSO in
open air for 12 h at 80 °C.
7
8
9
Under optimal hydroxylation conditions, arene substrates 4 were oxidized to the
corresponding phenol 7 in good to excellent yield (82–96%, see Table 5) with the oꢀmethoxylꢀ
substituted substrate as an exception, giving rise to phenol 7a in 51% yield. Unfortunately,
heteroarene substrates containing furan, thiophene and pyridine core structures failed to be
hydroxylated despite our extensive efforts.
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Table 5. Substrate Scope for Cu(OAc)2ꢀMediated Oxidative o-Hydroxylationa,b
aReaction conditions: Substrate 4 (0.19 mmol), Cu(OAc)2, (2 equiv), TMG (2 equiv) in
b
c
DMSO at 80 °C overnight in open air. Isolated yield. A mixture of 4:1 regioisomers of the
two ortho-positions with the one shown (7l) as the major product.
An intriguing reaction was observed in the process of evaluating Cu(OAc)2ꢀmediated
oxidative o-hydroxylation. When substrate 4q was subjected to our optimal reaction conditions
for ortho-hydroxylation, no anticipated hydroxylation product 7q was observed. Instead, as
shown in Scheme 2, demethylation product 7a was isolated in 51% yield.
Scheme 2. Demethylation in place of hydroxylation.
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Removal of the 2ꢀAPP directing groups was an interesting journey. Indeed, as shown in
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Scheme 3, basic hydrolysis21 of amide 7a proceeded uneventfully to deliver salicyclic acid 8 in
81% yield, along with recovered auxiliary 2ꢀAPP 9 in 93% yield. Releasing the 2ꢀAPP
directing groups from arylmethylene isoindolinone 6a proved to be not trivial. No reaction was
observed under strong acidic and basic hydrolysis conditions. Attempt using oxidative cleavage
with cerium ammonium nitrate (CAN) gave rise to phthalidmide 10 in 82% yield, an
interesting transformation worth noting on its own right. Hydrazinolysis5,6 of 6a recovered the
2ꢀAPP directing group in 87% yield along with phthalazinꢀ1(2H)ꢀone 11 in 84% yield.
Scheme 3. Removal of the directing group.
O
O
KOH, EtOH
reflux, 16 h
H2N
N
OH
H
N
N
N
N
OH
N
OH
8, 81%
7a
9, 93%
N
O
N
N
(NH4)2Ce(NO3)6
O
N
MeCN, rt, 10 h
82%
N
O
Ph
6a
10
O
.
NH2
H2NNH2 H2O, KOH
EtOH, 120 oC, 30 h
NH
N
N
N
Ph
11, 84%
9, 87%
In summary, we discovered that 2ꢀAPP may serve as a viable bidentate directing group
for copperꢀmediated aerobic oxidative C(sp2–H) bond alkynylation/annulation with terminal
alkynes to produce arylmethylene isoindolinones. Meanwhile, in the absence terminal alkynes,
a similar methodology has been developed to maximize orthoꢀselective C–H hydroxylation
using Cu(OAc)2 as the promoter and TMG as the base. Recovery of the 2ꢀAPP directing group
was achieved by hydrazinolysis of the arylmethylene isoindolinones and basic hydrolysis for
the hydroxylation products.
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Experimental Section
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General procedures for the preparation of anilide substrates and data for most of 4 may be
found in references 9 and 10 with exception of the following compounds:
N-(2-(1H-Pyrazol-1-yl)phenyl)-4-(trifluoromethyl)benzamide (4e)
7
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9
White solid, 1.49 g, 90% yield, mp: 103.9–104.4 ºC, flash chromatography eluting with ethyl
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acetate/hexanes (1:6→1:3), Rf = 0.62 [ethyl acetate/hexanes (1: 2)]. H NMR (500 MHz,
CDCl3) δ 11.58 (s, 1H), 8.72 (dd, J = 8.3, 1.3 Hz, 1H), 8.07 (d, J = 8.1 Hz, 2H), 7.90 (dd, J =
11.1, 2.2 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 7.43 (ddd, J = 16.5, 7.8, 1.4 Hz, 2H), 7.25 (td, J =
7.8, 1.4 Hz, 1H), 6.55 (t, J = 2.2 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 163.9, 141.2, 133.8–
133.0 (q, J = 32.69 Hz), 131.3, 130.2, 129.0, 128.1, 127.7, 125.8–125.7 (q, J = 3.87 Hz),
19
126.9–120.4 (q, J = 272.1 Hz), 124.5, 122.9, 121.9, 107.4. F NMR (470 MHz, CDCl3) δ –
