Copper-Catalyzed N -Arylation of Azoles and Mannich-Type Coupling of Ketones and Azoles under Metal-Free Conditions

Article abstract of DOI:10.1021/acs.joc.5b02593

(Chemical Equation Presented) A new process has been developed for the copper-catalyzed direct N-arylation of five-membered heterocycles with azoles. Five-membered heterocycles bearing an acetyl group also underwent a Mannich-type reaction with activated azoles to give the corresponding β-amino ketones under metal-free conditions. These reactions exhibited wide substrate scope, high functional group tolerance, and ease of operation, making them useful tools with numerous potential applications in synthetic chemistry.

Full text of DOI:10.1021/acs.joc.5b02593

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Article
Copper-Catalyzed N-Arylation of Azoles and Mannich-Type
Coupling of Ketones and Azoles under Metal-Free Conditions
Kai Sun, Zhonghong Zhu, Jingjing Sun, Lulu Liu, and Xin Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02593 • Publication Date (Web): 29 Jan 2016
Downloaded from http://pubs.acs.org on February 1, 2016
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Copper-Catalyzed N-Arylation of Azoles and Mannich-Type Coupling of
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Ketones and Azoles under Metal-Free Conditions
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Kai Sun,* Zhonghong Zhu, Jingjing Sun, Lulu Liu, and Xin Wang*
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College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang
455000, P. R. China. Eꢀmail: sunk468@nenu.edu.cn; wangx933@nenu.edu.cn
ABSTRACT: A new process has been developed for the copperꢀcatalyzed direct
Nꢀarylation of fiveꢀmembered heterocycles with azoles. Fiveꢀmembered heterocycles
bearing an acetyl group also underwent a Mannichꢀtype reaction with activated azoles
to give the corresponding βꢀamino ketones under metalꢀfree conditions. These
reactions exhibited wide substrate scope, high functional group tolerance, and ease of
operation, making them useful tools with numerous potential applications in synthetic
chemistry.
INTRODUCTION
The importance of nitrogenꢀcontaining compounds stems from their wide occurrence
nature, as well as their broad range of applications in chemistry, biology and materials
science.1 Fiveꢀmembered heterocycles bearing an amine substituent are commonly
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used in medicinal chemistry. For example, several 2ꢀaminothiophene derivatives are
currently used as inhibitors of APE 1 and tubulin polymerization.2 Furthermore,
Zyprexa (Olanzapine), which is based on a 2ꢀaminothiophene core, is ranked as one
the world’s top 200 drugs in terms of its sales. Based on their importance,
research efforts have been directed towards the development of direct and convenient
methods for the synthesis of fiveꢀmembered heterocycles bearing an amine substituent.
Compared with the cyclocondensation reaction of two functionalized precursors,3 the
convinent coupling of the N–H bond with 2ꢀhalogenated precursors is commonly
used in the industry.4 Recently, the direct C–H activation and C–N formation reaction
became an additional powerful methodology for the construction of C–N bonds,
could avoid prefunctionalization of the substrates and minimize environmental
The successful reports of Mori et al., Schreiber et al. and Chang et al. concerning the
Cuꢀcatalyzed direct C–H amination of azoles have inspired an impressive series of
achievements in the transition metalꢀcatalyzed amination of azoles.6 Despite these
achievements, further research is still required in several areas, including (1) the
suppression of the homoꢀdimerization pathway of fiveꢀmembered heterocycles; and (2)
improving the substrate scope of the nitrogen source, especially nitrogen containing
heterocyclic compounds.7
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Azoles are one of the most widely used and extensively studied heterocyclic
compounds, which have been reported to play important roles in medicinal and
pesticide chemistry with a wide range of bioactivities.8 The direct coupling of a
fiveꢀmembered heteroaromatic compound to another type of heteroarene (e.g., azole),
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represents an attractive but challenging transformation.1f As part of our ongoing
in the development of new methods for C–X (X = N, S, I) bond construction,9 more
recently, using the copper salt and selectfluor (1ꢀChloromethylꢀ4ꢀfluoroꢀ1,4ꢀ
diazoniabicyclo[2.2.2]octane bis(tetraꢀ fluoroborate)) combination, we developed the
direct amination of arenes and azines.9f, 9g Herein, our most recent research towards
copperꢀcatalyzed Nꢀarylation of fiveꢀmembered pyrrole, furan and thiophene
derivatives with azoles. Notably, under metalꢀfree conditions, this reaction also
provides access to the corresponding βꢀamino ketones for heterocyclic substrates
bearing an acetyl substituent via a Mannichꢀtype reaction. It is noteworthy that the
methylene derived from poisonous formaldehyde analogues in the Mannich reaction
could be replaced with DMF, DMSO or NMP.
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RESULTS AND DISCUSSION
The reaction of 2ꢀacetylthiophene (1a) with 1Hꢀbenzotriazole (2a) was selected as a
model reaction to identify the optimum conditions for this transformation (Table 1).
initially tested a variety of different copper salts instead of the palladium catalyst to
avoid the occurrence of unwanted side reaction such as homocoupling (For detailed
condition screenings, please see SI section). A variety of copper salts were tested and
only Cu(OTf)2 provided the a higher 56% yield of 2a (Table 1, entry 1). When the
loading of the catalyst was reduced from 10 to 2.5 mol %, we observed a significant
decrease in the yield (Table 1, entry 2). Several bases were also investigated and only
K2CO3 gave a slight increase in the yield (Table 1, entry 3). We also evaluated various
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other solvents, including toluene, DMF, DCE and CH3CN, but failed to provide a
substantial increase in the yield (Table 1, entries 4–6). It is noteworthy that none of
desired amination product 3a was observed in the absence of a copper salt (Table 1,
entry 7). Interestingly, however, this reaction led to the formation of the βꢀamino
5a via a Mannichꢀtype reaction in 21% yield . Intrigued by this result, we screened
reaction against a variety of different solvents, and managed to increase the yield of
βꢀamino ketone to 53% (Table 1, entries 8–11). A variety of different azoles were then
screened under these conditions. Pleasingly, imidazole proved to be the best coupling
partner and gave much higher yields of 5d in the range of 91–95% using DMF,
or NMP as the solvent (Table 1, entries 12–14).
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Table 1. Survey of the Reaction Conditionsa
yield of
yield of
entry
cat (10 mol %)
base
solvent
3a (%)b
5a/5d (%)b
1
2
3
4
Cu(OAc)2
Cu(OAc)2 (2.5 mol %)
Cu(OAc)2
no
CH3NO2
CH3NO2
CH3NO2
DMF
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27
61
0
0
0
0
0
no
K2CO3
K2CO3
Cu(OAc)2
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Cu(OAc)2
Cu(OAc)2
No
K2CO3
K2CO3
K2CO3
no
DCE
CH3CN
CH3NO2
CH3NO2
DMF
46
22
0
0
0
7
21
23
45
53
52
91c
95c
94c
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8
No
0
9
No
no
0
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14
No
no
DMSO
NMP
0
No
no
0
No
no
DMF
0
No
no
DMSO
NMP
0
No
no
0
a
Reactions were carried out with 2ꢀacetylthiophene (1a) (0.5 mmol),
1Hꢀbenzotriazole (2a) (1.0 mmol), Cu catalyst (10 mol %), base (2.0 equiv) and
Selectfluor (2.0 equiv) in solvent (2 mL) at 120 °C. Yield of the isolated product. c
b
Imidazole was used instead of 1Hꢀbenzotriazole.
