Rhodium(III)-catalyzed azacycle-directed intermolecular insertion of arene C-H bonds into α-diazocarbonyl compounds

Article abstract of DOI:10.1021/jo400572h

Cp*Rh(III)-catalyzed intermolecular C-C couplings between activated α-diazocarbonyl compounds and arenes bearing a range of azacyclic directing groups have been achieved. This catalytic alkylation reaction operates under mild conditions with good functional group tolerance.

Full text of DOI:10.1021/jo400572h

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Article
Rhodium(III)-Catalyzed Azacycle-Directed Intermolecular Insertion
of Arene C#H Bonds into alpha-Diazocarbonyl Compounds
Xinzhang Yu, Songjie Yu, Jian Xiao, Boshun Wan, and Xingwei Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400572h • Publication Date (Web): 10 May 2013
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The Journal of Organic Chemistry
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Rhodium(III)-Catalyzed
Azacycle-Directed
Intermolecular
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Insertion of Arene C-H Bonds into
α
-Diazocarbonyl Compounds
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Xinzhang Yu, Songjie Yu, Jian Xiao, Boshun Wan*, and Xingwei Li*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan
Road, Dalian 116023, China
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*Eꢀmail: xwli@dicp.ac.cn; bswan@dicp.ac.cn.
ABSTRACT
Cp*Rh(III)ꢀcatalyzed
intermolecular
CꢀC
couplings
between
activated
αꢀdiazocarbonyl compounds and arenes bearing a range of azacyclic directing groups
have been achieved. This catalytic alkylation reaction operates under mild conditions
with good functional group tolerance.
INTRODUCTION
The last several decades have witnessed the remarkable progress of CꢀC coupling
reactions via a CꢀH activation pathway, particularly using rhodium catalysts.1 While
Rh(I) and Rh(II) catalysts are both wellꢀknown in serving this purpose, it has been
recently well documented that under chelation assistance, Rh(III) complexes can
efficiently catalyze the activation of sp2 CꢀH bonds, leading to diversified couplings of
arenes and olefins with various unsaturated substrates.2 On the other hand, transition
metalꢀcatalyzed redoxꢀneutral insertion of an aromatic CꢀH bond into an
electronꢀdeficient π bond is highly attractive because this method represents an
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atomꢀeconomic strategy to construct CꢀC bonds without using any oxidant.3 Recent
studies have established that Rh(III) complexes are also highly active in catalyzing the
addition of sp2 CꢀH bonds into unsaturated polar groups, such as imines,4 aldehydes,5
isocyanates,6a and isocyanides.6b However, the insertion of aromatic CꢀH bonds into
carbenoids is still underexplored and is mostly limited to intramolecular reactions.7 So
far only very few systems of intermolecular carbeninod insertion into heteroaromatic
CꢀH bonds have been achieved probably because of low reactivity and poor
regioꢀselectivity.8 Recently, Wang and Miura independently reported the coupling of
azoles with Nꢀtosylhydrazones.9 In 2010, Yu demonstrated the Ru(II)ꢀcatalyzed
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functionalization of indoles by
α
ꢀaryldiazoesters with excellent regioselectivity.10
However, the intermolecular carbenoid insertion into aromatic CꢀH bonds proved to
be even more challenging. In 2009, Jung reported the first Rh(II)ꢀcatalyzed
intermolecular functionalization of phenyl CꢀH bonds using diazo compounds, where
only two examples were provided and a large excess of the arene substrate was
required.11 Significant progress was made by Yu’s group who elegantly achieved
Cp*Rh(III)ꢀcatalyzed intermolecular insertion of aromatic CꢀH bonds into
α
ꢀdiazomalonates.12 At the same time, a similar work was underway in our
laboratories.
Although Yu’s group accomplished the CꢀC coupling of diazomalonates with
arenes bearing four classes of directing groups (ketone oxime, amine, acid, and
pyridine),12 the scope of this coupling needs expansion and the selectivity of this type
of coupling needs further exploration. Herein, we report our findings on the
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intermolecular alkylation of arenes using αꢀdiazocarbonyl compounds.
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RESULTS AND DISCUSSION
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We initiated our studies with the coupling of Nꢀphenylpyrazole and ethyl
diazomelonate using [Cp*RhCl2]2 as a catalyst in the presence a silver salt additive
(Table 1). It was found that while almost all the Ag(I) additives examined can effect
this coupling, those with a less coordinating anion such as AgSbF6 proved to be most
effective when EtOH was designated as the solvent. Reactions performed in other
solvents such as DCE and THF gave slightly lower yield of 3a, but essentially no
desired reaction occurred when MeCN was used (Table 1, entry 15). A rather low
loading (1 mol%) of the rhodium catalyst was necessary when the temperature was
improved to 75 °C (entry 16). Thus the optimal yield was obtained when a
[Cp*RhCl2]2/AgSbF6 (1 mol%/5 mol%) catalyst was applied, and product 3a was
obtained in 95% HPLC yield (92% isolated yield). This observation is in contrast to
those reported by Yu in the reaction of acetophenone Oꢀmethyl oxime and dimethyl
diazomelonate,12 where using AgOAc as an additive, EtOH proved to be an
inappropriate solvent because of the undesired insertion of the carbenoid by EtOꢀH
bond, not the C(aryl)ꢀH bond. These results indicate that a combination of the silver
salt and the solvent plays a vital role for an efficient coupling.
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Table 1. Optimization Studiesa
entry [Cp*RhCl2]2
additive
solvent
T
yield
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(mol %)
(mol %)
(HPLC)b
87%
58%
94%
81%
85%
89%
89%
85%
95%
13%
84%
86%
17%
17%
3%
(°C)
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75
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2
2
2
2
2
2
2
2
1
AgOAc (20)
AgF (20)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
EtOH
tBuOH
THF
3
AgSbF6 (20)
AgNO3 (20)
AgOTf (20)
AgNTf2 (20)
AgPF6 (20)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (5)
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DCE
DMF
Toluene
CH3CN
EtOH
95%
a Condition: 1a (0.2 mmol), 2a (1.2 equiv.), [Cp*RhCl2]2, Ag(I) additive in
solvent (2 mL), 6 h. b HPLC yield.
Under the optimal conditions, the scope of the dizao substrate was next examined.
A series of diazomalonates smoothly coupled with 1a in yield ranging from 52% to 92%
in EtOH or DCE. In the case of methyl, benzyl, and isoꢀpropyl esters, DCE was used
to avoid any transesterification product (Table 2, 3aꢀ3d). Besides these
diazomalonates, high coupling efficiency was achieved when one of the ester groups
was be replaced by another electronꢀwithdrawing group such as phosphonate and
sulfonyl (3e, 3f), although a diminished yield was obtained when an amide or benzoyl
group was used (3g and 3h).
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Table 2. Rh(III)ꢀCatalyzed Alkylation of NꢀPhenylpyrazole (1a) with
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α
ꢀDiazocarbonyl Compounds.a
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N
O
N
R2
N
[Cp*RhCl2]2 (1 mol%)
N
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N2
OR1
OR1
+
AgSbF6 (5 mol%)
EtOH, 75 °C, 6 h
R2
O
R= CH(CO2Et)2
3
1a
2
a
Conditions: 1a (0.2 mmol), 2 (0.24 mmol), [Cp*RhCl2]2 (1 mol%), AgSbF6 (5
mol%), EtOH (2 mL), 75 °C, 6 h. b In DCE (2 mL), 75 °C, 24 h.
The scope of the pyrazole substrate was next assessed in the coupling with diethyl
diazomelonate under our standard conditions (Table 3). Different electronꢀdonating,
ꢀwithdrawing, and halogen substitutents in the pyrazole ring were tolerated, and the
coupling products were isolated in 72ꢀ94% yield, indicative of good functional group
compatibility and tolerance of steric hindrance of the directing group (3iꢀ3l).
Substitutents in the phenyl ring were next examined. Both donating (3mꢀ3r) and
withdrawing groups (3sꢀ3v) were allowed, and the expected products were isolated in
good to high yield. In particular, an unprotected para aminoꢀfunctionalized
Nꢀphenylpyrazole can be alkylated in high efficiency, and product 3r was isolated in
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88% yield. All the ortho- substituted phenylpyrazoles reacted with high efficiency,
with no detrimental steric effect of these ortho substituents (3m, 3p, 3s, and 3w).
When a metaꢀmethyl substituted substrate was applied, the coupling occurred
selectively at the less congested position (3n). It is noteworthy that no dialkylation
product was detected for all the Nꢀphenylpyrazoles examined.