63.0. HRMS (ESI, m/z) calcd for C17H12F3N3O [M+H]: 332.1004, found: 332.1002.
N-(2-(1H-Pyrazol-1-yl)phenyl)furan-3-carboxamide (4g)
White solid, 1.09 g, 86% yield, mp: 137.4–138.3 ºC, flash chromatography eluting with ethyl
1
acetate/hexanes (1:6→1:3), Rf = 0.33 [ethyl acetate/hexanes (1: 2)]. H NMR (500 MHz,
CDCl3) δ 11.06 (s, 1H), 8.66 (dd, J = 8.3, 1.4 Hz, 1H), 8.04 (d, J = 1.3 Hz, 1H), 7.88 (dt, J =
3.5, 1.5 Hz, 2H), 7.48 (q, J = 1.6 Hz, 1H), 7.44–7.34 (m, 2H), 7.23–7.15 (m, 1H), 6.78 (t, J =
1.5 Hz, 1H), 6.54 (q, J = 1.9 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 160.6, 145.4, 143.9,
141.0, 131.5, 130.3, 128.6, 128.1, 123.9, 123.7, 122.7, 122.0, 108.4, 107.3. HRMS (ESI, m/z)
calcd for C14H11N3O2 [M+H]: 254.0923, found: 254.0921.
N-(2-(1H-Pyrazol-1-yl)phenyl)-2-methoxybenzamide (4q)
White solid, 1.19 g, 81% yield, mp: 84.4–85.7 ºC, flash chromatography eluting with ethyl
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acetate/hexanes (1:6→1:3), Rf = 0.37 [ethyl acetate/hexanes (1: 2)]. H NMR (500 MHz,
CDCl3) δ 10.74 (s, 1H), 8.63 (dd, J = 8.3, 1.3 Hz, 1H), 8.19 (dd, J = 7.8, 1.8 Hz, 1H), 7.81 (d, J
= 1.8 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.45 (dddd, J = 8.6, 7.0, 5.0, 1.7 Hz, 2H), 7.30 (dd, J =
7.9, 1.5 Hz, 1H), 7.19 (td, J = 7.7, 1.3 Hz, 1H), 7.12–7.03 (m, 1H), 6.94 (d, J = 8.3 Hz, 1H),
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6.50 (t, J = 2.2 Hz, 1H), 4 (s, 3H). C NMR (126 MHz, CDCl3) δ 163.8, 157.3, 140.9, 133.2,
133.2, 132.4, 130.8, 130.5, 128.8, 125.0, 124.0, 123.8, 121.9, 121.1, 111.2, 106.9, 55.7. HRMS
(ESI, m/z) calcd for C17H15N3O2 [M+H]: 294.1236, found: 294.1235.
General Procedures for the C–H Alkynylation/Annulation
A 10 mL microwave vial was charged with the substrate 4 (0.19 mmol), then was added the
arylacetylene 5 (0.57 mmol), copper acetate (0.38 mmol) and Cs2CO3 (0.38 mmol). After
adding the solvent DMSO (2 mL), the reaction was heated at 100 °C open to air. After stirring
at 100 °C for 12 h, the reaction was judged complete by TLC, the reaction mixture was filtered.
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The filtrate was washed with saturated ammonium chloride, and brine, the organic layer was
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dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash
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chromatography to give the desired product 6.
(Z)-2-(2-(1H-Pyrazol-1-yl)phenyl)-3-benzylideneisoindolin-1-one (6a)
Yellow solid, 0.049 g, 71% yield, mp: 216.3–217.1 ºC, flash chromatography eluting with
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ethyl acetate/hexanes (1:8→1:3), Rf = 0.45 [ethyl acetate/hexanes (1: 2)]. H NMR (500 MHz,
CDCl3) δ 7.91 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.57–7.48
(m, 2H), 7.45 (d, J = 2.4 Hz, 1H), 7.31–7.17 (m, 3H), 7.12 (td, J = 7.6, 1.6 Hz, 1H), 7.04–6.93
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(m, 5H), 6.65 (s, 1H), 6.28 (t, J = 2.1 Hz, 1H). C NMR (126 MHz, CDCl3) δ 168.1, 140.9,
138.8, 137.5, 134.1, 132.9, 132.4, 130.7, 129.9, 129.6, 129.1, 129.0, 128.7, 127.5, 127.4, 127.1,
126.6, 125.0, 123.9, 119.4, 107.6, 106.6. HRMS (ESI, m/z) calcd for C24H17N3O [M+H]:
364.1444, found: 364.1452.