With the optimized conditions in hand (i.e., conditions A), we proceeded to
investigate the scope of the reaction using a series of fiveꢀmembered heterocycles
(Table 2). In all 15 examples, the product was obtained as a single regioisomer with
selectivity towards the C2 position. Thiophenes containing an electronꢀdonating group
such as Me, Et or OMe reacted smoothly under the optimized conditions to give the
corresponding C–N bond formation products 3c, 3d, 3e and 3f in moderate yields
(63–82%). Chloride substituents were well tolerated on the thiophene ring, as
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exemplified by 2ꢀchlorothiophene (1g) and 2,3ꢀdichlorothiophene (1h), which
3g and 3h in 89 and 83% yields, respectively, and provided a handle for further
synthetic manipulations. Several other heterocyclic partners were also briefly
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Table 2. Scope of Heterocyclic Compounds and Azolesa,b
N
S
N
N
N
S
S
S
O
O
N
N
N N
3b, 90%
N
N
N N
3d, 81%
3a, 61%
3c, 82%
N
N
N
Cl
O
Cl
N
N
S
S
Cl
N
O
S
N N
S
N N
N
N
3e, 77%
3f, 63%
3g, 89%
3h, 83%
N
N
N
N
N
N
N
N
S
S
N
N N
H
N
N
N
N
N
Cl
3i, 68%
3j, 82%
3k, 81%
3l, 84%
O
N
N
N
N
N
N
O
N
N N
N N
SO2Ph
3m, 94%
3n, 88%
3o, 83%
a Reactions were carried out with a fiveꢀmembered heterocycle 1 (0.5 mmol), azole 2
(1.0 mmol), Cu(OAc)2 (10 mol %) and Selectfluor (2.0 equiv) in CH3NO2 (2 mL ) at
120 °C. b Yield of the isolated product.
investigated, including 5ꢀmethylꢀ1Hꢀtetrazole and 6ꢀchloroꢀ7Hꢀpurine, which all
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reacted effectively to give the desired Nꢀarylation products 3i and 3j in 68% and 82%
yields. 1Hꢀpyrrole (1k), 1ꢀmethylꢀ1Hꢀpyrrole (1l), 1ꢀ(phenylsulfonyl)ꢀ1Hꢀpyrrole (1m)
and 1ꢀ(1ꢀmethylꢀ1Hꢀ pyrrolꢀ2ꢀyl)ethanone (1n) were also suitable for this method and
afforded 3k, 3l, 3m and 3n in 81, 84, 94 and 88% yields, respectively.
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The optimized conditions for the Michaelꢀtype reaction (i.e., conditions B) were
applied to 1ꢀ(thiophenꢀ3ꢀyl)ethanone (4e), 1ꢀ(furanꢀ2ꢀyl)ethanone (4f) and
1ꢀ(benzofuranꢀ 2ꢀyl)ethanone (4g), which reacted smoothly to give the corresponding
βꢀamino ketones 5e, 5f and 5g in 81–91% yields (Table 3). βꢀAmino ketones are an
important class of compounds with a wide range of biologically activities that can
be used as synthetic intermediates for the preparation of pharmaceutical agents and
natural products.10 Based on their importance, numerous approaches have been
developed for the synthesis of βꢀamino ketones.11 The classic threeꢀcomponent
Mannich reaction is a well established approach for the synthesis of βꢀamino ketones
which has achieved a great deal of success.12 However, the application of this reaction
to the preparation of pharmaceutical agents has been limited by its requirement for the
use of poisonous formaldehyde analogues. The common polar solvents
dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and methylꢀ2ꢀpyrrolidinone
(NMP) have attracted considerable attention as multipurpose building blocks,13 with
particular emphasis on C–N bond forming reactions involving N–H bondꢀcontaining
substrates and the C(sp3)–H bonds of these solvent molecules.14 Based on these
developments, the scope of this Mannichꢀtype reaction has been broadened to
acetophenone derivatives.
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As shown in Table 4, acetophenones bearing a methyl substituent at the orthoꢀ,
metaꢀ or paraꢀposition of the phenyl ring, including 1ꢀ(oꢀtolyl)ethanone (6b),
1ꢀ(mꢀtolyl)ethanone (6d) and 1ꢀ(pꢀtolyl)ethanone (6f) reacted smoothly with
1Hꢀpyrazole to give the corresponding Mannichꢀtype products 7b, 7d and 7f,
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Table 3. Scope of Heterocyclic Compounds and Azolesa,b
O
H
N
conditions B
Selectfluor
DMSO, 120 oC
O
X
X
+
X
N
N
X
X = O, S
4
N
2
5
a
Reactions were carried out with 4 (0.5 mmol), azole 2 (1.0 mmol) and Selectfluor
equiv) in DMSO (2 mL) at 120 °C. b Yield of the isolated product.
respectively, in excellent yields (91–96%). Acetophenone derivatives containing an
electronꢀdonating (e.g., Me, OMe, Ph) or electronꢀwithdrawing (F, Cl, Br, NO2 CO2Et
and CF3) group at the paraꢀposition of their aromatic ring were well tolerated under
optimized reaction conditions (i.e., conditions B) to afford the corresponding products
7b–p (87–97%). The multisubstituted substrate 6q and fused bicyclic
acetylnaphthalene 6r also reacted efficiently to provide the desired products 7q and 7r
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in high yield (85% and 94%). Furthermore, the substrate scope of this reaction was
extended to several propiophenone derivatives, including propiophenone (6s),
1ꢀ(4ꢀchlorophenyl)propanꢀ1ꢀone (6t) and 1ꢀ(pꢀtolyl)propanꢀ1ꢀone (6u), to give the
desired products 7s–u in 96, 94 and 95% yields, respectively.
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Table 4. Scope of Heterocyclic Compounds and Azolesa,b
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O
O
Cl
O
N
N
N
N
N
N
N
N
7a, 93%
7b, 91%
7c, 87%
O
O
O
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Cl
N
N
N
N
N
7d, 96%
7e, 97%
7f, 94%
O
O
O
N
N
N
N
N
Ph
O
7g, 93%
7h, 89%
7i, 93%
O
O
O
N
N
N
N
N
N
Cl
F
Br
7j, 96%
7k, 97%
7l, 91%
O
O
O
N
N
N
N
N
N
O2N
NC
F3C
7m, 93%
7n, 88%
7o, 87%
O
O
Cl
O
N
N
N
Cl
Cl
N
N
N
N
O
O
7p, 89%
7q, 85%
7r, 94%
O
O
O
N
N
N
N
N
Cl
7s, 96%
7t, 94%
7u, 95%
a
Reactions were carried out with 6 (0.5 mmol), azole 2 (1.0 mmol) and Selectfluor
(2.0 equiv) in DMSO (2 mL) at 120 °C. b Yield of the isolated product.