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Table 3. Rh(III)ꢀCatalyzed Alkylation of NꢀArylpyrazoles with Diethyl
2ꢀDiazomalonate (2a).a
a Conditions: 1 (0.2 mmol), 2a (0.24 mmol), [Cp*RhCl2]2 (1 mol%), AgSbF6 (5 mol%),
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EtOH (2 mL), 75 °C, 6 h.
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We next investigated the reactivity of 2ꢀarylpyrimidines for this reaction (Table
4). To avoid any complication of dialkylations, an oꢀMe blocking group was
introduced into the phenyl ring (4a). The standard conditions proved well applicable
for the coupling of 4a with a series of activated diazo compounds to readily give the
corresponding coupling product in high yield (5aꢀ5e), and the yields are generally
higher than those for Nꢀphenylpyrazoles. These results indicated that steric hindrance
of the oꢀMe group posed no issue. Besides an oꢀMe, other ortho substituents such as
OMe, F, and Cl groups all gave equally good results (5fꢀ5h). Selective dialkylation
can be readily achieved for arenes without an ortho blocking group when an excess of
diethyl diazomelonate was introduced. Thus 2ꢀphenylpyrimidines with a broad scope
of electronꢀdonating and ꢀwithdrawing para-substitutents underwent dialkylation in
78ꢀ99% yield (5kꢀ5o). This highꢀyielding coupling also applies to a metaꢀCl
substituted substrate (5p), indicative of the tolerance of a halogen group. Besides
dialkylation, monoalkylation of simple 2ꢀphenylpyrimidine has also been achieved
when the AgSbF6 additive was replaced by AgF, under which conditions the
monoalkylation product (5i) was isolated in 66% as a major product, together with the
dialkylation minor product (30% yield). We noted that the reactions of the pyrimidine
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substrates with the methyl or benzyl ester of αꢀdiazomalonates proceeded quickly in
EtOH, but there were some transesterification byꢀproducts, which were difficult to
separate from the desired product. Therefore, 1,2ꢀdichloroethane (DCE) was shosen
as the solvent (Table 4, 5b, 5c). In addition, the smooth orthoꢀalkylation also can be
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carried out using a related benzoxazole directing group (5q, 5r). In comparison, Yu’
conditions ([Cp*RhCl2]2/AgOAc) turned out to be inapplicable for these benzoxazole
substrates, under which only traces of the product could be detected (5q).
Table 4. Rh(III)ꢀCatalyzed Monoꢀ and Dialkylation of 2ꢀArylpyrimidinesa
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a Conditions: 4 (0.2 mmol), 2 (1.2 equiv.), [Cp*RhCl2]2 (1 mol%), AgSbF6 (5 mol%),
b
c
d
EtOH (2 mL), 75 °C, 6 h. In DCE (2 mL), 75 °C, 24 h. AgF (5 mol%). 4 (0.2
mmol), 2 (3 equiv.), [Cp*RhCl2]2 (2 mol %), AgSbF6 (10 mol%), EtOH (2 mL), 75
°C, 6 h. e Value in parentheses correspond to HPLC yield for 10 h at 75 °C in MeOH
using [Cp*RhCl2]2 (2 mol%), AgOAc (10 mol%).
The arene is not limited to a benzene platform, and heteroarenes such as furans,
thiophenes and pyroles can also undergo the same insertion into αꢀdiazomalonates to
afford to the desired alkylated product in good to high yields (Table 5). Analogously,
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dialkylation could also take place for pyrrole rings without any ortho blocking group.
Table 5. Rh(III)ꢀCatalyzed Alkylation of Heteroaromatics with Diethyl
2ꢀDiazomalonate (2a).a
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a Conditions: 6 (0.2 mmol), 2a (1.2 equiv.), [Cp*RhCl2]2 (1 mol%), AgSbF6 (5 mol%) ,
b
c
EtOH (2 mL), 75 °C, 6 h. AgF (5mol%). 48 h. d 2a (3 equiv.), [Cp*RhCl2]2 (2 mol%),
AgSbF6 (10 mol%).
In contrast to the efficient coupling using these diazo compounds activated by
two withdrawing groups, however, no desired reaction occurred when simple ethyl
diazoacetate (2m) was used
(Scheme 1, eq. 1), suggesting that the two
electronꢀwithdrawing groups are crucial to ensure high reactivity. Interestingly, when
the diazo derivative of meldrum’s acid (2n) was coupled with Nꢀphenylpyrazole
under the standard conditions, product 8a was isolated in 71% yield as a result of CꢀC
coupling in tandem with ethanolysis of the acetal functionality followed by
decarboxyation (8a). The successful isolation of products 8a-8c offers an applicable
path to circumvent the poor reactivity of ethyl diazoacetate (2m).
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Scheme 1. Rh(III)ꢀCatalyzed Alkylation of Arenes with the Diazo derivative of
Meldrum’s Acid 2i.a
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a Conditions: arene (0.2 mmol), 2n (1.2 equiv.), [Cp*RhCl2]2 (1 mol%), AgSbF6 (5
mol%), EtOH (2 mL), 75 °C, 6 h. b AgF (5 mol%).
To probe the CꢀH activation step in the reaction of Nꢀphenylpyrazole (1a) and
diethyl diazomelonate, KIE was measured using an equimolar mixture of 1a and
1aꢀd5. 1H NMR analysis of the product mixture gave KIE (kH/kD) = 4. This large value
suggests that cleavage of the CꢀH bond (cyclometalation) is involved in the
turnoverꢀlimiting step. Despite this information, it remains a question whether the
2
reaction proceeds via a Rhꢀcarbene pathway or via a SN ꢀlike denitrogenative pathway
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with concomitant RhꢀC(aryl) bond cleavage.12
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CONCLUSION
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We have extended the scope of rhodium(III)ꢀcatalyzed azacycleꢀdirected CꢀH
activation of (hetero)arenes and coupling with activated diazo esters, leading to the
alkylation of CꢀH bonds under mild conditions. A broad scope of (hetero)aromatics
assisted by a directing group (pyrazole, pyrimidine, and oxazole) has been alkylated
with good functional group compatibility. Silver additive played an important role,
and both AgSbF6 and AgF can be used as an optimal additive, depending on the entity
of the substrate. Future work on CꢀH activation/coupling with other electrophilic
unsaturated substrates is underway in our laboratory.
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EXPERIMENTAL SECTION
General Information. Commercially available reagents were used without
further purification. Solvents were treated prior to use according to the standard
methods. All reactions were carried out under an atmosphere of argon using standard
Schlenk techniques. NMR spectra were recorded at room temperature in CDCl3 on
400 MHz or 500 MHz spectrometers. Column chromatography was performed on
silica gel 300ꢀ400 mesh. Mixture of Petroleum ether (boiling rang 60ꢀ90 °C) and ethyl
acetate were used as an eluant. When solvent gradients were used, the increase in
polarity was made from neat petroleum ether to mixtures of ethyl acetate/petroleum
ether, with ethyl acetate being increased by 10% each time until the isolation of the
product.
General procedure for the Rh(III)-catalyzed ortho C-H functionalizations
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arenes with diazo compounds (1a as an example). A dried 10 mL Schlenk tube
equipped with a magnetic stirrer was charged with 1ꢀphenylꢀ1Hꢀpyrazole 1a (0.2
mmol), [Cp*RhCl2]2 (1 mg, 2 ꢀmol), AgSbF6 (3 mg, 10 ꢀmol), and EtOH (2 mL)
under Ar. After the reaction mixture was stirred at room temperature for 1 h, diazo
compound 2a (0.24 mmol) was then added in oneꢀpot and the mixture was stirred at
75 °C for 6 h. The reaction mixture was cooled to room temperature, and then filtered
through a pad of Celite and concentrated under reduced pressure. The residue was
then charged on silica gel column and eluted with a mixture of ethyl
acetate/petroleum ether (1:8) to give the desired product 3a. (All the following
reactions were carried out using this procedure unless otherwise indicated).
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Diethyl 2-(2-(1H-pyrazol-1-yl)phenyl)malonate (3a). Colorless oil 56 mg, 92%
1
yield; H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.68–7.59 (m, 2H), 7.47–7.36 (m,
2H), 7.33 (d, J = 7.8 Hz, 1H), 6.43 (d, J = 1.5 Hz, 1H), 4.89 (s, 1H), 4.19 (q, J = 7.1
Hz, 4H), 1.23 (t, J = 7.1 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 167.9, 140.9, 139.6,
130.8, 130.1, 128.9, 128.7, 128.4, 125.8, 106.7, 61.7, 52.6, 13.8; HRMS
(ESI–Orbitrap) calcd for C16H18N2O4H+[M+H]: 303.1339, found: 303.1332.