(Z)-2-(2-(1H-Pyrazol-1-yl)phenyl)-3-benzylidene-6-methylisoindolin-1-one (6b)
Yellow solid, 0.055 g, 77% yield, mp: 121.8–123.3 ºC, flash chromatography eluting with
1
ethyl acetate/hexanes (1:8→1:3), Rf = 0.38 [ethyl acetate/hexanes (1: 2)]. H NMR (500 MHz,
CDCl3) δ 7.71 (s, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.45 (dd, J = 6.9, 1.9
Hz, 2H), 7.31–7.27 (m, 1H), 7.26–7.16 (m, 2H), 7.12 (td, J = 7.7, 1.5 Hz, 1H), 7.02–6.90 (m,
5H), 6.59 (s, 1H), 6.27 (t, J = 2.1 Hz, 1H), 2.50 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 168.2,
140.9, 139.4, 137.5, 136.4, 134.2, 133.5, 133.1, 130.7, 130.0, 129.6, 129.2, 129.1, 128.7, 127.7,
127.38, 127.1, 126.5, 125.0, 124.0, 119.3, 106.9, 106.6, 21.6. HRMS (ESI, m/z) calcd for
C25H19N3O [M+H]: 378.1600, found: 378.1602.
(Z)-2-(2-(1H-Pyrazol-1-yl)phenyl)-3-benzylidene-6-methoxyisoindolin-1-one (6c)
Yellow solid, 0.060 g, 80% yield, mp: 150.6–152.1 ºC, flash chromatography eluting with
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ethyl acetate/hexanes (1:8→1:3), Rf = 0.31 [ethyl acetate/hexanes (1: 2)]. H NMR (500 MHz,
CDCl3) δ 7.64 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 1.7 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.36 (d, J
= 2.5 Hz, 1H), 7.27–7.16 (m, 4H), 7.11 (td, J = 7.6, 1.5 Hz, 1H), 7.01–6.90 (m, 5H), 6.53 (s,
1H), 6.28 (t, J = 2.2 Hz, 1H), 3.91 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 168.1, 160.9, 140.9,
137.4, 134.0, 133.1, 131.7, 130.7, 123.0, 129.6, 129.01, 128.7, 128.7, 128.6, 128.5, 127.4,
127.1, 126.5, 125.0, 121.23, 120.8, 106.6, 105.9, 55.8. HRMS (ESI, m/z) calcd for C25H19N3O2
[M+H]: 394.1549, found: 394.1550.
(Z)-6-(2-(1H-Pyrazol-1-yl)phenyl)-7-benzylidene-6,7-dihydro-5H-[1,3]dioxolo[4,5-
f]isoindol-5-one (6d)
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Yellow solid, 0.071 g, 92% yield (a mixture of 1:1 regioisomers onto the
methylenedioxybenzene ring), mp: 93.7–95.8 ºC, flash chromatography eluting with ethyl
acetate/hexanes (1:8→1:3), Rf = 0.19 [ethyl acetate/hexanes (1: 2)] (a mixture of 1:1
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regioisomers) H NMR (500 MHz, CDCl3) δ 7.54 (dd, J = 10.0, 1.7 Hz, 2H), 7.51–7.45 (m,
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2H), 7.43 (d, J = 2.4 Hz, 1H), 7.23–7.15 (m, 3H), 7.14–7.09 (m, 3H), 6.99–6.96 (m, 2H), 6.95–
6.92 (m, 5H), 6.69 (s, 1H), 6.43 (s, 1H), 6.29 (dt, J = 11.2, 2.1 Hz, 2H), 6.21 (s, 2H), 6.12 (s,
2H). 13C NMR (126 MHz, CDCl3) δ 167.7, 167.4, 152.2, 151.8, 149.3, 140.9, 140.8, 137.4,
137.4, 135.0, 134.0, 133.2, 132.9, 131.6, 130.7, 130.6, 130.0, 129.9, 129.6, 129.6, 129.1, 129.0,
128.7, 128.6, 127.4, 127.4, 127.01, 127.1, 126.6, 126.6, 125.0, 125.0, 122.6, 122.1, 120.6,
118.9, 111.7, 109.1, 107.1, 106.6, 106.5, 103.1, 102.7, 102.2, 99.6. HRMS (ESI, m/z) calcd for
C25H17N3O3 [M+H]: 408.1342, found: 408.1341.
