Visible-Light-Mediated Monoselective Ortho C-H Arylation of 6-Arylpurine Nucleosides with Diazonium Salts

Article abstract of DOI:10.1021/acs.joc.7b00659

A combined palladium- and photoredox-catalyzed monoselective arylation of 6-arylpurine nucleosides has been developed by employing purine as a directing group via the photoredox reaction, and many functional groups are well tolerated in this direct C-H arylation condition. Various of functionalized purines (nucleosides) which are potentially of great importance in medicinal chemistry could be obtained under visible light irradiation at room temperature within 4 h.

Full text of DOI:10.1021/acs.joc.7b00659

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Note
Visible-Light-Mediated Mono-Selective Ortho C–H Arylation
of 6-Arylpurine Nucleosides with Diazonium Salts
Lei Liang, Ming-Sheng Xie, Hai-Xia Wang, Hong-Ying Niu, Gui-Rong Qu, and Hai-Ming Guo
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 09 May 2017
Downloaded from http://pubs.acs.org on May 9, 2017
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Visible-Light-Mediated Mono-Selective Ortho C-H
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Arylation of 6-Arylpurine Nucleosides with Diazonium Salts
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Lei Liang,† MingꢀSheng Xie,‡ HaiꢀXia Wang,‡ HongꢀYing Niu,† GuiꢀRong Qu,‡ HaiꢀMing
Guo*,†,‡
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† School of Environment, Henan Normal University, Xinxiang, Henan Province 453007, China
‡ School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan
Province 453007, China
† School of Chemistry and Chemical Engineering, Henan Institute of Science and Technology,
Xinxiang, Henan Province 453003, China
ABSTRACT
A combined palladiumꢀ and photoredoxꢀcatalyzed monoꢀselective arylation of 6ꢀarylpurine
nucleosides has been developed by employing purine as a directing group via the photoredox
reaction and many functional groups are well tolerated in this direct C–H arylation condition.
Various of functionalized purines (nucleosides) which are potentially of great importance in
medicinal chemistry could be obtained under visible light irradiation at room temperature within 4
hours.
As the universal structural units in RNA and DNA, purine bases and nucleosides have displayed
unique biological activities such as cytostatic,1 antiꢀHCV,2 antiviral and antimicrobacterial3
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activities. In particular, C6 arylꢀ and heteroaryl purine analogues possess high inhibitory activity
against Mycobacterium tuberculosis.4 Nowdays, nitrogenꢀbased directed C–H bond arylation has
been regarded as an efficient method to construct biaryl compounds which are ubiquitous building
blocks in biological and pharmaceutical sciences.5 Our group firstly described purine as the new
directing group (DG) for Pdꢀcatalyzed Csp2–H bond arylation (Scheme 1, path i), but, the reaction
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o
could not be regarded as an efficient method because of the high temperature (120 C) and long
reaction time (48ꢀ60 hours). Later, the Lakshman’s group utilized the identical directing group for
the arylation of Csp2–H bonds under ruthenium catalysis (Scheme 1, path ii).6 Although their
condition provides a broader substrate scope (especially deoxyribonucleosides), its practical
application in synthesis has been limited due to its lower regioselectivity (mono/diarylation), long
o
reaction time (24 hours) and high temperature (120 C). Thus, exploring an efficient route to
obtain C6ꢀarylated purines (nucleosides) with high regioselectivity under mild condition is
challenging and fascinating.
Recently, many efforts have been devoted to direct C–H functionalization using combined
transmetal with photoredox catalyst.7 The concept of visibleꢀlightꢀmediated direct C–H
functionalizations has received significant attention as a promising strategy for the cross coupling
reactions including cycloaddition,8 radical addition,9 alkylation,10 arylation11 and others.12 At first,
Sanford and coꢀworkers reported ligandꢀdirected CꢀH arylation reactions by using aryl diazonium
salts and diaryliodonium salts as cross partners under visible light irradiation, which provided a
new strategy for the construction of biaryl compounds (Scheme 1).7aꢀb Different directing groups
(such as amides, pyrazoles, pyrimidines, and oxime ethers) were examined. However, no example
of photocatalyzed purine modifucation has been reported up to now. Based on our long standing
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goals on the selective modification of nucleoside analogues and the established work on the
arylation reaction,13 we describe a mild and highly regioselective method for the direct arylation
of 6ꢀarylꢀpurines (nucleosides) using photoredox catalyst, palladium and diazonium salts under
visible light irradiation.