Dimethyl 2-(2-(1H-pyrazol-1-yl)phenyl)malonate (3b). Following the general
procedure except DCE as solvent and reacted for 24 h. Colorless oil 42 mg, 76% yield;
1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 1.5 Hz, 1H), 7.67–7.64 (m, 1H), 7.63–7.60
(m, 1H), 7.47–7.39 (m, 2H), 7.35–7.32 (m, 1H), 6.46–6.43 (m, 1H), 4.96 (s, 1H), 3.72
(s, 6H); 13C NMR (126 MHz, CDCl3) δ 168.6, 141.2, 139.8, 131.1, 130.4, 129.1,
128.9, 128.8, 126.1, 107.0, 53.0, 52.4; HRMS (ESI–TOF) calcd for C14H14N2O4Na+
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[M+Na]: 297.0846, found 297.0854.
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Dibenzyl 2-(2-(1H-pyrazol-1-yl)phenyl)malonate (3c). Following the general
procedure except DCE as solvent and reacted for 24 h. Colorless oil 57 mg, 67% yield;
1H NMR (500 MHz, CDCl3) δ 7.66 (dd, J = 1.8, 0.4 Hz, 1H), 7.60–7.57 (m, 2H),
7.45–7.38 (m, 2H), 7.36–7.31 (m, 7H), 7.30–7.26 (m, 4H), 6.42–6.38 (m, 1H), 5.19 (q,
J = 12.4 Hz, 4H), 5.08 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 167.9, 141.2, 139.9,
135.4, 131.0, 130.5, 129.1, 128.8, 128.6, 128.6, 128.4, 128.3, 125.9, 107.0, 67.5, 53.0;
HRMS (ESI–TOF) calcd for C26H22N2O4Na+ [M+Na]: 449.1472, found: 449.1471.
Diisopropyl 2-(2-(1H-pyrazol-1-yl)phenyl)malonate (3d). Following the general
procedure except DCE as solvent and reacted for 24 h. Colorless oil 56 mg, 85% yield;
1H NMR (500 MHz, CDCl3) δ 7.72–7.68 (m, 1H), 7.65 (dd, J = 2.4, 0.5 Hz, 1H), 7.61
(dd, J = 7.6, 1.8 Hz, 1H), 7.46–7.37 (m, 2H), 7.36–7.31 (m, 1H), 6.45–6.41 (m, 1H),
5.10–5.01 (m, 2H), 4.80 (s, 1H), 1.24 (d, J = 6.3 Hz, 6H), 1.21 (d, J = 6.3 Hz, 6H);
13C NMR (126 MHz, CDCl3) δ 167.7, 141.0, 140.0, 131.1, 130.3, 129.4, 128.8, 128.6,
126.1, 106.9, 69.5, 53.3, 21.6; HRMS (ESI–TOF) calcd for C18H22N2O4Na+ [M+Na]:
353.1472, found: 353.1480.
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Ethyl 2-(2-(1H-pyrazol-1-yl)phenyl)-2-tosylacetate (3e). Colorless oil 70 mg, 91%
1
yield; H NMR (400 MHz, CDCl3) δ 8.08–7.99 (m, 1H), 7.64 (s, 1H), 7.40 (dd, J =
5.7, 3.5 Hz, 2H), 7.34 (d, J = 8.4 Hz, 3H), 7.22–7.16 (m, 1H), 7.13 (d, J = 8.1 Hz, 2H),
6.33 (s, 1H), 5.84 (s, 1H), 4.22–4.04 (m, 2H), 2.33 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 164.5, 145.1, 141.3, 140.6, 134.8, 131.7, 131.4, 130.3,
129.4, 129.1, 128.3, 125.9, 123.8, 106.9, 67.8, 62.6, 21.6, 13.8; HRMS (ESI–Orbitrap)
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calcd for C20H20N2O4SH+ [M+H]: 385.1217, found: 385.1208.
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Ethyl 2-(2-(1H-pyrazol-1-yl)phenyl)-2-(diethoxyphosphoryl) acetate (3f).
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Colorless oil 63 mg, 86% yield; H NMR (400 MHz, CDCl3) δ 8.01 (dt, J = 7.8, 1.8
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Hz, 1H), 7.70 (dd, J = 5.5, 1.9 Hz, 2H), 7.46–7.33 (m, 2H), 7.30 (d, J = 7.7 Hz, 1H),
6.42 (t, J = 2.1 Hz, 1H), 4.63 (d, J = 24.7 Hz, 1H), 4.16 (dd, J = 13.9, 7.0 Hz, 2H),
4.07–3.99 (m, 2H), 3.99–3.87 (m, 2H), 1.21 (t, J = 7.1 Hz, 6H), 1.12 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 167.3 (d, J = 3.9 Hz), 141.1, 139.9 (d, J = 8.5
Hz), 131.5, 131.4 (d, J = 4.7 Hz), 128.6 (d, J = 2.6 Hz), 128.5 (d, J = 2.6 Hz), 127.3 (d,
J = 6.9 Hz), 126.5 (d, J = 1.9 Hz), 106.8, 63.2 (dd, J = 10.1, 6.8 Hz), 62.0, 45.3 (d, J =
134.8 Hz), 16.3 (dd, J = 12.6, 6.1 Hz), 14.0; HRMS (ESI–Orbitrap) calcd for
C17H23N2O5PH+ [M+H]: 367.1417, found: 367.1404.
Ethyl 2-(2-(1H-pyrazol-1-yl)phenyl)-3-amino-3-oxopropanoate (3g). Colorless oil
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28mg, 52% yield; H NMR (500 MHz, CDCl3) δ 8.06 (s, 1H), 7.94 (dd, J = 7.9, 1.5
Hz, 1H), 7.79–7.75 (m, 1H), 7.73 (dd, J = 2.4, 0.5 Hz, 1H), 7.47 (td, J = 7.7, 1.4 Hz,
1H), 7.41 (td, J = 7.7, 1.6 Hz, 1H), 7.27 (dd, J = 7.9, 1.3 Hz, 1H), 6.52–6.48 (m, 1H),
5.51 (s, 1H), 4.86 (s, 1H), 4.24–4.09 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (126
MHz, CDCl3) δ 170.1, 168.5, 141.1, 138.9, 131.7, 131.5, 129.7, 128.9, 128.8, 125.6,
107.4, 61.8, 51.7, 14.1; HRMS (ESI–TOF) calcd for C14H15N3O3Na+ [M+Na]:
296.1006, found: 296.1004.
Ethyl
2-(2-(1H-pyrazol-1-yl)phenyl)-3-oxo-3-phenylpropanoate
&
(E)-ethyl
2-(2-(1H-pyrazol-1-yl)phenyl) -3-hydroxy-3-phenylacrylate (4:1) (3h). Colorless oil
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37 mg, 56% yield; H NMR (400 MHz, CDCl3) δ 13.56 (s, 1H), 7.83 (d, J = 8.0 Hz,
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2H), 7.73 (s, 1H), 7.60 (s, 1H), 7.46 (d, J = 6.8 Hz, 2H), 7.34 (dd, J = 9.3, 5.9 Hz, 5H),
7.22 (t, J = 7.2 Hz, 1H), 7.18–7.09 (m, 1H), 7.07 (d, J = 7.7 Hz, 1H), 6.45 (s, 1H),
6.30 (s, 1H), 5.99 (s, 1H), 4.17 (q, J = 7.1 Hz, 2H), 4.04 (dd, J = 7.1, 3.7 Hz, 1H),
1.17 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
194.0, 172.6, 171.2, 168.9, 141.3 140.4, 139.4, 135.6, 134.2, 133.6, 131.1, 130.9,
130.0, 129.6, 129.4, 129.1, 129.0, 128.9, 128.8, 128.7, 128.6, 127.8, 127.3, 126.2,
125.0, 107.1, 106.6, 61.8, 61.2, 55.2, 14.1; HRMS (ESI–TOF) calcd for
C20H18N2O3Na+ [M+Na]: 357.1215, found: 357.1203.
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Diethyl 2-(2-(3-methyl-1H-pyrazol-1-yl)phenyl)malonate (3i). Colorless oil 46
mg, 72% yield; 1H NMR (500 MHz, CDCl3) δ 7.60–7.56 (m, 1H), 7.54 (d, J = 2.2 Hz,
1H), 7.40–7.36 (m, 2H), 7.32–7.29 (m, 1H), 6.20 (d, J = 2.2 Hz, 1H), 4.91 (s, 1H),
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4.19 (qd, J = 7.1, 0.5 Hz, 4H), 2.32 (s, 3H), 1.24 (t, J = 7.1 Hz, 7H); C NMR (126
MHz, CDCl3) δ 168.3, 150.3, 139.9, 131.6, 130.3, 128.9, 128.8, 128.2, 125.8, 106.8,
61.8, 53.1, 14.1, 13.6; HRMS (ESI–TOF) calcd for C17H20N2O4Na+ [M+Na]:
339.1321, found: 339.1331.