From a mechanistic point of view, the C(sp2)–N bond formation observed in the
Nꢀarylation reaction most likely proceeds via an electrophilic mechanism. Indeed, our
methodology furnished the C2 functionalized products exclusively, which therefore
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supports this kind of mechanism. When the reaction was conducted in the absence of
copper salt, the mode of reactivity switched to the Mannichꢀtype reaction. We
that the methylene adjacent to the nitrogen atom of the βꢀamino ketone product
from the decomposition of DMSO and that this would be the initial step in the
bond formation between DMSO and the azole. To obtain some mechanistic evidence
for this transformation, we reacted DMSO with 1Hꢀbenzo[d][1,2,3]triazole (2a),
which gave the 1ꢀ((methylsulfinyl)methyl)ꢀ1Hꢀ benzo[d][1,2,3]triazole A in
reasonable yield (eq. 1).15 The structure of this addition product was confirmed by 1H
and 13C NMR spectroscopy (see ESI). As expected, the desired βꢀamino ketone 5a
was obtained in 74% yield when 4a was reacted with A
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under the optimized conditions (i.e., conditions B) (eq. 2). Furthermore, the reaction
of 4a with 1ꢀmethylꢀ1Hꢀbenzo[d][1,2,3]triazole (B) instead of 1Hꢀbenzoꢀ
[d][1,2,3]triazole (2a) under the optimized conditions gave 5a in a lower isolated
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yield of 17% (eq. 3). Based on these results, we have proposed a mechanism for this
reaction, which is shown in Scheme 1.
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The initial substitution of 1Hꢀpyrazole to an electrophilic fluoro(methylsulꢀ
finyl)methane I delivers the 1ꢀ((methylsulfinyl)methyl)ꢀ1Hꢀimidazole II, which then
undergoes a C–S bond cleavage reaction mediated by selectfluor to afford the the key
iminium ion III and CH3SOH. The final nucleophilic addition between III and the
enol tautomer of the ketone affords the desired product.
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Scheme 1. Proposed Mechanism
In conclusion, we have successfully developed a copperꢀcatalyzed process for the
direct Nꢀarylation of the C(sp2)–H bonds of fiveꢀmembered heterocycles with azoles,
which are well known to be crucial precursors for the synthesis of numerous
biologically active compounds. In addition, we have developed a new Mannichꢀtype
reaction for the synthesis of βꢀamino ketones under metalꢀfree conditions from
fiveꢀmembered heterocycles bearing an acetyl groups, including acetophenone
derivatives. Notably, this reaction exhibited broad substrate scope and wide functional
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group compatibility, as well as being easy to operate, making it an attractive
supplement to the traditional Mannich reaction. Further research towards the
application of this protocol to the synthesis of bioactive molecules and a detailed
mechanistic investigation are currently in progress.
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Experimental Section
General Information. All of the reagents were purchased from commercial
sources and used without further purification. H NMR and 13C NMR spectra were
1
recorded on a 400 spectrometer in deuterated solvents containing TMS as an internal
reference standard. Highꢀresolution mass spectrometry (HRMS) analyses were
measured at 70 eV using a double focusing magnetic sector mass analyzer with an EI
source. Melting points were measured on a melting point apparatus equipped with a
thermometer and were uncorrected. All of the reactions were monitored by thinꢀlayer
chromatography (TLC) using GF254 silica gelꢀcoated TLC plates. Purifications by
flash column chromatography were carried out over SiO2 (silica gel 200−300 mesh).
General procedure (condition A) for the N-arylation reactions of the heterocyclic
compounds and the azoles to generate compounds 3a–r:
1HꢀBenzo[d][1,2,3]triazole 2a (1.0 mmol, 119.0 mg), Cu(OAc)2 (10 mol %, 9.5 mg )
and Selectfluor (2.0 equiv, 354.2 mg) were added to a sealable reactor vial containing
a fiveꢀmembered heterocycle 1a (0.5 mmol, 62.5 mg) in CH3NO2 (2 mL). The tube
was then sealed and the mixture was stirred at 120 °C for 8–14 h. Upon completion of
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the reaction (monitored by TLC), the mixture was cooled to room temperature and
quenched with water before being extracted with dichloromethane (5 × 3 mL). The
combined organic layers were dried over anhydrous Na2SO4 and concentrated under
reduced pressure to give a residue, which was purified by flash column
chromatography over silica gel (EtOAc/petroleum ether = 1:6, v/v) to give compound
3a (74.1 mg) in 61% yield.
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General procedure (condition B) for the Mannich type reaction between ketones
and azoles (5aꢀ5h, 7a-7u):
1HꢀPyrazole 2b (1.0 mmol, 68.0 mg) and Selectfluor (2.0 equiv, 354.2 mg) were
added to a sealable reactor vial containing a fiveꢀmembered heterocycle 4d (0.5 mmol,
63.0 mg) in 2 mL DMSO. The tube was then sealed and the mixture was stirred at
120 °C for 2–6 h. Upon completion of the reaction (monitored by TLC), the mixture
was cooled to room temperature and quenched with water before being extracted with
dichloromethane (5 × 3 mL). The combined organic layers were dried over anhydrous
Na2SO4 and concentrated under reduced pressure to give a residue, which was
purified by flash column chromatography over silica gel (EtOAc/petro ether = 1:5,
v/v) to give compound 5d (97.9 mg) in 95% yield.
1-(5-(1H-benzo[d][1,2,3]triazol-1-yl)thiophen-2-yl)ethanone (3a). White solid
o
(61%, 74.1 mg), melting point: 94ꢀ95 C; 1H NMR (400 MHz; CDCl3): δ = 3.69 (s,
3H), 7.01 (d, J = 4.4, 1H), 7.17 (d, J = 4.0, 1H), 7.45 (t, J = 6.8, 1H), 7.58 (t, J = 8.0,
1H), 7.73 (d, J = 8.4, 1H), 8.13 (d, J = 8.8, 1H). 13C NMR (100 MHz; CDCl3): δ =
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33.5, 105.9, 107.5, 110.2, 120.0, 122.4, 123.5, 124.4, 128.5, 134.9, 145.2, 190.2.
HRMS (ESIꢀTOF) Calcd for C12H10N3SO, [M+H]+ 244.0541; Found 244.0537.
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1-(thiophen-2-yl)-1H-benzo[d][1,2,3]triazole (3b). White solid (90%，90.5 mg),
melting point: 74ꢀ76 oC; 1H NMR (400 MHz; CDCl3): δ = 7.17ꢀ7.47 (m, 4H), 7.60 (t,
J = 7.6, 1H), 7.77 (d, J = 8.4, 1H), 8.15 (d, J = 8.4, 1H). 13C NMR (100 MHz; CDCl3):
δ = 108.4, 118.0, 118.6, 121.5, 122.9, 124.5, 129.9, 130.9, 135.7, 144.3. HRMS
(ESIꢀTOF) Calcd for C10H8N3S, [M+H]+ 202.0435; Found 202.0439.
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1-(5-methylthiophen-2-yl)-1H-benzo[d][1,2,3]triazole (3c). White oil (82%, 68.2
1
mg); H NMR (400 MHz; CDCl3): δ = 2.58 (s, 3H), 6.81 (d, J = 2.0, 1H), 7.17 (d, J =
3.6, 1H), 7.45 (t, J = 6.8, 1H), 7.58 (t, J = 7.6, 1H), 7.73 (d, J = 8.4, 1H), 8.13 (d, J =
8.4, 1H). 13C NMR (100 MHz; CDCl3): δ = 15.5, 110.3, 120.3, 120.4, 124.6, 128.5,
132.9, 134.4, 138.5, 145.9. HRMS (ESIꢀTOF) Calcd for C11H10N3S, [M+H]+ 216.0594;
Found 216.0599.