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Scheme 1. Strategies for the ortho arylation of 6–arylpurine (nucleoside).
Initially, we began our study by using 6ꢀphenylꢀ9ꢀbenzylꢀpurine 1a and phenyldiazonium
tetrafluoroborate 2a as model substrates to optimize the reaction conditions (Table 1). The finding
that photoredox catalyst can be used to enable a Pd(IV)/Pd(II) catalytic cycle,7a the dual
palladium/photoredox catalytic system was firstly used to test the arylation reaction. As shown in
Table 1, white LED irradiation of a mixture of 6ꢀarylꢀ9ꢀbenzylꢀpurine, aryl diazonium salt,
Ru(bpy)3Cl2·6H2O and Pd(OAc)2 in MeOH at room temperature under air provided 3aa as a
product in trace amounts (Table 1, entry 1). When the reaction was carried out in an inert
atmosphere and irradiated with blue LED bulb, the yield of product 3aa was obviously increased
(Table 1, entries 1ꢀ3). Subsequently, other palladium sources and transitionꢀmentalꢀcatalysts were
also screened, which revealed Pd(OAc)2 to be the suitable catalyst for this reaction (Table 1,
entries 4ꢀ7).
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Table 1. Optimization of the reaction conditions.a
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yield (%)b
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entry
catalyst
photocatalyst
1c,d
2d
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
trace
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73
4
69
5
Pd2(dba)3
N.R.
6
7
Cu(OTf)2
Ru(bpy)3Cl2·6H2O
N.R.
N.R.
62
[{RuCl2(C6H6)}2] Ru(bpy)3Cl2·6H2O
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ru(bpy)3(PF6)2
Eosin Y
9
41
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13f
Ir(ppy)3
N.R.e
N.R.e
N.R.e
trace
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Pd(OAc)2
a Reaction conditions: 1a (0.2 mmol), 2a (1.2 mmol), catalyst (5 mol %), and photoredox catalyst
(2.5 mol %) in MeOH (2 mL) at room temperature irradiation with 4*7W blue LED bulb under
N2. b Isolated yield. c Without N2 protection. d Irradiation with 4*7W white LED bulb. e N.R.= No
Reaction. f In the absence of light.
Ru(bpy)3Cl2·6H2O was the best photoredox catalyst that gave the optimal reaction effect (Table 1,
entries 3, 8ꢀ10). Control reactions confirmed that both Pd(OAc)2, Ru(bpy)3Cl2·6H2O and light
played a crucial role for significant conversion to the product (Table 1, entries 11ꢀ13). Thus, the
optimal reaction conditions were 5 mol % Pd(OAc)2, 2.5 mol % Ru(bpy)3Cl2·6H2O in MeOH at
room temperature under N2 irradiation with blue LED bulb (Table 1, entry 3).
Under the optimized reaction conditions (Table 1, entry 3), the substrate scope of C–H arylation
reaction was examined. As shown in Scheme 2, the reaction of N9ꢀsubstituted substrates
(including alkyl, benzyl, ester, sugar) with Pd(OAc)2/Ru(bpy)3Cl2·6H2O catalytic system afforded
the corresponding arylation products in 63%ꢀ86% yields (Scheme 2). The N9 alkyl or cycloalkyl
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Scheme 2. Direct C–H monophenylation of various purines (nucleoside) with ArN2BF4.a
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a Unless otherwise mentioned, all of the reactions were carried out with 1a-1e (0.2 mmol), 2a (1.2
mmol), Pd(OAc)2 (5 mol %), Ru(bpy)3Cl2·6H2O (2.5 mol %) in MeOH (2 mL) at room
temperature irradiation with 4*7W blue LED bulb for 4 h under N2. b 2a (1.6 mmol), 2 h.
substituted substrates reacted smoothly and gave the desired products in higher yields (Scheme 2,
3ba-3da), while substrates bearing some active groups such as –bromine, –ester or –sugar resulted
in slightly lower yields (Scheme 2, 3ea-3ga). It was worth mentioning that the reaction time of
substrate with ester and sugar should be shortened to 2 hours in order to avoid generating
excessive byproducts (not the diarylation products), and it was necessary to increase the amount of
aryl diazonium for their conversion (Scheme 2, 3fa-3ga).