Diethyl 2-(2-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)malonate (3j). White solid 62
mg, mp 55–56 °C, 94% yield; 1H NMR (500 MHz, CDCl3) δ 7.62 (dd, J = 7.8, 1.5 Hz,
1H), 7.45 (td, J = 7.6, 1.4 Hz, 1H), 7.40 (td, J = 7.6, 1.6 Hz, 1H), 7.24 (dd, J = 7.7, 1.4
Hz, 1H), 5.96 (s, 1H), 4.48 (s, 1H), 4.16 (q, J = 7.1 Hz, 4H), 2.26 (s, 3H), 2.06 (d, J =
0.4 Hz, 3H), 1.22 (t, J = 7.1 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 168.0, 149.3,
141.1, 138.8, 132.0, 130.20, 129.2, 128.7, 127.8, 105.8, 61.8, 52.6, 14.1, 13.6, 11.4;
HRMS (ESIꢀOrbitrap) calcd for C18H22N2O4H+ [M+H]: 331.1652, found: 331.1654.
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Diethyl 2-(2-(5-chloro-3-methyl-1H-pyrazol-1-yl)phenyl)malonate (3k). Colorless
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oil 60 mg, 85% yield; H NMR (500 MHz, CDCl3) δ 7.65 (dd, J = 7.9, 1.5 Hz, 1H),
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7.46 (dd, J = 7.7, 1.4 Hz, 1H), 7.40 (td, J = 7.7, 1.5 Hz, 1H), 7.28 (dd, J = 7.8, 1.3 Hz,
1H), 6.15 (s, 1H), 4.49 (s, 1H), 4.15 (q, J = 7.1 Hz, 4H), 2.26 (s, 3H), 1.20 (t, J = 7.1
Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 167.7, 150.3, 137.0, 131.5, 130.4, 129.7,
129.0, 128.6, 128.1, 105.3, 61.9, 52.6, 14.1, 14.0; HRMS (ESI–TOF) calcd for
C17H19ClN2O4Na+ [M+Na]: 373.0931, found: 373.0944.
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Diethyl 2-(2-(4-acetyl-5-methyl-1H-pyrazol-1-yl)phenyl)malonate (3l). Colorless
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oil 59 mg, 83% yield; H NMR (500 MHz, CDCl3) δ 8.01 (s, 1H), 7.69 (dd, J = 7.9,
1.4 Hz, 1H), 7.53 (td, J = 7.7, 1.4 Hz, 1H), 7.45 (td, J = 7.7, 1.5 Hz, 1H), 7.21 (dd, J =
7.8, 1.3 Hz, 1H), 4.34 (s, 1H), 4.21–4.07 (m, 4H), 2.50–2.44 (m, 3H), 2.35 (s, 3H),
1.19 (t, J = 7.1 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 193.3, 167.5, 144.8, 142.3,
137.4, 131.5, 130.6, 130.2, 129.0, 127.6, 120.7, 62.1, 52.3, 28.7, 14.0, 11.7; HRMS
(ESI–TOF) calcd for C19H22N2O5Na+ [M+Na]: 381.1426, found: 381.1418.
Diethyl 2-(3-methyl-2-(1H-pyrazol-1-yl)phenyl)malonate (3m). Colorless oil 49
mg. 78% yield. 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.52 (d, J = 9.9 Hz, 2H),
7.47 (d, J = 7.4 Hz, 1H), 7.36 (d, J = 7.3 Hz, 1H), 6.53 (s, 1H), 4.35–4.15 (m, 5H),
2.08 (s, 3H), 1.29 (t, J = 6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 168.1, 140.9,
139.2, 136.7, 131.8, 131.6, 130.6, 129.4, 127.2, 106.5, 61.9, 52.6, 17.5, 14.1; HRMS
(ESI–Orbitrap) calcd for C17H20N2O4H+ [M+H]: 317.1496, found: 317.1461.
Diethyl 2-(4-methyl-2-(1H-pyrazol-1-yl)phenyl)malonate (3n). White solid 52 mg,
mp 91ꢀ93 °C, 82% yield, 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 0.8 Hz, 1H), 7.65
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(d, J = 2.4 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 0.6
Hz, 1H), 6.43 (t, J = 2.0 Hz, 1H), 4.82 (s, 1H), 4.19 (q, J = 7.1 Hz, 4H), 2.38 (s, 3H),
1.23 (t, J = 7.1 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 168.3, 141.0, 139.7, 139.2,
131.1, 130.2, 129.5, 126.8, 126.1, 106.8, 61.9, 52.5, 21.0, 14.1; HRMS (ESI–TOF)
calcd for C17H20N2O4Na+ [M+Na]: 339.1315, found: 339.1329.
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Diethyl 2-(5-methyl-2-(1H-pyrazol-1-yl)phenyl)malonate (3o). Colorless oil 56
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mg, 88% yield; H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 1.5 Hz, 1H), 7.60 (d, J =
2.3 Hz, 1H), 7.40 (s, 1H), 7.20 (d, J = 1.9 Hz, 2H), 6.43–6.38 (m, 1H), 4.83 (s, 1H),
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4.18 (qd, J = 7.1, 2.1 Hz, 4H), 2.40 (s, 3H), 1.23 (t, J = 7.1 Hz, 6H); C NMR (126
MHz, CDCl3) δ 168.2, 140.9, 138.7, 137.5, 131.1, 130.6, 129.6, 128.8, 125.9, 106.7,
61.8, 52.6, 21.3, 14.0; HRMS (ESI–TOF) calcd for C17H20N2O4Na+ [M+Na]:
339.1315, found: 339.1327.
Diethyl 2-(3-methoxy-2-(1H-pyrazol-1-yl)phenyl)malonate (3p). White solid 56
mg, mp 91ꢀ93 °C, 85% yield; 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 1.5 Hz, 1H),
7.53 (d, J = 2.1 Hz, 1H), 7.42 (t, J = 8.2 Hz, 1H), 7.19 (dd, J = 8.0, 1.1 Hz, 1H), 7.00
(dd, J = 8.4, 1.0 Hz, 1H), 6.47–6.38 (m, 1H), 4.42 (s, 1H), 4.17 (q, J = 7.1 Hz, 4H),
3.75 (s, 3H), 1.22 (t, J = 7.1 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 168.0, 155.2,
140.8, 132.9, 132.8, 130.0, 129.2, 121.4, 111.8, 106.2, 61.9, 56.2, 52.8, 14.1; HRMS
(ESI–TOF) calcd for C17H20N2O5Na+ [M+Na]: 355.1264, found: 355.1274.
Diethyl 2-(5-methoxy-2-(1H-pyrazol-1-yl)phenyl)malonate (3q). Colorless oil 48
1
mg, 73% yield; H NMR (500 MHz, CDCl3) δ 7.71–7.64 (m, 1H), 7.56 (dd, J = 2.3,
0.4 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 7.15 (d, J = 2.8 Hz, 1H), 6.91 (dd, J = 8.7, 2.9
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Hz, 1H), 6.40 (t, J = 2.1 Hz, 1H), 4.72 (s, 1H), 4.18 (qd, J = 7.1, 1.9 Hz, 4H), 3.83 (s,
3H), 1.23 (t, J = 7.1 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 167.9, 159.6, 140.8,
133.2, 131.4, 130.7, 127.5, 115.2, 114.3, 106.6, 61.9, 55.7, 52.7, 14.1; HRMS
(ESI–TOF) calcd for C17H20N2O5Na+ [M+Na]: 355.1270, found: 355.1285.
Diethyl 2-(5-amino-2-(1H-pyrazol-1-yl)phenyl)malonate (3r). Colorless oil 56 mg,
88% yield. 1H NMR (500 MHz, CDCl3) δ 7.66 (dd, J = 1.8, 0.4 Hz, 1H), 7.52 (dd, J =
2.3, 0.5 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 2.6 Hz, 1H), 6.63 (dd, J = 8.4,
2.6 Hz, 1H), 6.39–6.36 (m, 1H), 4.61 (s, 1H), 4.17 (qd, J = 3.6, 1.1 Hz, 4H),
3.99–3.61 (m, 2H), 1.23–1.20 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 168.2, 147.2,
140.6, 131.4, 130.3, 127.5, 115.6, 115.2, 114.9, 106.3, 61.9, 52.4, 14.1. HRMS
(ESI–Orbitrap) calcd for C16H19N3O4H+ [M+H]: 318.1454, found: 318.1447.