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(Z)-2-(2-(1H-Pyrazol-1-yl)phenyl)-3-benzylidene-5-(trifluoromethyl)isoindolin-1-one (6e)
Yellow solid, 0.067 g, 82% yield, mp: 79.2–82.2 ºC, flash chromatography eluting with ethyl
1
acetate/hexanes (1:8→1:3), Rf = 0.47 [ethyl acetate/hexanes (1: 2)]. H NMR (500 MHz,
CDCl3) δ 8.02 (d, J = 11.2 Hz, 2H), 7.77 (dd, J = 8.0, 1.3 Hz, 1H), 7.47–7.43 (m, 1H), 7.38 (d,
J = 2.4 Hz, 1H), 7.23 (qd, J = 8.1, 7.6, 1.5 Hz, 3H), 7.16 (td, J = 7.5, 1.8 Hz, 1H), 7.07–6.92 (m,
5H), 6.71 (s, 1H), 6.29 (t, J = 2.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 166.8, 141.2, 139.0,
137.1, 134.6– 133.8 (q, J = 32.51 Hz), 133.1, 132.3, 130.7, 130.2, 129.6, 129.6, 129.1, 129.0,
128.6, 127.6, 127.12, 127.01, 125.8–125.7 (q, J = 3.6 Hz), 124.8, 124.6, 122.7, 116.9–116.8 (q,
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J = 4.0 Hz), 109.2, 106.7. F NMR (470 MHz CDCl3) δ –62.5. HRMS (ESI, m/z) calcd for
C25H16F3N3O [M+H]: 432.1317, found: 432.1320.
(Z)-2-(2-(1H-Pyrazol-1-yl)phenyl)-3-benzylidene-2,3-dihydro-1H-benzo[e]isoindol-1-one
(6f)
Yellow solid, 0.037 g, 47% yield, mp: 167.3–168.5 ºC, flash chromatography eluting with
dichloromethane/hexanes (1:4), Rf = 0.33 (CH2Cl2). 1H NMR (500 MHz, CDCl3) δ 9.12 (d, J =
8.3 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.70
(ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.61 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.46 (dd, J = 9.9, 2.1 Hz,
2H), 7.32 (td, J = 7.8, 1.7 Hz, 1H), 7.30–7.23 (m, 2H), 7.20 (td, J = 7.5, 1.8 Hz, 1H), 7.07–6.94
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(m, 5H), 6.73 (s, 1H), 6.23 (t, J = 2.1 Hz, 1H). C NMR (126 MHz, CDCl3) δ 169.0, 140.9,
138.8, 137.6, 134.4, 133.7, 133.1, 132.9, 131.0, 130.0, 129.6, 129.2, 129.1, 128.7, 128.5, 128.2,
127.4, 127.1, 126.9, 125.1, 124.5, 121.3, 116.8, 109.4, 106.6. HRMS (ESI, m/z) calcd for
C28H19N3O [M+H]: 414.1600, found: 414.1601.
(Z)-5-(2-(1H-Pyrazol-1-yl)phenyl)-6-benzylidene-5,6-dihydro-4H-furo[3,4-c]pyrrol-4-one
(6g)
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Yellow solid, 0.028g, 41% yield, mp: 76.4–77.8 ºC, flash chromatography eluting with ethyl
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acetate/hexanes (1:8→1:3), Rf = 0.09 [ethyl acetate/hexanes (1: 2)]. H NMR (500 MHz,
CDCl3) δ 7.56 (dd, J = 14.5, 1.9 Hz, 2H), 7.51–7.43 (m, 2H), 7.39–7.28 (m, 3H), 7.23–7.16 (m,
1H), 7.12 (dd, J = 8.3, 6.8 Hz, 2H), 7.05 (d, J = 2.0 Hz, 1H), 6.98–6.88 (m, 2H), 6.53 (s, 1H),
6.29 (t, J = 2.1 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 160.2, 159.8, 146.4, 143.6, 140.9,
138.0, 134.7, 131.8, 131.7, 129.9, 129.5, 129.0, 128.6, 127.6, 127.6, 125.5, 114.8, 107.8, 107.2,
98.0. HRMS (ESI, m/z) calcd for C22H15N3O2 [M+H]: 354.1236, found: 354.1233.
(Z)-5-(2-(1H-Pyrazol-1-yl)phenyl)-4-benzylidene-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-
one (6h)
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Yellow solid, 0.044 g, 63% yield, mp: 172.9–174.0 ºC, flash chromatography eluting with
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ethyl acetate/hexanes (1:8→1:3), Rf = 0.15 [ethyl acetate/hexanes (1: 2)]. H NMR (500 MHz,
CDCl3) δ 7.78 (d, J = 5.1 Hz, 1H), 7.57 (d, J = 1.7 Hz, 1H), 7.53–7.44 (m, 2H), 7.36 (dp, J =
8.7, 4.6 Hz, 1H), 7.30 (d, J = 4.4 Hz, 2H), 7.24 (d, J = 5.1 Hz, 1H), 7.21–7.17 (m, 1H), 7.12 (t,
J = 7.5 Hz, 2H), 6.96–6.90 (m, 2H), 6.62 (s, 1H), 6.28 (s, 1H). 13C NMR (126 MHz, CDCl3) δ
159.3, 145.3, 145.3, 140.9, 138.0, 134.9, 134.3, 131.7, 131.6, 123.0, 129.5, 129.2, 128.9, 128.4,
127.6, 127.5, 125.5, 124.5, 107.2, 105.0. HRMS (ESI, m/z) calcd for C22H15N3OS [M+H]:
370.1008, found: 370.1011.