1-(5-ethylthiophen-2-yl)-1H-benzo[d][1,2,3]triazole (3d). White solid (81%, 62.8
o
1
mg), melting point: 66ꢀ67 C; H NMR (400 MHz; CDCl3): δ = 1.39 (t, J = 7.6, 3H),
2.93 (d, J = 7.6, 2H), 6.84 (t, J = 7.2, 1H), 7.20 (d, J = 7.6, 1H), 7.45 (t, J = 8.0, 1H),
7.58 (d, J = 7.6, 1H), 7.74 (d, J = 8.4, 1H), 8.13 (d, J = 8.0, 1H). 13C NMR (100 MHz;
CDCl3): δ = 15.7, 23.6, 110.3, 120.1, 120.3, 122.3, 124.5, 128.5, 132.9, 134.3, 146.0,
146.1. HRMS (ESIꢀTOF) Calcd for C12H12N3S, [M+H]+ 230.0752; Found 230.0746.
1-(5-methoxythiophen-2-yl)-1H-benzo[d][1,2,3]triazole (3e). White oil (77%,
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88.9 mg); 1H NMR (400 MHz; CDCl3): δ = 3.90 (s, 3H), 6.24 (d, J = 2.0, 1H), 7.10 (d,
J = 2.0, 1H), 7.47 (d, J = 8.4, 1H), 7.60 (t, J = 8.0, 1H), 7.79 (d, J = 8.4, 1H), 8.14 (d, J
= 8.4, 1H). 13C NMR (100 MHz; CDCl3): δ = 57.2, 93.9, 110.3, 112.0, 120.5, 124.8,
128.8, 132.4, 146.2, 155.6. HRMS (ESIꢀTOF) Calcd for C11H10N3OS, [M+H]+
232.0541; Found 232.0536.
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1-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-1H-benzo[d][1,2,3]triazole
(3f).
o
White solid (63%, 81.6 mg), melting point: 93ꢀ94 C; 1H NMR (400 MHz; CDCl3): δ
= 4.24ꢀ4.26 (m, 4H), 6.43 (d, J = 9.6, 1H), 7.37ꢀ7.42 (m, 1H), 7.50ꢀ7.59 (m, 2H), 8.07
(t, J = 8.8, 1H). 13C NMR (100 MHz; CDCl3): δ = 64.6, 65.1, 98.3, 110.7, 120.0, 124.5,
128.3, 134.1, 136.1, 140.5, 145.4. HRMS (ESIꢀTOF) Calcd for C12H10N3O2S, [M+H]+
260.0494; Found 260.0498.
1-(5-chlorothiophen-2-yl)-1H-benzo[d][1,2,3]triazole (3g). White solid (89%,
106.6 mg), melting point: 94ꢀ95 oC; 1H NMR (400 MHz; CDCl3): δ = 7.00 (d, J = 2.0,
1H), 7.17 (d, J = 3.6, 1H), 7.49 (d, J = 8.4, 1H), 7.61 (t, J = 8.0, 1H) 7.72 (d, J = 8.4,
1H), 8.15 (d, J = 8.4, 1H). 13C NMR (100 MHz; CDCl3): δ = 109.9, 110.0, 113.5,
119.3, 120.5, 120.6, 121.4, 124.6, 125.3, 128.7, 129.0, 132.0, 132.6, 134.9, 146.1.
HRMS (ESIꢀTOF) Calcd for C10H7ClN3S, [M+H]+ 236.0049; Found 236.0043.
1-(4,5-dichlorothiophen-2-yl)-1H-benzo[d][1,2,3]triazole (3h). White solid (83%,
112.0 mg), melting point: 160ꢀ162 oC; 1H NMR (400 MHz; CDCl3): δ = 7.20 (s, 1H),
7.51 (d, J = 8.0, 1H), 7.66 (d, J = 6.8, 1H), 7.74 (d, J = 8.4, 1H), 8.15 (d, J = 8.4, 1H).
13C NMR (100 MHz; CDCl3): δ = 106.0, 109.8, 118.1, 120.1, 124.7, 129.1, 130.3,
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130.6, 134.5, 145.3. HRMS (ESIꢀTOF) Calcd for C10H6Cl2N3S, [M+H]+ 269.9653;
Found 269.9658.
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5-methyl-1-(thiophen-2-yl)-1H-tetrazole (3i). White solid (68% ， 56.5 mg),
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melting point: 72ꢀ73 C; H NMR (400 MHz; CDCl3): δ = 2.65 (s, 3H), 7.15 (q, J =
4.0, 1H), 7.24 (t, J = 2.4, 1H), 7.45 (q, J = 1.2, 1H). 13C NMR (100 MHz; CDCl3): δ =
9.63, 124.0, 126.1, 126.5, 133.2, 152.4. HRMS (ESIꢀTOF) Calcd for C6H7N4S,
[M+H]+ 167.0388; Found 167.0393.
6-chloro-7-(thiophen-2-yl)-7H-purine (3j). White solid (82%, 96.7 mg), melting
point: 153ꢀ154 C; 1H NMR (400 MHz; CDCl3): δ = 7.14 (t, J = 3.6, 1H), 7.28 (q, J =
o
4.4, 1H), 7.17 (q, J = 2.4, 1H), 7.49 (d, J = 8.4, 1H), 8.35 (s, 1H) 8.97 (s, 1H). 13C
NMR (100 MHz; CDCl3): δ = 121.9, 124.1, 126.1, 126.5, 128.1, 144.4, 149.9, 152.9,
153.2. HRMS (ESIꢀTOF) Calcd for C9H6ClN4S, [M+H]+ 237.0004; Found 237.0012.
1-(1H-pyrrol-2-yl)-1H-benzo[d][1,2,3]triazole (3k). White solid (81%, 74.5 mg),
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melting point: 119ꢀ121 C; H NMR (400 MHz; CDCl3): δ = 6.40 (d, J = 3.2, 1H),
6.48 (d, J = 1.2, 1H), 6.90 (d, J = 1.2, 1H), 7.45 (d, J = 3.6, 1H), 7.55 (d, J = 8.0, 1H),
7.74 (d, J = 8.4, 1H), 8.10 (d, J = 8.4, 1H), 9.40 (s, 1H). 13C NMR (100 MHz; CDCl3):
δ = 99.4, 109.1, 110.5, 116.8, 120.1, 124.6, 125.0, 128.5, 131.9, 145.8. HRMS
(ESIꢀTOF) Calcd for C10H9N4, [M+H]+ 185.0821; Found 185.0816.
1-(1-methyl-1H-pyrrol-2-yl)-1H-benzo[d][1,2,3]triazole (3l). White solid (84%,
o
1
63.2 mg), melting point: 104ꢀ106 C; H NMR (400 MHz; CDCl3): δ = 3.47 (s, 3H),
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6.31 (d, J = 3.6, 1H), 6.40 (t, J = 2.0, 1H), 6.79 (t, J = 2.4, 1H), 7.40ꢀ7.54 (m, 3H),
8.13 (d, J = 8.4, 1H). 13C NMR (100 MHz; CDCl3): δ = 33.5, 105.9, 107.5, 110.2,
120.0, 122.4, 123.5, 124.4, 128.5, 134.9, 145.2. HRMS (ESIꢀTOF) Calcd for
C11H11N4, [M+H]+ 199.0987; Found 199.0982.