Diethyl 2-(3-fluoro-2-(1H-pyrazol-1-yl)phenyl)malonate (3s). Colorless oil 52 mg,
82% yield; 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 1.5 Hz, 1H), 7.61 (t, J = 2.0 Hz,
1H), 7.46–7.39 (m, 2H), 7.21 (ddd, J = 9.6, 6.8, 2.9 Hz, 1H), 6.49–6.45 (m, 1H), 4.66
(s, 1H), 4.19 (q, J = 7.1 Hz, 4H), 1.23 (t, J = 7.1 Hz, 6H); 13C NMR (126 MHz, CDCl3)
δ 167.7, 157.3 (d, J = 251.4 Hz), 141.5, 133.0, 132.8 (d, J = 1.9 Hz), 130.0 (d, J = 8.4
Hz), 128.4 (d, J = 13.0 Hz), 125.5 (d, J = 3.6 Hz), 116.2 (d, J = 20.3 Hz), 107.0, 62.1,
52.7 (d, J = 1.9 Hz), 14.1; HRMS (ESI–TOF) calcd for C16H17FN2O4Na+ [M+Na]:
343.1065, found: 343.1070.
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Diethyl 2-(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)malonate (3t). Colorless oil 60 mg,
93% yield; 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 1.5 Hz, 1H), 7.62–7.59 (m, 1H),
7.39 (dd, J = 9.4, 2.9 Hz, 1H), 7.31 (dd, J = 8.7, 5.2 Hz, 1H), 7.11 (ddd, J = 8.7, 7.6,
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2.9 Hz, 1H), 6.45–6.42 (m, 1H), 4.78 (d, J = 0.8 Hz, 1H), 4.24–4.14 (m, 4H), 1.24 (t,
J = 7.1 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 167.6, 162.1 (d, J = 248.7 Hz), 141.3,
136.2 (d, J = 2.9 Hz), 131.6 (d, J = 8.8 Hz), 131.3, 128.0 (d, J = 8.9 Hz), 117.4 (d, J =
24.5 Hz), 115.9 (d, J = 22.8 Hz), 107.1, 62.2, 52.7, 14.0; HRMS (ESI–TOF) calcd for
C16H17FN2O4Na+ [M+Na]: 343.1065, found: 343.1082.
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Diethyl 2-(5-chloro-2-(1H-pyrazol-1-yl)phenyl)malonate (3u). Colorless oil 60
mg, 83% yield; 1H NMR (500 MHz, CDCl3) δ 7.74–7.70 (m, 1H), 7.66–7.61 (m, 2H),
7.39 (dd, J = 8.5, 2.4 Hz, 1H), 7.30–7.25 (m, 1H), 6.48–6.41 (m, 1H), 4.88 (s, 1H),
4.25–4.17 (m, 4H), 1.25 (t, J = 7.1 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 167.6,
141.4, 138.5, 134.4, 131.1, 130.7, 130.6, 129.1, 127.2, 107.3, 62.2, 52.6, 14.1; HRMS
(ESI–TOF) calcd for C16H17ClN2O4Na+ [M+Na]: 359.0769, found: 359.0778.
Diethyl 2-(5-(ethoxycarbonyl)-2-(1H-pyrazol-1-yl)phenyl) malonate (3v).
Colorless oil 51 mg, 68% yield. 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.08 (d, J
= 8.3 Hz, 1H), 7.72 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 6.46 (s, 1H), 5.09 (s, 1H),
4.46–4.31 (m, 2H), 4.21 (q, J = 6.9 Hz, 4H), 1.38 (t, J = 7.0 Hz, 3H), 1.24 (t, J = 7.0
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 167.8, 165.4, 143.0, 141.7, 132.1, 130.9,
130.3, 130.2, 128.8, 125.4, 107.6, 62.1, 61.4, 53.2, 14.4, 14.1; HRMS (ESI–Orbitrap)
calcd for C19H22N2O6H+ [M+H]: 375.1551, found: 375.1554.
Diethyl 2-(1-(1H-pyrazol-1-yl)naphthalen-2-yl)malonate (3w). Colorless oil 49
mg, 70% yield; 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 8.7 Hz, 1H), 7.91–7.85 (m,
2H), 7.76 (d, J = 8.7 Hz, 1H), 7.67 (dd, J = 2.3, 0.5 Hz, 1H), 7.52 (ddd, J = 8.1, 6.9,
1.2 Hz, 1H), 7.44 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.15 (dd, J = 8.5, 0.8 Hz, 1H),
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6.60–6.56 (m, 1H), 4.46 (s, 1H), 4.26–4.15 (m, 4H), 1.24 (t, J = 11.1 Hz, 6H); 13C
NMR (126 MHz, CDCl3) δ 168.1, 167.7, 141.2, 136.4, 133.6, 133.1, 131.3, 129.7,
129.0, 127.8, 127.7, 127.1, 126.1, 123.3, 106.7, 77.4, 77.2, 76.9, 62.0, 52.8, 14.1.;
HRMS (ESI–TOF) calcd for C20H20N2O4Na+ [M+Na]: 375.1315, found: 375.1308
Diethyl 2-(3-methyl-2-(pyrimidin-2-yl)phenyl)malonate (5a). Colorless oil 59 mg,
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90% yield; H NMR (500 MHz, CDCl3) δ 8.83 (d, J = 4.9 Hz, 2H), 7.38 (d, J = 0.4
Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.27–7.21 (m, 2H), 4.43 (s, 1H), 4.14 (qd, J = 7.1,
3.2 Hz, 4H), 2.13 (s, 3H), 1.18 (t, J = 7.1 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ
168.3, 167.1, 157.1, 139.1, 136.4, 131.3, 130.2, 128.8, 126.7, 119.2, 61.6, 55.3, 20.4,
14.0. HRMS (ESI–TOF) calcd for C18H20N2O4Na+ [M+Na]: 351.1315, found:
351.1313;
Dimethyl 2-(3-methyl-2-(pyrimidin-2-yl)phenyl)malonate (5b). Following the
general procedure except DCE as solvent and reacted for 24 h. White solid 55 mg, mp
1
107–108 °C, 91% yield; H NMR (500 MHz, CDCl3) δ 8.85 (d, J = 4.9 Hz, 2H),
7.42–7.30 (m, 2H), 7.26 (dd, J = 8.0, 3.1 Hz, 2H), 4.49 (s, 1H), 3.67 (s, 6H), 2.13 (s,
3H).; 13C NMR (126 MHz, CDCl3) δ 168.8, 167.1, 157.2, 139.1, 136.6, 131.0, 130.4,
129.0, 126.8, 119.3, 54.9, 52.8, 20.4.; HRMS (ESI–Orbitrap) calcd for C16H16N2O4H+
[M+H]: 301.1183, found 301.1178.
Dibenzyl 2-(3-methyl-2-(pyrimidin-2-yl)phenyl)malonate (5c). Following the
general procedure except DCE as solvent and reacted for 24 h. Colorless oil 89 mg,
98% yield; 1H NMR (500 MHz, CDCl3) δ 8.68 (d, J = 4.9 Hz, 2H), 7.35 (dd, J = 7.7,
0.9 Hz, 1H), 7.33–7.28 (m, 7H), 7.27–7.23 (m, 5H), 7.16 (t, J = 4.9 Hz, 1H), 5.13 (dd,
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J = 33.4, 12.4 Hz, 4H), 4.57 (s, 1H), 2.15 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
168.2, 167.0, 157.1, 139.1, 136.6, 135.6, 131.1, 130.5, 128.9, 128.6, 128.4, 128.3,
126.9, 119.2, 67.3, 55.3, 20.5; HRMS (ESI–Orbitrap) calcd for C28H24N2O4H+ [M+H]:
453.1809, found: 453.1799.
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Ethyl 2-(3-methyl-2-(pyrimidin-2-yl)phenyl)-2-tosylacetate (5d). Colorless oil 76
mg, 93% yield; 1H NMR (500 MHz, CDCl3) δ 8.83 (d, J = 4.9 Hz, 2H), 7.55–7.51 (m,
1H), 7.44–7.40 (m, 2H), 7.30–7.27 (m, 1H), 7.26 (dd, J = 5.6, 4.3 Hz, 1H), 7.23 (t, J =
7.7 Hz, 1H), 7.17 (dd, J = 8.5, 0.5 Hz, 2H), 5.55 (s, 1H), 4.28–4.11 (m, 2H), 2.40 (s,
3H), 2.14 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 166.4,
165.4, 157.1, 145.0, 140.2, 137.3, 134.2, 131.8, 130.1, 129.2, 128.5, 127.6, 126.4,
119.2, 70.5, 62.5, 21.8, 20.8, 14.0; HRMS (ESI–TOF) calcd for C22H22N2O4SNa+
[M+Na]: 433.1192, found: 433.1199.