Subsequently, the tolerance of this reaction to a range of aryldiazonium salts and the electronic
effect on the 6ꢀarylpurines were examined (Scheme 3). Firstly, purine nucleoside was reacted with
various substituted aryldiazonium salts, and the corresponding biarylꢀpurine nucleosides were
obtained in moderate to good yields (see Supporting Information for competition reactions). The
reaction proceeded smoothly with diazonium salts having bromine substituted at each position of
the aryl ring, giving acceptable yields of desired products (Scheme 3, 3ge-3gg) except that the
yield of the desired product 3gf was somewhat low. This might be due to the steric hindrance of
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oꢀBr. Both electronꢀwithdrawing and electronꢀdonating groups at the C6ꢀAr of purine lead to
subtle decrease in reaction yields (scheme 3, 3gkꢀ3ik). Notably, some strong electronꢀwithdrawing
groups such as –F, –CF3 and –CN were well tolerated in this photoreaction that is not feasible in
the previous ways6 (Scheme 3, 3gh-3gj). Moreover, a range of functional groups (–Cl, –Br,
–CO2Et) could successfully remain in the products, which were useful for the further
modifications (Scheme 3, 3gd-3gg and 3gk-3kk). Therefore, 2k was selected as the cross partner
to react with challenge purine nucleosides. Deoxyribosyl purine nucleoside and arabinoribosyl
purine nucleoside show well antiꢀHIV/HBV activity,14 and its derivatives (1j and 1k) proceeded
well and affored the corresponding products with good yields at 0 oC (Scheme 3, 3jk and 3kk).
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Scheme 3. Substrates scope of purine nucleosides.a
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a
Reaction conditions: 1g-1i (0.2 mmol), 2b-2k (1.6 mmol), Pd(OAc)2 (5 mol %),
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Ru(bpy)3Cl2·6H2O (2.5 mol %) in MeOH (2 mL) at room temperature irradiation with 4*7W blue
LED bulb for 2 h under N2. b At 0 oC.
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To further evaluate the prospect of the methodology in synthesis, a gramꢀscale synthesis of
nucleoside analogue 3jk was performed. As shown in Scheme 4, 3jk was obtained in 65 % yield
(1.06 g) by treatment of 3 mmol of deoxyribosyl purine nucleoside 1j in the presence of 5 mol %
Pd(OAc)2, 2.5 mol
%
of Ru(bpy)3Cl2·6H2O and pꢀethoxycarbonylbenzenediazonium
tetrafluoroborate 2k. After that, in the present of NH3/MeOH solution, the deprotection of the
product 3jk could be carried out, affording the biarylꢀpurine nucleoside with free hydroxyl group
4 in 95% yield which can be directly used as active fragment in bological test.
Scheme 4. Gramꢀscaled synthesis of 3jk and deprotection of 3jk.
H
N2BF4
N
N
N
N
N
N
EtO2
C
N
N
EtO2
C
N
condition b
condition a
+
N
N
N
AcO
AcO
HO
O
O
O
CO2Et
OAc
3jk: 1.06 g, 65% yield
OAc
1j
3 mmol, 1.19 g
OH
4: 95% yield
2k
4 equiv
condition a: Pd(OAc)2 (5 mol %), Ru(bpy)3Cl2 6H2O (2.5 mol %), N2, 15 mL MeOH, 0 oC, 2 h, 4*7W blue LED
condition b: NH3/MeOH, rt, 1 h
On the basis of the previous work and our experimental results,7a, 13 a plausible mechanism was
outlined in Scheme 5, a. i) photoexcitation of Ru2+ generated Ru2+*, and aryl radical was formed
by SET (single electron transfer) from the Ru2+*, ii) purineꢀdirected abstraction of 1 with
Pd(OAc)2 gave the N1 atomꢀmediated palladacycle intermediate A (Intermediate A was prepared,
see Supporting Information for more details), iii) addition of aryl radical to intermediate A
afforded the PdIII intermediate B, iv) oneꢀelectron oxidation of B by Ru3+ regenerated the
photocatalyst and formed PdIV intermediate C, v) the following step involved arylꢀaryl bond
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formation and the regeneration of Pd(OAc)2 via reductive elimination. In order to trap the aryl
radical generated in the reaction, TEMPO was added to the reaction mixture. Only trace amounts
of the target product 1jk was detected and the radicalꢀtrapping product 5 was isolated in 85% yield
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(Scheme 5, b).