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1-(1-(phenylsulfonyl)-1H-pyrrol-2-yl)-1H-benzo[d][1,2,3]triazole (3m). Yellow
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solid (94%，152.3 mg), melting point: 98ꢀ100 C; H NMR (400 MHz; CDCl3): δ =
6.48 (d, J= 3.6, 1H), 6.54 (t, J = 2.0, 1H), 7.30 (t, J = 8.4, 1H), 7.41ꢀ7.58 (m, 8H), 8.11
(d, J = 8.4, 1H). 13C NMR (100 MHz; CDCl3): δ = 110.4, 111.1, 114.7, 119.1, 123.5,
124.5, 127.6, 128.7, 129.3, 134.5, 134.7, 144.8. HRMS (ESIꢀTOF) Calcd for
C16H13N4O2S, [M+H]+ 325.0754; Found 325.0759.
1-(5-(1H-benzo[d][1,2,3]triazol-1-yl)-1-methyl-1H-pyrrol-2-yl)ethanone (3n).
o
1
White solid (88%, 105.6 mg), melting point: 134ꢀ136 C; H NMR (400 MHz;
CDCl3): δ = 2.51 (s, 3H), 3.69 (s, 3H), 6.41 (d, J = 4.0, 1H), 7.10 (d, J = 4.4, 1H), 7.43
(q, J = 7.6, 2H), 7.54 (d, J = 7.6, 1H), 8.12 (d, J = 8.0, 1H). 13C NMR (100 MHz;
CDCl3): δ = 27.3, 33.4, 106.1, 109.8, 118.1, 120.4, 124.8, 129.1, 130.4, 130.7, 134.5,
145.3, 189.1. HRMS (ESIꢀTOF) Calcd for C13H13N4O, [M+H]+ 241.1084; Found
241.1080.
1
1-(furan-2-yl)-1H-benzo[d][1,2,3]triazole (3o). Yellow oil (83%, 76.8 mg); H
NMR (400 MHz; CDCl3): δ = 6.65 (d, J = 2.0, 1H) 6.71 (q, J = 2.8, 1H), 7.44ꢀ7.61 (m,
3H), 7.81 (d, J = 8.4, 1H), 8.13 (d, J = 8.4, 1H). 13C NMR (100 MHz; CDCl3): δ =
100.5, 110.7, 111.9, 120.2, 124.0, 128.8, 140.4, 145.5. HRMS (ESIꢀTOF) Calcd for
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C10H8N3O, [M+H]+ 186.0664; Found 186.0669.
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3-(1H-benzo[d][1,2,3]triazol-1-yl)-1-(thiophen-2-yl)propan-1-one (5a). White
solid (53%, 68.1 mg), melting point: 74ꢀ76 oC; 1H NMR (400 MHz; CDCl3): δ = 3.77
(t, J = 7.2, 2H), 5.11 (t, J = 6.8, 2H), 6.41 (d, J = 1.6, 1H), 6.94 (d, J = 1.6, 1H), 7.10 (d,
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J = 4.4, 1H), 7.41ꢀ7.45 (m, 2H), 7.54 (d, J = 7.6, 1H), 8.12 (d, J = 8.0, 1H). C NMR
(100 MHz; CDCl3): δ = 39.9, 46.5, 110.3, 120.1, 120.3, 122.3, 124.5, 128.5, 132.9,
134.3, 146.0, 146.1, 191.1. HRMS (ESIꢀTOF) Calcd for C13H12N3OS, [M+H]+
258.0702; Found 258.0706.
1-(thiophen-2-yl)-3-(1H-1,2,4-triazol-1-yl)propan-1-one (5b). White solid (84%,
o
86.9 mg), melting point: 68ꢀ70 C; 1H NMR (400 MHz; CDCl3): δ = 3.52 (d, J = 6.4,
2H), 4.62 (t, J = 6.4, 2H), 7.11 (t, J = 4.8, 1H), 7.65ꢀ7.69 (m, 2H), 7.91 (s, 1H), 8.21 (s,
13
1H). C NMR (100 MHz; CDCl3): δ = 38.5, 44.0, 128.3, 132.5, 134.5, 143.1, 152.0,
189.3. HRMS (ESIꢀTOF) Calcd for C9H10N3OS, [M+H]+ 208.0544; Found 208.0540.
3-(5-phenyl-1H-tetrazol-1-yl)-1-(thiophen-2-yl)propan-1-one (5c). White solid
(53%, 75.2 mg), melting point: 53ꢀ55 oC; 1H NMR (400 MHz; CDCl3): δ = 3.77 (d, J
= 6.8, 2H), 5.11 (t, J = 6.8, 2H), 7.16 (t, J = 4.4, 1H), 7.48 (q, J1 = 1.6, J2 = 5.2, 3H),
7.70 (d, J = 3.6, 1H), 7.77 (d, J = 3.6, 1H), 8.13(J1 = 2.8, J2 = 7.6, 2H). 13C NMR (100
MHz; CDCl3): δ = 37.9, 47.9, 126.8, 127.3, 128.3, 128.9, 130.3, 132.5, 134.6, 143.0,
165.2, 188.4. HRMS (ESIꢀTOF) Calcd for C14H13N4OS, [M+H]+ 285.0810; Found
285.0815.
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3-(1H-pyrazol-1-yl)-1-(thiophen-2-yl)propan-1-one (5d). White solid (95%, 97.8
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6
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mg), melting point: 58ꢀ59 C; H NMR (400 MHz; CDCl3): δ = 3.51 (t, J = 6.4, 2H),
4.57 (t, J = 6.8, 2H), 6.19 (t, J = 2.0, 1H), 7.10 (J = 4.0, 1H), 7.49 (dd, J1 = 1.2, J2 = 7.2,
2H), 7.63ꢀ7.69 (m, 2H). 13C NMR (100 MHz; CDCl3): δ = 39.4, 45.6, 105.3, 128.2,
130.1, 132.4, 134.2, 139.7, 143.5, 190.2. HRMS (ESIꢀTOF) Calcd for C10H11N2OS,
[M+H]+ 207.0591; Found 207.0587.
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3-(1H-pyrazol-1-yl)-1-(thiophen-3-yl)propan-1-one (5e). White solid (91%, 93.8
o
1
mg), melting point: 63ꢀ64 C; H NMR (400 MHz; CDCl3): δ = 3.51 (t, J = 6.4, 2H),
13
4.58 (t, J = 6.8, 2H), 7.31 (q, J = 3.2, 1H), 7.48ꢀ7.51 (m, 3H), 8.05 (q = 1.2, 1H). C
NMR (100 MHz; CDCl3): δ = 39.9, 46.5, 105.3, 126.6, 126.7, 130.1, 132.5, 139.6,
141.7, 191.7. HRMS (ESIꢀTOF) Calcd for C10H11N2OS, [M+H]+ 207.0591; Found
207.0586.
1-(furan-2-yl)-3-(1H-pyrazol-1-yl)propan-1-one (5f). White solid (87%, 62.7 mg),
melting point: 55ꢀ57 oC; 1H NMR (400 MHz; CDCl3): δ = 3.44 (t, J = 6.4, 2H), 4.57 (t,
J = 6.8, 2H), 6.19 (t, J = 2.0, 1H), 6.52 (q, J = 2.0, 1H), 7.18 (d, J = 3.6, 1H), 7.49 (dd,
J1 = 2.0, J2 = 7.2, 2H), 7.57 (d, J = 1.6, 1H). 13C NMR (100 MHz; CDCl3): δ = 38.6,
46.2, 105.3, 112.4, 117.7, 130.0, 139.6, 146.8, 152.2, 188.2. HRMS (ESIꢀTOF) Calcd
for C10H11N2O2, [M+H]+ 191.0821; Found 191.0824.