Ethyl 2-(diethoxyphosphoryl)-2-(3-methyl-2-(pyrimidin-2-yl)phenyl)acetate (5e).
Yellow oil 71 mg, 90% yield; 1H NMR (500 MHz, CDCl3) δ 8.83 (dd, J = 4.8, 4.3 Hz,
2H), 7.85 (d, J = 7.7 Hz, 1H), 7.32 (td, J = 7.8, 3.6 Hz, 1H), 7.25 (td, J = 4.9, 3.6 Hz,
1H), 7.19 (d, J = 7.5 Hz, 1H), 4.23 (dd, J = 24.5, 3.4 Hz, 1H), 4.12 (dqd, J = 10.8, 7.3,
3.7 Hz, 2H), 4.03–3.89 (m, 4H), 2.06 (d, J = 3.4 Hz, 3H), 1.17 (dddd, J = 10.8, 9.1,
7.0, 3.8 Hz, 9H); 13C NMR (126 MHz, CDCl3) δ 167.7 (d, J = 3.3 Hz), 167.3, 157.2,
139.5 (d, J = 8.9 Hz), 136.4 (s), 130.0 (d, J = 1.7 Hz), 129.1 (d, J = 7.0 Hz), 128.5,
127.9 (d, J = 4.8 Hz), 119.3, 63.2 (dd, J = 69.0, 6.8 Hz), 61.8, 48.3 (d, J = 134.7 Hz),
20.5, 16.3 (d, J = 5.7 Hz), 14.1; 31P NMR (202 MHz, CDCl3) δ 19.3; HRMS
(ESI–TOF) calcd for C19H25N2O5PNa+ [M+Na]: 415.1393, found: 415.1383.
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Diethyl 2-(3-methoxy-2-(pyrimidin-2-yl)phenyl)malonate (5f). Colorless oil 56
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mg, 94% yield; H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 4.9 Hz, 2H), 7.39 (t, J =
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8.1 Hz, 1H), 7.24 (t, J = 4.9 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 6.95 (d, J = 8.3 Hz,
1H), 4.41 (s, 1H), 4.13 (qd, J = 7.1, 2.8 Hz, 4H), 3.70 (s, 3H), 1.17 (t, J = 7.1 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 168.1, 164.9, 157.1, 157.0, 132.6, 129.9, 129.1, 121.2,
119.24, 110.9, 61.6, 55.9, 54.8, 14.0; HRMS (ESI–TOF) calcd for
C18H20N2O5Na+[M+Na]: 367.1264, found: 367.1276.
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Diethyl 2-(3-fluoro-2-(pyrimidin-2-yl)phenyl)malonate (5g). White solid 62 mg,
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mp 89–90 °C, 93% yield; H NMR (500 MHz, CDCl3) δ 8.87 (d, J = 4.9 Hz, 2H),
7.48–7.42 (m, 1H), 7.39 (dd, J = 7.9, 1.0 Hz, 1H), 7.30 (t, J = 4.9 Hz, 1H), 7.18 (ddd,
J = 9.5, 8.2, 1.2 Hz, 1H), 4.81 (s, 1H), 4.25–4.11 (m, 4H), 1.22 (t, J = 7.1 Hz, 6H);13C
NMR (126 MHz, CDCl3) δ 168.0, 162.7, 160.5 (d, J = 249.8 Hz), 157.2, 133.8 (d, J =
2.0 Hz), 130.6 (d, J = 9.1 Hz), 127.6 (d, J = 14.5 Hz), 125.2 (d, J = 3.3 Hz), 119.6,
115.8 (d, J = 22.2 Hz), 61.8, 54.7 (d, J = 2.2 Hz), 14.0; 19F NMR (471 MHz, CDCl3) δ
–115.6; HRMS (ESI–TOF) calcd for C17H17FN2O4Na+ [M+Na]: 355.1065, found
355.1054.
Diethyl 2-(3-chloro-2-(pyrimidin-2-yl)phenyl)malonate (5h). White solid 51 mg,
mp 79–80 °C, 73% yield; 1H NMR (500 MHz, CDCl3) δ 8.92–8.82 (m, 2H), 7.52 (dd,
J = 7.8, 1.2 Hz, 1H), 7.46 (dd, J = 8.1, 1.2 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.32 (t, J
= 4.9 Hz, 1H), 4.42 (s, 1H), 4.21–4.09 (m, 4H), 1.19 (dd, J = 9.2, 5.1 Hz, 6H); 13C
NMR (126 MHz, CDCl3) δ 167.7, 165.0, 157.3, 138.4, 133.4, 133.1, 129.9, 129.6,
127.9, 119.9, 61.9, 55.1, 14.0; HRMS (ESI–TOF) calcd for C17H17ClN2O4Na+
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[M+Na]: 371.0769, found: 371.0789.
Diethyl 2-(2-(pyrimidin-2-yl)phenyl)malonate
(5i).
A
mixture
of
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2ꢀphenylpyrimidine (0.2 mmol), [Cp*RhCl2]2 (1 mg, 2 ꢀmol, 1 mol%), AgF (1 mg,
10 ꢀmol, 5 mol%) was stirred in EtOH (2 mL) for 1h under Ar. Then 2a (0.24 mmol,
1.2 equiv) was added. The was kept at 75 °C for 6 h. After cooling to rt, the mxture
was filtered through a pad of Celite and then concentrateed under reduced pressure.
The residue was purified by flash column chromatography to give the 5i as colorless
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oil 35 mg in 66% yield; H NMR (500 MHz, CDCl3) δ 8.78 (d, J = 4.9 Hz, 2H),
8.15–8.07 (m, 1H), 7.53–7.42 (m, 3H), 7.19 (t, J = 4.9 Hz, 1H), 5.61 (s, 1H), 4.22 (dtt,
J = 10.8, 7.1, 3.7 Hz, 4H), 1.23 (t, J = 7.1 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ
169.1, 166.0, 156.9, 137.6, 132.6, 131.2, 130.2, 129.9, 128.2, 118.9, 61.5, 55.8, 14.1;
HRMS (ESI–TOF) calcd for C17H18N2O4Na+ [M+Na]: 337.1159, found: 337.1171.
The procedure of disubstitution of arenes with diazo compounds (for: 5jꢀ5p,
5r, 7e, and 7f). A dried 10 mL Schlenk tube equipped with a magnetic stirrer was
charged with 2ꢀarylpyrimidine 4 (0.2 mmol), [Cp*RhCl2]2 (2.5 mg, 4 ꢀmol, 2 mol%),
AgSbF6 (7 mg, 20 ꢀmol, 10 mol%), and EtOH (2 mL) under Ar. After the reaction
mixture was stirred at room temperature for 1 h, diazo compound 2a (1.5 mmol, 3
equiv.) was then added t and the mixture was heated at 75 °C for 6 h. The reaction
mixture was cooled to room temperature, and then filtered through a pad of Celite and
concentrated under reduced pressure. The residue was then purified by flash column
chromatography to give the desired product.
Tetraethyl 2,2'-(2-(pyrimidin-2-yl)-1,3-phenylene) dimalonate (5j). White solid
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77 mg, mp 91–92 °C, 82% yield; H NMR (500 MHz, CDCl3) δ 8.83 (d, J = 4.9 Hz,
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2H), 7.58–7.53 (m, 2H), 7.49 (dd, J = 8.7, 6.9 Hz, 1H), 7.29 (t, J = 4.9 Hz, 1H), 4.60
(s, 2H), 4.17 (q, J = 7.1 Hz, 8H), 1.21 (t, J = 7.1 Hz, 12H); 13C NMR (126 MHz,
CDCl3) δ 168.4, 165.7, 157.0, 139.0, 132.2, 129.3, 129.3, 119.5, 61.8, 55.6, 14.1;
HRMS (ESI–TOF) calcd for C24H28N2O8Na+ [M+Na]: 495.1738, found: 495.1728.
Tetraethyl 2,2'-(5-methyl-2-(pyrimidin-2-yl)-1,3-phenylene) dimalonate (5k).