(Z)-2-(2-(1H-Pyrazol-1-yl)phenyl)-3-benzylidene-7-fluoroisoindolin-1-one (6i)
Yellow solid, 0.026 g, 36% yield (the hydroxylation product 7i was isolated in 42% while the
alkynylation/annulation product 6i in 36% yield, respectively), mp: 203.7–206.9 ºC, flash
chromatography eluting with ethyl acetate/hexanes (1:8→1:3), Rf = 0.37 [ethyl acetate/hexanes
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(1: 2)]. H NMR (500 MHz, CDCl3) δ 8.07–8.00 (m, 1H), 7.63–7.49 (m, 4H), 7.44 (d, J = 2.4
Hz, 1H), 7.26–7.23 (m, 2H), 7.22–7.20 (m, 1H), 7.18–7.12 (m, 2H), 6.99–6.93 (m, 3H), 6.65 (s,
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1H), 6.29 (t, J = 2.1 Hz, 1H). F NMR (470 MHz, CDCl3) δ –116.4. HRMS (ESI, m/z) calcd
for C24H16FN3O [M+ H]: 382.1349, found: 382.1351.
General Procedures for the Alkynylation/Annulation with various terminal alkynes
A 10 mL microwave vial was charged with substrate 4 (0.19 mmol), then was added terminal
alkyne 5 (0.57 mmol), copper acetate (0.38 mmol) and Cs2CO3 (0.38 mmol). After adding the
solvent DMSO (2 mL), the reaction was heated at 100 °C open to air. After stirring at 100 °C
for 12 h, the reaction was judged complete by TLC, the reaction mixture was filtered. The
filtrate was washed with saturated ammonium chloride, and brine, the organic layer was dried
over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash
chromatography to give the desired product 6.
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(Z)-2-(2-(1H-Pyrazol-1-yl)phenyl)-5-methyl-3-(4-methylbenzylidene)isoindolin-1-one (6k)
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Yellow solid, 0.058 g, 78% yield, mp: 118.8–120.0 ºC, flash chromatography eluting with
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ethyl acetate/hexanes (1:8→1:3), Rf = 0.33 [ethyl acetate/hexanes (1: 2)]. H NMR (500 MHz,
CDCl3) δ 7.79 (d, J = 7.8 Hz, 1H), 7.55–7.50 (m, 2H), 7.45–7.41 (m, 2H), 7.34–7.28 (m, 2H),
7.26–7.19 (m, 2H), 6.83–6.74 (m, 4H), 6.58 (s, 1H), 6.26 (t, J = 2.0 Hz, 1H), 2.52 (s, 3H), 2.21
(s, 3H). 13C NMR (126 MHz, CDCl3) δ 168.3, 143.1, 140.8, 139.4, 139.3, 136.4, 133.6, 132.4,
130.7, 130.1, 129.7, 129.2, 129.2, 129.0, 128.5, 127.8, 127.4, 125.1, 123.8, 119.7, 107.6, 106.6,
22.2, 21.2. HRMS (ESI, m/z) calcd for C26H21N3O [M+H]: 392.1757, found: 392.1755.
(Z)-2-(2-(1H-Pyrazol-1-yl)phenyl)-6-bromo-3-(4-methylbenzylidene)isoindolin-1-one (6l)
Yellow solid, 0.081 g, 94% yield, mp: 166.4–170.1 ºC, flash chromatography eluting with
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ethyl acetate/hexanes (1:8→1:3), Rf = 0.53 [ethyl acetate/hexanes (1: 2)]. H NMR (500 MHz,
CDCl3) δ 8.03 (d, J = 1.7 Hz, 1H), 7.73 (dd, J = 8.2, 1.8 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.47
(d, J = 1.7 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.29–7.20 (m, 3H), 7.16 (ddd, J = 8.3, 6.4, 2.4 Hz,
1H), 6.82 (d, J = 7.9 Hz, 2H), 6.76 (d, J = 7.9 Hz, 2H), 6.57 (s, 1H), 6.27 (t, J = 2.1 Hz, 1H),
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2.21 (s, 3H). C NMR (126 MHz, CDCl3) δ 166.6, 141.0, 137.6, 137.3, 136.8, 135.2, 132.9,
130.6, 129.9, 129.6, 129.6, 129.2, 129.0, 128.7, 127.9, 127.5, 126.9, 125.0, 122.7, 121.0, 108.7,
106.6, 21.2. HRMS (ESI, m/z) calcd for C25H18BrN3O [M+H]: 456.0705, found: 456.0705.