1-(benzofuran-2-yl)-3-(1H-pyrazol-1-yl)propan-1-one (5g). White solid (81%,
o
1
97.2 mg) melting point: 64ꢀ65 C; H NMR (400 MHz; CDCl3): δ = 3.59 (t, J = 6.4,
2H), 4.62 (t, J = 6.8, 2H), 6.20 (t, J = 2.0, 1H), 7.31 (s, 1H), 7.48ꢀ7.57 (m, 5H), 7.70 (d,
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J = 8.0, 1H). 13C NMR (100 MHz; CDCl3): δ = 39.1, 46.2, 105.4, 112.5, 113.5, 123.4,
124.0, 126.9, 128.6, 130.1, 139.7, 152.0, 155.7, 188.3. HRMS (ESIꢀTOF) Calcd for
C14H12N2O2, [M+H]+ 241.0977; Found 241.0970.
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1-phenyl-3-(1H-pyrazol-1-yl)propan-1-one (7a). White solid (93%, 93.0 mg),
melting point: 66ꢀ67 oC; 1H NMR (400 MHz; CDCl3): δ = 3.60 (t, J = 6.4, 2H), 4.62 (t,
J = 6.8, 2H), 6.21 (t, J = 2.0, 1H), 7.44ꢀ7.52 (m, 4H), 7.57 (t, J = 7.6, 1H), 7.94 (t, J =
7.2, 2H). 13C NMR (100 MHz; CDCl3): δ = 38.8, 46.6, 105.3, 128.0, 128.7, 130.1,
133.5, 136.4, 139.6, 197.4. HRMS (ESIꢀTOF) Calcd for C12H13N2O, [M+H]+
201.1028; Found 201.1023.
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3-(1H-pyrazol-1-yl)-1-(o-tolyl)propan-1-one (7b). White oil (91%, 97.4 mg); H
NMR (400 MHz; CDCl3): δ = 2.46 (s, 3H), 3.51 (t, J = 6.4, 2H), 4.58 (t, J = 6.4, 2H),
6.21 (t, J = 2.4, 1H), 7.23 (t, J = 6.8, 2H), 7.35 (t, J = 2.0, 1H), 7.49 (t, J = 3.2, 2H),
7.61 (d, J = 1.6, 1H). 13C NMR (100 MHz; CDCl3): δ = 21.4, 41.4, 46.8, 105.3, 125.8,
128.7, 130.1, 131.8, 132.1, 137.0, 138.5, 139.6, 201.1. HRMS (ESIꢀTOF) Calcd for
C13H15N2O, [M+H]+ 215.1184; Found 215.1181.
1-(2-chlorophenyl)-3-(1H-pyrazol-1-yl)propan-1-one (7c). White oil (87%, 101.8
1
mg); H NMR (400 MHz; CDCl3): δ = 3.56 (dd, J1 = 1.2, J2 = 6.4, 2H), 4.59 (dd, J1 =
1.2, J2 = 6.4, 2H), 6.21 (t, J = 1.6, 1H), 7.29ꢀ7.49 (m, 6H). 13C NMR (100 MHz;
CDCl3): δ = 42.9, 46.6, 105.4, 126.9, 129.2, 130.0, 131.1, 132.2, 138.4, 139.6, 200.2.
HRMS (ESIꢀTOF) Calcd for C12H12ClN2O, [M+H]+ 235.0634; Found 235.0630.
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3-(1H-pyrazol-1-yl)-1-(m-tolyl)propan-1-one (7d). White oil (96%, 102.7 mg);
1H NMR (400 MHz; CDCl3): δ = 2.36 (s, 3H), 3.55 (t, J = 6.4, 2H), 4.58 (t, J = 6.4,
2H), 6.18 (t, J = 2.0, 1H), 7.32 (t, J = 6.8, 2H), 7.49 (t, J = 2.4, 2H), 7.71 (d, J = 8.8,
2H). 13C NMR (100 MHz; CDCl3): δ = 21.3, 38.4, 46.6, 105.3, 125.3, 128.5, 128.6,
130.1, 134.2, 138.5, 139.5, 197.6. HRMS (ESIꢀTOF) Calcd for C13H15N2O, [M+H]+
215.1184; Found 215.1188.
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1-(3-chlorophenyl)-3-(1H-pyrazol-1-yl)propan-1-one (7e). White oil (97%, 113.5
1
mg); H NMR (400 MHz; CDCl3): δ = 3.56 (m, 2H), 4.58 (t, J = 6.4, 2H), 6.21 (t, J =
2.0, 1H), 7.38ꢀ7.55 (m, 4H), 7.79ꢀ7.91 (m, 2H). 13C NMR (100 MHz; CDCl3): δ =
38.9, 46.5, 105.4, 126.1, 128.2, 129.5, 130.0, 130.1, 133.4, 135.1, 137.8, 139.7, 196.2.
HRMS (ESIꢀTOF) Calcd for C12H12ClN2O, [M+H]+ 235.0634; Found 235.0639.
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3-(1H-pyrazol-1-yl)-1-(p-tolyl)propan-1-one (7f). White oil (94%, 100.6 mg); H
NMR (400 MHz; CDCl3): δ = 2.38 (s, 3H), 3.55 (t, J = 6.4, 2H), 4.58 (t, J = 6.4, 2H),
6.19 (t, J = 2.0, 1H), 7.23 (d, J = 8.0, 2H), 7.49 (d, J = 2.0, 2H), 7.82 (d, J = 8.0, 2H).
13C NMR (100 MHz; CDCl3): δ = 21.7, 38.7, 46.7, 105.3, 128.2, 129.4, 130.1, 133.9,
139.5, 144.4, 197.1. HRMS (ESIꢀTOF) Calcd for C13H15N2O, [M+H]+ 215.1184;
Found 215.1189.
1-(4-methoxyphenyl)-3-(1H-pyrazol-1-yl)propan-1-one (7g). White oil (93%,
107.0 mg); 1H NMR (400 MHz; CDCl3): δ = 3.55 (t, J = 6.4, 2H), 3.87 (s, 3H), 4.58 (t,
J = 6.4, 2H), 6.20 (t, J = 2.0, 1H), 6.92 (d, J = 9.2, 2H), 7.50 (d, J = 2.0, 2H), 7.92 (dd,
J1 = 2.0, J2 = 7.6, 2H). 13C NMR (100 MHz; CDCl3): δ = 21.7, 38.7, 46.7, 105.3,
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128.2, 129.4, 130.1, 133.9, 139.5, 144.4, 197.1. HRMS (ESIꢀTOF) Calcd for
C13H15N2O2, [M+H]+ 231.1134; Found 231.1130.