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White solid 95 mg, mp 127–128 °C, 98% yield; H NMR (500 MHz, CDCl3) δ 8.80
(d, J = 4.9 Hz, 2H), 7.34 (d, J = 0.5 Hz, 2H), 7.24 (t, J = 4.9 Hz, 1H), 4.62 (s, 2H),
4.16 (q, J = 7.1 Hz, 8H), 2.41 (s, 3H), 1.20 (t, J = 7.1 Hz, 12H); 13C NMR (126 MHz,
CDCl3) δ 168.5, 165.7, 156.9, 139.2, 136.2, 132.0, 129.9, 119.2, 61.6, 55.5, 21.7, 14.1;
HRMS (ESI–TOF) calcd for C25H30N2O8Na+ [M+Na]: 509.1900, found: 509.1910.
Tetraethyl 2, 2'-(5-methoxy-2-(pyrimidin-2-yl)-1,3-phenylene) dimalonate (5l).
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White solid 78 mg, mp 113–114 °C, 78% yield; H NMR (500 MHz, CDCl3) δ 8.79
(d, J = 4.9 Hz, 2H), 7.24 (d, J = 4.9 Hz, 1H), 7.10 (s, 2H), 4.69 (s, 2H), 4.18 (tt, J =
7.2, 3.7 Hz, 8H), 3.84 (s, 3H), 1.21 (t, J = 7.1 Hz, 12H); 13C NMR (126 MHz, CDCl3)
δ 168.4, 165.6, 159.8, 156.9, 133.8, 131.8, 119.0, 115.0, 61.7, 55.7, 55.5, 14.1; HRMS
(ESI–TOF) calcd for C25H30N2O9Na+ [M+Na]: 525.1849, found: 525.1873.
Tetraethyl 2,2'-(5-(ethoxycarbonyl)-2-(pyrimidin-2-yl)-1,3-phenylene)dimalonate
1
(5m). White solid 105 mg, mp 71–72 °C, 96% yield; H NMR (500 MHz, CDCl3) δ
8.84 (d, J = 4.9 Hz, 2H), 8.22 (s, 2H), 7.32 (t, J = 4.9 Hz, 1H), 4.61 (s, 2H), 4.38 (q, J
= 7.1 Hz, 2H), 4.22–4.14 (m, 8H), 1.38 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 12H);
13C NMR (126 MHz, CDCl3) δ 167.9, 165.6, 165.0, 157.2, 142.7, 132.8, 131.3, 130.5,
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119.8, 61.9, 61.3, 55.7, 14.4, 14.1; HRMS (ESI–TOF) calcd for C27H32N2O10Na+
[M+Na]: 567.1955, found: 567.1940.
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Tetraethyl 2,2'-(5-fluoro-2-(pyrimidin-2-yl)-1,3-phenylene) dimalonate (5n).
White solid 95 mg, mp 89–90 °C, 97% yield; 1H NMR (500 MHz, CDCl3) δ 8.82 (d, J
= 4.9 Hz, 2H), 7.32 (d, J = 9.4 Hz, 2H), 7.29 (t, J = 4.9 Hz, 1H), 4.61 (d, J = 0.7 Hz,
2H), 4.17 (q, J = 7.1 Hz, 8H), 1.21 (t, J = 7.1 Hz, 12H); 13C NMR (126 MHz, CDCl3)
δ 167.8, 165.0, 162.4 (d, J = 248.2 Hz), 157.1, 135.3 (d, J = 3.0 Hz), 134.5 (d, J = 8.7
Hz), 119.5, 116.7 (d, J = 23.2 Hz), 62.0, 55.4, 14.0; HRMS (ESI–TOF) calcd for
C24H27FN2O8Na+ [M+Na]:513.1649, found:513.1666.
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Tetraethyl 2,2'-(2-(pyrimidin-2-yl)-5-(trifluoromethyl)-1,3-phenylene)dimalonate
(5o). White solid 107 mg, mp 106–107 °C, 99% yield; 1H NMR (500 MHz, CDCl3) δ
8.87 (d, J = 4.9 Hz, 2H), 7.87 (s, 2H), 7.35 (t, J = 4.9 Hz, 1H), 4.61 (s, 2H), 4.22–4.15
(m, 8H), 1.22 (t, J = 7.1 Hz, 12H); 13C NMR (126 MHz, CDCl3) δ 167.6, 164.7, 157.3,
142.2, 133.2, 131.2 (q, J = 32.9 Hz), 126.5 (d, J = 3.6 Hz), 123.8 (d, J = 272.7 Hz),
120.0, 62.1, 55.4, 14.0; 19F NMR (471 MHz, CDCl3) δ –62.8; HRMS (ESI–TOF)
calcd for C25H27F3N2O8Na+ [M+Na]:563.1617, found: 563.1629.
Tetraethyl 2, 2'-(4-chloro-2-(pyrimidin-2-yl)-1,3-phenylene) dimalonate (5p).
1
White solid 87 mg, mp 122–123 °C, 86% yield; H NMR (500 MHz, CDCl3) δ 8.83
(d, J = 4.9 Hz, 2H), 7.54 (s, 2H), 7.31 (t, J = 4.9 Hz, 1H), 4.58 (s, 1H), 4.48 (s, 1H),
4.25–4.11 (m, 8H), 1.21 (td, J = 7.1, 5.0 Hz, 12H); 13C NMR (126 MHz, CDCl3) δ
167.9, 167.0, 165.5, 157.2, 141.7, 135.9, 131.3, 131.1, 130.8, 130.4, 119.9, 62.0, 61.8,
55.2, 55.0, 14.1; HRMS (ESI–Orbitrap) calcd for C24H27ClN2O8H+ [M+H]: 507.1529;
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Diethyl 2-(2-(benzo[d]oxazol-2-yl)-3-methylphenyl)malonate (5q). Colorless oil
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62 mg, 85% yield; H NMR (500 MHz, CDCl3) δ 7.85–7.80 (m, 1H), 7.58 (ddd, J =
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4.7, 2.9, 0.6 Hz, 1H), 7.49–7.44 (m, 2H), 7.42–7.38 (m, 2H), 7.34–7.30 (m, 1H), 4.90
(s, 1H), 4.19 (q, J = 7.1 Hz, 4H), 2.37 (s, 3H), 1.21 (t, J = 7.1 Hz, 6H); 13C NMR (126
MHz, CDCl3) δ 168.2, 161.7, 150.8, 141.6, 139.3, 133.9, 130.8, 130.5, 128.2, 127.1,
125.5, 124.7, 120.6, 110.9, 61.9, 55.5, 20.9, 14.1; HRMS (ESI–Orbitrap) calcd for
C21H21NO5H+ [M+H]: 368.1492, found: 368.1493.
Tetraethyl 2, 2'-(2-(benzo[d]oxazol-2-yl)-5-methyl-1,3-phenylene)dimalonate (5r).
1
White solid 81 mg, mp 116–118 °C, 77% yield; H NMR (500 MHz, CDCl3) δ 7.81
(ddd, J = 4.0, 2.9, 0.6 Hz, 1H), 7.53 (ddd, J = 4.9, 2.8, 0.6 Hz, 1H), 7.43 (d, J = 0.5
Hz, 2H), 7.42–7.36 (m, 2H), 4.91 (s, 2H), 4.19 (qd, J = 7.1, 1.1 Hz, 8H), 2.45 (s, 3H),
13
1.21 (t, J = 7.1 Hz, 12H); C NMR (126 MHz, CDCl3) δ 168.1, 160.6, 150.7, 141.5,
141.4, 133.9, 130.3, 125.7, 125.6, 124.8, 120.8, 110.8, 62.0, 55.5, 21.9, 14.0; HRMS
(ESI–Orbitrap) calcd for C28H31NO9H+ [M+H]: 526.2072, found: 526.2067.
Diethyl 2-(2-(pyrimidin-2-yl)thiophen-3-yl)malonate (7a). Colorless oil 60 mg, 94%
yield; 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J = 4.9 Hz, 2H), 7.40 (d, J = 5.2 Hz, 1H),
7.21 (d, J = 5.3 Hz, 1H), 7.05 (t, J = 4.9 Hz, 1H), 6.46 (s, 1H), 4.21 (qd, J = 7.1, 1.3
Hz, 4H), 1.24 (t, J = 7.1 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 168.5, 161.8, 156.8,
139.1, 134.4, 130.5, 128.3, 118.4, 61.6, 52.3, 14.1; HRMS (ESI–TOF) calcd for
C15H16N2O4SNa+ [M+Na]: 343.0723; found: 343.0731.