(Z)-2-(2-(1H-Pyrazol-1-yl)phenyl)-3-(cyclohexylmethylene)isoindolin-1-one (6m)
Yellow solid, 0.046 g, 65% yield, mp: 133.2–135.7 ºC, flash chromatography eluting with
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ethyl acetate/hexanes (1:8→1:3), Rf = 0.46 [ethyl acetate/hexanes (1: 2)]. H NMR (500 MHz,
CDCl3) δ 7.91–7.80 (m, 2H), 7.66–7.55 (m, 5H), 7.52–7.41 (m, 3H), 6.21 (t, J = 2.2 Hz, 1H),
5.39 (d, J = 10.8 Hz, 1H), 1.65–1.53 (m, 3H), 1.42–1.30 (m, 3H), 1.00–0.85 (m, 4H), 0.70
(dddd, J = 16.4, 13.1, 8.2, 3.7 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 168.4, 141.0, 139.6,
138.5, 132.3, 132.2, 130.8, 130.3, 130.1, 129.7, 128.4, 128.1, 127.4, 126.0, 123.6, 119.2, 116.6,
107.3, 34.6, 33.2, 33.0, 25.7, 25.6, 25.5. HRMS (ESI, m/z) calcd for C24H23N3O [M+H]:
370.1913, found: 370.1912.
(Z)-2-(2-(1H-Pyrazol-1-yl)phenyl)-3-(2,2-dimethylpropylidene)isoindolin-1-one (6n)
Yellow solid, 0.045 g, 69% yield, mp: 175.4–177.0 ºC, flash chromatography eluting with
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ethyl acetate/hexanes (1:8→1:3), Rf = 0.41 [ethyl acetate/hexanes (1: 2)]. H NMR (500 MHz,
CDCl3) δ 7.92–7.80 (m, 2H), 7.68–7.64 (m, 2H), 7.64–7.53 (m, 3H), 7.51–7.40 (m, 3H), 6.23 (t,
J = 2.1 Hz, 1H), 5.70 (s, 1H), 0.86 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 169.5, 140.9, 140.8,
139.4, 132.4, 132.4, 131.8, 131.3, 130.1, 129.7, 128.4, 127.8, 126.4, 126.1, 123.8, 121.3, 119.0,
107.2, 32.5, 31.3. HRMS (ESI, m/z) calcd for C22H21N3O [M+H]: 344.1757, found: 344.1755.
General Procedures for the C–H Hydroxylation
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A 10 mL microwave vial was charged with the substrate 4 (0.19 mmol) in DMSO (2 mL), then
was added the copper acetate (0.38 mmol) and 1,1,3,3,ꢀtetramethylguanidine(TMG) (0.38
mmol). The reaction was heated at 80 °C open to air. After stirring at 80 °C for 12 h, the
reaction was judged complete by TLC, the reaction mixture was filtered. The filtrate was
washed with saturated ammonium chloride and brine, the organic layer was dried over MgSO4,
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filtered and concentrated in vacuo. The residue was purified by flash chromatography to give
the desired product 7.
N-(2-(1H-Pyrazol-1-yl)phenyl)-6-hydroxybenzo[d][1,3]dioxole-5-carboxamide (7d)
White solid, 0.059 g, 96% yield, mp: 202.4–203.4 ºC, flash chromatography eluting with
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dichloromethane/hexanes (4:1), Rf = 0.53 (CH2Cl2). H NMR (500 MHz, CDCl3) δ 12.28 (s,
1H), 11.53 (s, 1H), 8.55–8.50 (m, 1H), 7.90 (t, J = 2.7 Hz, 2H), 7.42 (dd, J = 9.4, 7.2 Hz, 2H),
7.29–7.25 (m, 2H), 6.58–6.48 (m, 2H), 6.08 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 168.5,
152.4, 146.8, 141.2, 135.0, 130.6, 130.2, 129.4, 127.9, 124.6, 123.4, 122.1, 120.9, 111.5, 107.4,
102.4, 100.6. HRMS (ESI, m/z) calcd for C17H13N3O4 [M+H]: 324.0978, found: 324.0976.