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1-(4-cyclohexylphenyl)-3-(1H-pyrazol-1-yl)propan-1-one (7h). White oil (89%,
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125.5 mg); H NMR (400 MHz; CDCl3): δ = 1.23ꢀ1.46 (m, 5H), 1.74ꢀ1.86 (m, 5H),
2.55 (d, J = 10.0, 1H), 3.56 (t, J = 6.4, 2H), 4.59 (t, J = 6.4, 2H), 6.19 (s, 1H), 7.28 (d,
J = 8.4, 2H), 7.49 (d, J = 2.0, 2H), 7.86 (d, J = 8.0, 2H). 13C NMR (100 MHz; CDCl3):
δ = 25.9, 28.7, 34.1, 38.8, 44.6, 46.6, 109.2, 127.2, 128.3, 130.1, 134.2, 139.5, 156.2,
197.0. HRMS (ESIꢀTOF) Calcd for C18H23N2O, [M+H]+ 283.1807; Found 283.1810.
1-([1,1'-biphenyl]-4-yl)-3-(1H-pyrazol-1-yl)propan-1-one (7i). White solid (93%,
o
1
128.3 mg), melting point: 119ꢀ120 C; H NMR (400 MHz; CDCl3): δ = 3.63 (t, J =
6.4, 2H), 4.63 (t, J = 6.4, 2H), 6.23 (t, J = 2.0, 1H), 7.40ꢀ7.53 (m, 5H), 7.61ꢀ8.02 (m,
13
6H). C NMR (100 MHz; CDCl3): δ = 38.8, 46.7, 109.3, 127.3, 128.4, 128.7, 128.9,
130.1, 135.1, 139.6, 146.1, 196.9. HRMS (ESIꢀTOF) Calcd for C18H17N2O, [M+H]+
277.1341; Found 277.1346.
1-(4-fluorophenyl)-3-(1H-pyrazol-1-yl)propan-1-one (7j). White oil (96%, 104.6
1
mg); H NMR (400 MHz; CDCl3): δ = 3.57 (t, J = 6.4, 2H), 4.60 (t, J = 6.4, 2H), 6.21
(s, 1H), 7.12 (t, J = 8.4, 2H), 7.60 (t, J = 6.4, 2H), 7.97 (q, J = 5.6, 2H). 13C NMR (100
MHz; CDCl3): δ = 38.7, 46.6, 105.3, 115.7, 115.9, 130.1, 130.7, 130.8, 132.8, 139.6,
1
164.7, 167.2 (d, JCꢀF = 254 Hz), 195.8. HRMS (ESIꢀTOF) Calcd for C12H12FN2O,
[M+H]+ 219.0934; Found 219.0936.
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1-(4-chlorophenyl)-3-(1H-pyrazol-1-yl)propan-1-one (7k). White solid (97%,
113.9 mg), melting point: 72ꢀ73 oC; 1H NMR (400 MHz; CDCl3): δ = 3.57 (t, J = 6.4,
2H), 4.60 (t, J = 6.4, 2H), 6.21 (t, J = 2.0, 1H), 7.44 (t, J = 2.0, 2H), 7.50 (q, J = 2.4,
2H), 7.89 (d, J = 8.8, 2H). 13C NMR (100 MHz; CDCl3): δ = 38.8, 46.6, 105.3, 129.0,
129.4, 130.1, 134.7, 139.7, 140.0, 196.3. HRMS (ESIꢀTOF) Calcd for C12H12ClN2O,
[M+H]+ 235.0634; Found 235.0638.
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1-(4-bromophenyl)-3-(1H-pyrazol-1-yl)propan-1-one (7l). White solid (91%,
1
126.5 mg), melting point: 95ꢀ97 oC (91%, 126.5 mg); H NMR (400 MHz; CDCl3): δ
= 3.55 (t, J = 6.4, 2H), 4.58 (t, J = 6.4, 2H), 6.21 (t, J = 2.0, 1H), 7.49 (q, J = 2.4, 2H),
7.58 (t, J = 7.2, 2H), 7.78 (d, J = 8.4, 2H). 13C NMR (100 MHz; CDCl3): δ = 38.7,
46.5, 105.3, 128.7, 129.5, 130.0, 132.0, 135.1, 139.7, 196.5. HRMS (ESIꢀTOF) Calcd
for C12H12BrN2O, [M+H]+ 279.0134; Found 279.0137.
1-(4-nitrophenyl)-3-(1H-pyrazol-1-yl)propan-1-one (7m). White solid (93%,
o
1
113.9 mg), melting point: 106ꢀ107 C; H NMR (400 MHz; CDCl3): δ = 3.65 (t, J =
6.4, 2H), 4.62 (t, J = 6.4, 2H), 6.22 (t, J = 2.0, 1H), 7.50 (d, J = 8.8, 2H), 8.10 (d, J =
8.8, 2H), 8.30 (d, J = 8.4, 2H). 13C NMR (100 MHz; CDCl3): δ = 39.2, 46.3, 105.5,
123.9, 129.1, 130.2, 139.8, 140.7, 196.1. HRMS (ESIꢀTOF) Calcd for C12H12N3 O3,
[M+H]+ 246.0877; Found 246.0871.
4-(3-(1H-pyrazol-1-yl)propanoyl)benzonitrile (7n). White oil (88%, 100.3 mg);
1H NMR (400 MHz; CDCl3): δ = 3.60 (t, J = 6.4, 2H), 4.59 (t, J = 6.4, 2H), 6.20 (t, J =
2.0, 1H), 7.48 (d, J = 2.0, 2H), 7.75 (d, J = 6.4, 2H), 8.01 (dd, J1 = 1.6, J2 = 6.8, 2H).
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13C NMR (100 MHz; CDCl3): δ = 38.9, 46.3, 105.4, 116.7, 117.6, 128.5, 130.2, 132.6,
139.2, 139.8, 196.3. HRMS (ESIꢀTOF) Calcd for C13H12N3O, [M+H]+ 226.0980;
Found 226.0975.
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3-(1H-pyrazol-1-yl)-1-(4-(trifluoromethyl)phenyl)propan-1-one (7o). White
o
1
solid (87%, 116.6 mg), melting point: 51ꢀ52 C; H NMR (400 MHz; CDCl3): δ =
3.61 (t, J = 6.4, 2H), 4.60 (t, J = 6.4, 2H), 6.20 (t, J = 2.0, 1H), 7.50 (d, J = 1.6, 2H),
7.71 (d, J = 8.4, 2H), 8.02 (d, J = 8.0, 2H). 13C NMR (100 MHz; CDCl3): δ = 39.0,
1
46.3, 105.9, 122.1, 125.7, 125.8, 128.4 (d, JCꢀF = 258 Hz), 130.1, 134.5, 134.8,
138.9, 139.7, 196.6. HRMS (ESIꢀTOF) Calcd for C13H12F3N2O, [M+H]+ 269.0904;
Found 269.0909.
methyl 4-(3-(1H-pyrazol-1-yl)propanoyl)benzoate (7p). White oil (89%, 114.8
1
mg); H NMR (400 MHz; CDCl3): δ = 3.63 (t, J = 6.4, 2H), 3.96 (s, 1H), 4.62 (t, J =
6.4, 2H), 6.22 (t, J = 2.0, 1H), 7.52 (s, 2H), 8.00 (d, J = 8.8, 2H), 8.12 (d, J = 8.4, 2H).
13C NMR (100 MHz; CDCl3): δ = 39.1, 46.5, 52.5, 105.4, 127.9, 129.8, 130.1, 134.2,
139.5, 139.7, 166.1, 197.0. HRMS (ESIꢀTOF) Calcd for C14H15N2O3, [M+H]+
259.1083; Found 259.1080.