Diethyl 2-(1-(pyridin-2-yl)-1H-pyrrol-2-yl)malonate (7b). Stir a mixture of
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2ꢀ(1Hꢀpyrrolꢀ1ꢀyl)pyridine 6b (0.2 mmol), [Cp*RhCl2]2 (1 mg, 2 ꢀmol, 1 mol%),
AgF (1 mg, 10 ꢀmol, 5 mol%) in EtOH (2 mL) for 1h under Ar. Add 2a (0.24 mmol,
1.2 equiv.) in oneꢀpot and keep the solution at 75 °C for 6 h. Cool to room
temperature, filter through a pad of Celite and concentrate under reduced pressure.
The residue was then purified by flash column chromatography to give the 7b as
colorless oil 37 mg, 62% yield; 1H NMR (500 MHz, CDCl3) δ 8.37 (ddd, J = 4.9, 1.9,
0.8 Hz, 1H), 7.76 (ddd, J = 8.2, 7.5, 1.9 Hz, 1H), 7.32 (dd, J = 4.8, 4.1 Hz, 1H), 7.14
(ddd, J = 7.4, 4.9, 0.9 Hz, 1H), 7.10 (dd, J = 3.1, 1.7 Hz, 1H), 6.34 (ddd, J = 3.5, 1.7,
0.6 Hz, 1H), 6.31 (t, J = 3.3 Hz, 1H), 5.45 (s, 1H), 4.21 (q, J = 7.1 Hz, 4H), 1.24 (t, J
= 7.1 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 168.2, 152.6, 148.1, 138.8, 125.2,
121.1, 120.9, 115.6, 112.3, 110.2, 61.7, 52.7, 14.2; HRMS (ESI–TOF) calcd for
C16H18N2O4Na+ [M+Na]: 325.1164, found: 325.1167.
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Diethyl 2-(2-(pyridin-2-yl)thiophen-3-yl)malonate (7c). Following the general
procedure and reacted for 48 h. Colorless oil 33 mg, 51% yield; 1H NMR (500 MHz,
CDCl3) δ 8.60 (d, J = 4.3 Hz, 1H), 7.68 (dd, J = 7.7, 1.7 Hz, 1H), 7.56 (d, J = 7.9 Hz,
1H), 7.32 (d, J = 5.3 Hz, 1H), 7.24 (d, J = 5.2 Hz, 1H), 7.16 (dd, J = 7.0, 5.1 Hz, 1H),
5.84 (s, 1H), 4.22 (tt, J = 7.2, 3.6 Hz, 4H), 1.25 (t, J = 7.1 Hz, 6H); 13C NMR (126
MHz, CDCl3) δ 168.5, 152.8, 149.5, 140.2, 136.9, 131.0, 130.3, 125.3, 122.5, 122.0,
61.8, 52.3, 14.2; HRMS (ESI–TOF) calcd for C16H17NO4SNa+ [M+Na]: 342.0776,
found: 342.0775.
Diethyl 2-(2-(isoquinolin-1-yl)furan-3-yl)malonate (7d). Colorless oil 69 mg, 98%
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7.88 (d, J = 8.6 Hz, 1H), 7.75 (dd, J = 8.1, 1.2 Hz, 1H), 7.67 (ddd, J = 8.4, 6.9, 1.4 Hz,
1H), 7.57–7.51 (m, 1H), 7.47 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 6.78–6.71 (m, 1H), 6.40
(s, 1H), 4.28 (dd, J = 7.1, 5.5 Hz, 4H), 1.30 (t, J = 7.1 Hz, 6H); 13C NMR (126 MHz,
CDCl3) δ 168.6, 150.1, 149.4, 147.8, 142.5, 136.5, 129.7, 129.4, 127.6, 126.9, 126.3,
118.6, 117.8, 114.0, 61.8, 50.2, 14.2; HRMS (ESI–Orbitrap) calcd for C20H19NO5H+
[M+H]: 354.1336, found: 354.1339.
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Tetraethyl 2,2'-(1-(pyridin-2-yl)-1H-pyrrole-2,5-diyl) dimalonate (7e). Followed
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the procedure of disubstitution. Colorless oil 78 mg, 85% yield; H NMR (400 MHz,
CDCl3) δ 8.56 (dd, J = 4.8, 1.2 Hz, 1H), 7.82 (td, J = 7.7, 1.9 Hz, 1H), 7.36–7.27 (m,
2H), 6.42 (s, 2H), 4.60 (s, 2H), 4.19–4.08 (m, 8H), 1.19 (t, J = 7.1 Hz, 12H); 13C
NMR (100 MHz, CDCl3) δ 167.3, 150.3, 149.7, 138.5, 125.3, 123.3, 122.7, 110.5,
61.9, 51.0, 14.0; HRMS (ESI–Orbitrap) calcd for C23H28N2O8H+ [M+H]: 461.1918,
found:461.1912.
Tetraethyl 2,2'-(1-(4-methylpyridin-2-yl)-1H-pyrrole-2,5-diyl)dimalonate (7f).
Followed the procedure of disubstitution. White solid 84 mg, mp 130–132 °C, 88%
yield; 1H NMR (500 MHz, CDCl3) δ 8.40 (d, J = 5.0 Hz, 1H), 7.15–7.12 (m, 1H),
7.10–7.08 (m, 1H), 6.41 (s, 2H), 4.59 (s, 2H), 4.19–4.11 (m, 8H), 2.39 (s, 3H), 1.21 (t,
J = 7.1 Hz, 12H); 13C NMR (126 MHz, CDCl3) δ 167.4, 150.4, 150.2, 149.4, 125.3,
124.3, 123.5, 110.6, 61.9, 51.1, 21.1, 14.1; HRMS (ESI–TOF) calcd for
C24H30N2O8Na+ [M+Na]: 497.1900, found: 497.1919.
Ethyl 2-(2-(1H-pyrazol-1-yl)phenyl)acetate (8a). Colorless oil 33mg, 71% yield.
1H NMR (500 MHz, CDCl3) δ 7.74–7.63 (m, 2H), 7.43–7.31 (m, 4H), 6.46–6.37 (m,
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1H), 4.07 (q, J = 7.1 Hz, 2H), 3.68 (s, 2H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR (126
MHz, CDCl3) δ 171.2, 140.7, 140.2, 131.8, 131.0, 130.4, 128.6, 128.2, 126.2, 106.5,
60.9, 37.6, 14.2; HRMS (ESI–TOF) calcd for C13H14N2O2Na+ [M+Na]: 253.0953,
found: 253.0962.
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Ethyl 2-(3-methyl-2-(pyrimidin-2-yl)phenyl)acetate (8b). Colorless oil 43 mg, 84%
yield. 1H NMR (500 MHz, CDCl3) δ 8.85 (d, J = 4.9 Hz, 2H), 7.29 (t, J = 7.6 Hz, 1H),
7.26 (t, J = 4.9 Hz, 1H), 7.21 (dd, J = 7.6, 3.6 Hz, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.49
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(s, 2H), 2.15 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H); C NMR (126 MHz, CDCl3) δ 171.3,
167.7, 157.1, 139.1, 136.4, 132.4, 129.5, 128.8, 128.5, 119.1, 60.7, 39.6, 20.3, 14.2.
HRMS (ESI–TOF) calcd for C15H16N2O2Na+ [M+Na]: 279.1104; found 279.1123.
Ethyl 2-(2-(pyridin-2-yl)phenyl)acetate (8c). Stir a mixture of 2ꢀphenylpyridine
(0.2 mmol), [Cp*RhCl2]2 (1 mg, 2 ꢀmol, 1 mol%), AgF (1 mg, 10 ꢀmol, 5 mol%) in
EtOH (2 mL) for 1h under Ar. Add 2n (0.24 mmol, 1.2 equiv.) in oneꢀpot and keep
the solution at 75 °C for 6 h. Cool to room temperature, filter through a pad of Celite
and concentrate under reduced pressure. The residue was then purified by flash
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column chromatography to give the 8c as colorless oil 24 mg in 49% yield. H NMR
(500 MHz, CDCl3) δ 8.65 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.75 (td, J = 7.7, 1.8 Hz,
1H), 7.49–7.43 (m, 2H), 7.39–7.34 (m, 3H), 7.24 (ddd, J = 7.6, 4.9, 1.1 Hz, 1H), 4.05
(q, J = 7.1 Hz, 2H), 3.83 (s, 2H), 1.16 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 172.0, 159.7, 149.0, 140.6, 136.6, 132.7, 131.5, 130.0, 128.7, 127.5, 124.1,
121.9, 60.7, 39.5, 14.3; HRMS (ESI–Orbitrap) calcd for C15H15NO2H+ [M+H]:
242.1176, found 242.1167.
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