N-(2-(1H-Pyrazol-1-yl)phenyl)-2-hydroxy-4-(trifluoromethyl)benzamide (7e)
White solid, 0.054 g, 82% yield, mp: 120.2–121.0 ºC, flash chromatography eluting with
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dichloromethane/hexanes (4:1), Rf = 0.66 (CH2Cl2). H NMR (500 MHz, CDCl3) δ 12.41 (s,
1H), 11.93 (s, 1H), 8.57 (dd, J = 8.6, 1.4 Hz, 1H), 7.93 (dd, J = 3.9, 2.2 Hz, 2H), 7.79 (d, J =
8.3 Hz, 1H), 7.44 (ddd, J = 7.4, 4.0, 2.5 Hz, 2H), 7.32–7.26 (m, 2H), 7.19 (dd, J = 8.3, 1.7 Hz,
1H), 6.57 (t, J = 2.2 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 167.6, 162.2, 141.2, 136.2–135.4
(q, J = 32.9 Hz), 130.2, 130.1, 129.4, 127.9, 126.8, 126.5–120.0 (q, J = 273.1 Hz), 125.2, 123.5,
121.8, 117.7, 116.1–116.0 (q, J = 3.9 Hz), 115.3–115.2 (q, J = 3.57 Hz), 107.6. 19F NMR (470
MHz, CDCl3) δ –63.7. HRMS (ESI, m/z) calcd for C17H12F3N3O2 [M+H]: 348.0954, found:
348.0955.
N-(2-(1H-Pyrazol-1-yl)phenyl)-5-bromo-2-hydroxybenzamide (7l)
White solid, 0.063 g, 93% yield (a mixture of 4:1 regioisomers of the two ortho-positions with
the one (7l) as the major product), mp: 164.4–166.8 ºC, flash chromatography eluting with
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dichloromethane/hexanes (4:1), Rf = 0.71 (CH2Cl2). H NMR (500 MHz, CDCl3) δ 12.21 (s,
1H), 11.95 (s, 1H), 8.59 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.95–7.89 (m, 1H), 7.84
(d, J = 2.3 Hz, 1H), 7.51 (dd, J = 8.9, 2.3 Hz, 1H), 7.43 (td, J = 8.2, 3.5 Hz, 2H), 7.28 (dd, J =
8.1, 1.3 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.59 (t, J = 2.2 Hz, 1H). 13C NMR (126 MHz,
CDCl3) δ 167.4, 161.1, 141.3, 137.0, 130.2, 130.1, 129.0, 127.9, 125.0, 124.9, 123.1, 121.7,
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120.6, 119.5, 110.5, 107.7. HRMS (ESI, m/z) calcd for C16H12BrN3O2 [M+H]: 358.0185,
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found: 358.0186.
N-(2-(1H-Pyrazol-1-yl)phenyl)-2-hydroxy-4-methylbenzamide (7o)
White solid, 0.050 g, 89% yield, mp: 120.6–121.6 ºC, flash chromatography eluting with
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dichloromethane/hexane (4:1), Rf = 0.59 [ethyl acetate/hexanes (1: 2)]. H NMR (500 MHz,
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CDCl3) δ 12.21 (d, J = 0.7 Hz, 1H), 11.53 (s, 1H), 8.54 (dd, J = 8.2, 1.3 Hz, 1H), 7.90 (dd, J =
10.5, 2.2 Hz, 2H), 7.54 (d, J = 8.2 Hz, 1H), 7.46–7.38 (m, 2H), 7.24 (ddd, J = 8.4, 7.5, 1.4 Hz,
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1H), 6.84–6.80 (m, 1H), 6.76 (dd, J = 8.3, 1.6 Hz, 1H), 6.54 (s, 1H), 2.36 (s, 3H). C NMR
(126 MHz, CDCl3) δ 168.7, 162.2, 145.6, 141.2, 130.7, 130.2, 129.5, 127.9, 125.9, 124.6,
123.5, 122.1, 120.2, 118.8, 112.3, 107.4, 21.7. HRMS (ESI, m/z) calcd for C17H15N3O2 [M+H]:
294.1236, found: 294.1233.
N-(2-(1H-Pyrazol-1-yl)phenyl)-2-hydroxy-6-methylbenzamide (7p)
White solid, 0.053 g, 96% yield, mp: 136.3–137.3 ºC, flash chromatography eluting with
dichloromethane/hexane (4:1), Rf = 0.28 (CH2Cl2). 1H NMR (500 MHz, CDCl3) δ 10.61 (s, 1H),
10.27 (s, 1H), 8.53 (dd, J = 8.3, 1.3 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 1.9 Hz, 1H),
7.45 (ddd, J = 8.6, 7.5, 1.5 Hz, 1H), 7.38 (dd, J = 8.0, 1.5 Hz, 1H), 7.27–7.22 (m, 2H), 6.84 (d,
J = 8.2 Hz, 1H), 6.76 (d, J = 7.5 Hz, 1H), 6.50 (t, J = 2.2 Hz, 1H), 2.58 (s, 3H). 13C NMR (126
MHz, CDCl3) δ 168.7, 159.8, 141.5, 136.1, 132.5, 130.6, 130.1, 129.9, 128.0, 125.0, 123.9,
122.9, 122.8, 118.7, 115.4, 107.5, 21.6. HRMS (ESI, m/z) calcd for C17H15N3O2 [M+H]:
294.1236, found: 294.1233.