3-(1H-pyrazol-1-yl)-1-(2,3,4-trichlorophenyl)propan-1-one (7q). White oil (85%,
128.4 mg); 1H NMR (400 MHz; CDCl3): δ = 3.51 (t, J = 6.4, 2H), 4.57 (t, J = 6.4, 2H),
6.21 (t, J = 2.0, 1H), 7.20 (d, J = 8.4, 1H), 7.40ꢀ7.48 (m, 3H). 13C NMR (100 MHz;
CDCl3): δ = 42.9, 46.5, 105.5, 126.6, 128.6, 130.1, 130.9, 133.1, 136.8, 139.0, 139.7,
199.2. HRMS (ESIꢀTOF) Calcd for C12H10Cl3N2O, [M+H]+ 302.9859; Found
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1-(naphthalen-2-yl)-3-(1H-pyrazol-1-yl)propan-1-one
(7r).
White
solid
9
(94%,117.5 mg), melting point: 98ꢀ100 oC; 1H NMR (400 MHz; CDCl3): δ = 3.74 (t, J
= 6.4, 2H), 4.63 (t, J = 6.4, 2H), 6.23 (t, J = 2.0, 1H), 7.54ꢀ7.61 (m, 4H), 7.86ꢀ8.02 (m,
4H), 8.45 (s, 1H). 13C NMR (100 MHz; CDCl3): δ = 38.3, 46.8, 105.3, 123.5, 126.9,
127.8, 128.6, 128.7, 129.6, 130.0, 130.1, 132.4, 133.7, 135.7, 139.7, 197.4. HRMS
(ESIꢀTOF) Calcd for C16H15N2O, [M+H]+ 251.1184; Found 251.1180.
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2-methyl-1-phenyl-3-(1H-pyrazol-1-yl)propan-1-one (7s). White oil (96%, 102.7
mg); 1H NMR (400 MHz; CDCl3): δ = 1.21 (d, J = 6.4, 3H), 4.19ꢀ4.26 (m, 2H), 4.62 (t,
J = 9.36, 1H), 6.15 (s, 1H), 7.39ꢀ7.56 (m, 5H), 7.91 (d, J = 8.0, 2H). 13C NMR (100
MHz; CDCl3): δ = 16.1, 41.9, 54.0, 105.1, 128.4, 128.7, 130.4, 133.4, 135.8, 139.8,
202.2. HRMS (ESIꢀTOF) Calcd for C13H15N2O, [M+H]+ 215.1183; Found 215.1179.
2-methyl-3-(1H-pyrazol-1-yl)-1-(p-tolyl)propan-1-one (7t). White oil (94%,
1
107.2 mg); H NMR (400 MHz; CDCl3): δ = 1.20 (d, J = 7.2, 3H), 2.39 (s, 3H), 4.22
(q, J = 6.4, 2H), 4.57 (d, J = 6.4, 1H), 6.15 (t, J = 2.0, 1H), 7.22ꢀ7.51 (m, 5H), 7.84 (d,
J = 8.8, 2H), 8.01 (d, J = 8.0, 1H). 13C NMR (100 MHz; CDCl3): δ = 15.9, 21.6, 41.8,
54.0, 105.2, 129.0, 129.8, 130.4, 134.1, 139.9, 201.8. HRMS (ESIꢀTOF) Calcd for
C14H17N2O, [M+H]+ 229.1338; Found 229.1341.
1-(4-chlorophenyl)-2-methyl-3-(1H-pyrazol-1-yl)propan-1-one (7u). White oil
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(95%, 117.8 mg); H NMR (400 MHz; CDCl3): δ = 1.20 (d, J = 7.2, 3H), 4.22 (q, J =
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6.4, 2H), 4.57 (d, J = 6.4, 1H), 6.15 (t, J = 2.0, 1H), 7.36ꢀ7.49 (m, 4H), 7.84 (d, J = 8.8,
2H). 13C NMR (100 MHz; CDCl3): δ = 16.2, 21.6, 41.7, 54.0, 105.1, 128.5, 129.1,
129.4, 130.1, 130.6, 133.3, 139.7, 144.3, 201.6. HRMS (ESIꢀTOF) Calcd for
C13H14ClN2O, [M+H]+ 249.0791; Found249.0794.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications
website at DOI: xxx.
Optimization details, Xꢀray data for compounds 3k and 7r, Copies of H and 13C
1
NMR spectra for 3, 5, 7 and A (PDF), Crystallographic data for 3k and 7r (CIF).
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: sunk468@nenu.edu.cn; wangx933@nenu.edu.cn.
ACKNOWLEDGMENTS
We are grateful for the reviewers’ useful suggestions on this manuscript. This work
was supported by the National Natural Science Foundation of China (U1504210),
China Postdoctoral Science Foundation funded project (2015M572110), and Science
and Technology Plan Projects of Henan Province (15A150030).
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References and Notes
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1. For selected reviews, see: (a) Hartwig, J. F. Acc. Chem. Res. 2012, 45, 864. (b)
Mueller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905. (c) Dick, A. R.; Sanford, M. S.
Tetrahedron 2006, 62, 2439. (d) Davies, H. M. L.; Long, M. S. Angew. Chem., Int. Ed.
2005, 44, 3518. (e) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417. (f) Cho,
S. H.; Kim, J. Y.; Kwak, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (g)
Louillat, M. L.; Patureau, F. W. Chem. Soc. Rev. 2014, 43, 901.
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2. (a) Chen, X.; Huang, X.; He, Q.; Xie, Y.; Yang, C. Chem. Commun. 2014, 50, 3996.
(b) Hou, C.; He, Q.; Yang, C. Org. Lett. 2014, 16, 5040. (c) Gronowitz, S. In
Thiophene and Its Derivatives; Gronowitz, S., Ed.; Wiley & Sons: New York, 1985;
Part 1, p 88. (d) Luo, X.ꢀY.; Ge, L.ꢀS.; An, X.ꢀL.; Jin, J.ꢀH.; Wang, Y.; Sun, P.ꢀP.;
Deng, W.ꢀP. J. Org. Chem. 2015, 80, 4611 and references cited therein.
3. Armstrong, A.; Collins J. C. Angew. Chem., Int. Ed. 2010, 49, 2282.
4. (a) Ogawa, K.; Radke, K. R.; Rothstein, S. D.; Rasmussen, S. C. J. Org. Chem.
2001, 66, 9067. (b) Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. .J. Org. Chem.
2003, 68, 2861. (c) Charles, M. D.; Schultz, P.; Buchwald, S. L. Org. Lett. 2005, 7,
3965.
5. For selected reviews about C–N bond formation, please see (a) Cho, S. H.; Kim, J.
Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (b) Bariwal, J.; Van der E.; E.
Chem Soc Rev. 2013, 42, 9283. (c) Louillat, M. L.; Patureau, F. W. Chem. Soc. Rev.
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2014, 43, 901.
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6. For select papers, see: (a) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org.
Lett. 2009, 11, 1607. (b) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11, 5178. (c) Cho,
S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem., Int. Ed. 2009, 48, 9127. (d)
Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S. Angew. Chem., Int. Ed. 2010, 49, 9899. (e)
Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2010, 132, 6900. (f)
Guo, S.; Qian, B.; Xie, Y.; Xia, C.; Huang, H. Org. Lett. 2011, 13, 522.
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