Procedures for Removal of the Directing Group
To a solution of the 7a (0.21 mmol) and KOH (2.10 mmol) was added EtOH (3 mL). After
refluxing for 16 h, the reaction was judged complete by TLC. After filtration via a pad of
Celite, the filtrate was washed with 1M HCl and saturated brine, the organic layer was dried
over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash
chromatography to give the desired acid 8 as a white solid. 2-Hydroxybenzoic acid (8) White
solid, 0.024g, 81% yield, mp: 159.5–160.1 ºC, flash chromatography eluting with ethyl
acetate/hexanes (1:6→1:2), Rf = 0.41 [ethyl acetate/hexanes (1:2)]. 1H NMR (500 MHz, CDCl3)
δ 10.39 (s, 1H), 7.95 (dd, J = 8.0, 1.7 Hz, 1H), 7.54 (ddd, J = 8.8, 7.1, 1.8 Hz, 1H), 7.03 (dd, J
= 8.4, 1.0 Hz, 1H), 6.96 (ddd, J = 8.2, 7.2, 1.1 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 174.9,
162.2, 137.0, 131.0, 119.6, 117.8, 111.3. HRMS (ESI, m/z) calcd for C7H6O3 [M+H]: 139.0389,
found: 139.0394.
2-(2-(1H-Pyrazol-1-yl)phenyl)isoindoline-1,3-dione (10)
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To a solution of the 6a (0.13 mmol) and CAN (1.30 mmol) was added MeCN (2 mL). After
stirring for 10 h, the reaction was judged complete by TLC. The filtrate was extracted with
NH4Cl and saturated brine, the organic layer was dried over MgSO4, filtered and concentrated
in vacuo. The residue was purified by flash chromatography to give the desired product 10 as a
pale yellow solid, 0.031 g, 82% yield, mp: 130.3–132.0 ºC, flash chromatography eluting with
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ethyl acetate/hexanes (1:8→1:2), Rf = 0.35 [ethyl acetate/hexanes (1: 2)]. H NMR (500 MHz,
CDCl3) δ 7.88 (dd, J = 5.5, 3.0 Hz, 2H), 7.76 (dd, J = 5.5, 3.1 Hz, 2H), 7.70 (d, J = 2.4 Hz, 1H),
7.63–7.57 (m, 2H), 7.57–7.52 (m, 1H), 7.52 – 7.42 (m, 2H), 6.33 (t, J = 2.2 Hz, 1H). 13C NMR
(126 MHz, CDCl3) δ 167.0, 141.5, 137.76, 134.1, 132.1, 130.9, 130.1, 129.6, 128.31, 125.8,
125.2, 123.8, 107.1. HRMS (ESI, m/z) calcd for C17H11N3O2 [M+H]: 290.0923, found:
290.0922.
4-Benzylphthalazin-1(2H)-one (11)
To a solution of the 6a (0.13 mmol), N2H4•H2O (1.30 mmol) and KOH (1.30 mmol) was added
EtOH (3 mL). After stirring at 120 ºC for 30 h, the reaction was judged complete by TLC. The
filtrate was washed with 1 M HCl and saturated brine, the organic layer was dried over MgSO4,
filtered and concentrated in vacuo. The residue was purified by flash chromatography to give
the desired product 11 as a pale yellow solid, 0.026g, 84% yield, mp: 194.2–195.6 ºC flash
chromatography eluting with ethyl acetate/hexanes (1:8→1:1), Rf = 0.18 ([ethyl
acetate/hexanes (1: 2)]. 1H NMR (500 MHz, CDCl3) δ 11.08 (s, 1H), 8.53–8.45 (m, 1H), 7.81–
7.70 (m, 3H), 7.30 (d, J = 4.4 Hz, 4H), 7.25–7.21 (m, 1H), 4.33 (s, 2H). 13C NMR (126 MHz,
CDCl3) δ 160.8, 146.4, 137.6, 133.4, 131.3, 129.8, 128.7, 128.5, 128.3, 127.0, 126.8, 125.4,
38.9. HRMS (ESI, m/z) calcd for C15H12N2O [M+H]: 237.1022, found: 237.1018.
Supporting Information
Experimental procedures and compound characterization data. This material is available free
of charge via the Internet at http://pubs.acs.org.
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