Scheme 5. Plausible mechanism for monophenylation reaction.
In summary, a combined photoredoxꢀ and palladiumꢀcatalyzed system for monoꢀselective
CAr–H bond arylation of purine nucleoside has been reported for the first time. The reaction
operates at room temperature in only 2ꢀ4 hours and is mediated by visible light from household
blue LED. Catalytic amounts of photoredox catalyst can generate aryl radical and enable a Pd(II)ꢀ
Pd(III)ꢀPd(IV)ꢀPd(II) catalytic cycle, so that external oxidants can be avoided. This C–H arylation
approach provided a broad substrate scope reaction condition to a variety of functionalized purines
(nucleosides) which are potentially of great importance in medicinal chemistry.
EXPERIMENTAL SECTION
General information:
1H NMR spectra were recorded on commercial instruments (400/600 MHz). Chemical shifts are
recorded in ppm relative to tetramethylsilane and with the solvent resonance as the internal
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standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t =
triplet, q = quaternary, m = multiplet, br = broad), coupling constants (Hz), integration. 13C NMR
data were collected on commercial instruments (100/150 MHz) with complete proton decoupling.
Chemical shifts are reported in ppm from the tetramethylsilane with the solvent resonance as
internal standard. Highꢀresolution mass spectra were taken with electrospray ionization (ESI) as
the ionization method used for the HRMS measurement. For column chromatography silica gel
(200ꢀ300 mesh) was used as the stationary phase. All regents and solvents were purchased from
commercial sources and purified commonly before used. Experiments upon visibleꢀlight
irradiation were carried out using household blue LED lamps (λmax = 465 nm, 4*7 W).
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Synthesis of starting materials
Synthesis of 6-aryl-9-substitudent-purine 1a-1k.
Staring materials 1a-1k were synthesized by Suzuki crossꢀcoupling reactions of
6ꢀchloroꢀ9ꢀsubstituted purine with aryl boronic acid according to the corresponding reference. [15]
6ꢀchloroꢀ9ꢀsubstitudentꢀpurine (3 mmol), boronic acid (4.5 mmol), K2CO3 (6 mmol), toluene (20
mL) were added in a 100 mL tube. The tube was refluxed in a 110 oC bath and stirred for 8ꢀ12 h
under N2 gas. The mixture was then allowed to cool to room temperature. The mixture was diluted
with water then extracted with ethyl acetate. The extracts were combined, washed with brine, and
then dried over anhydrous Na2SO4. The crude material was purified by column chromatography
on silica gel (VPE/VEA = 3:1 as eluent) to give the 6ꢀarylꢀ9ꢀsubstitudentꢀpurine.
Synthesis of diazonium tetrafluoroborate salts 2a-2k.
Aniline (10 mmol) was dissolved in a mixture of 4 mL of distilled water and 3.4 mL of 50 %
hydrofluoroboric acid. After cooling the reaction mixture to 0° C, sodium nitrite (0.69 g) dissolved
in 1.5 mL of water, was added dropwise. The resulting mixture was stirred for 1 h and the
precipitate was collected by filtration, washed with water and redissolved in minimum amount of
acetone. Diethyl ether was added until precipitation of the corresponding diazonium
tetrafluoroborate, which was filtered, washed several times with diethyl ether and dried under
vacuum.
General procedure for the mono-selective ortho C-H arylation
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In a 25 mL sealed tube was charged with 1a-1e (0.2 mmol), Pd(OAc)2 (2.2 mg, 0.01 mmol),
Ru(bpy)3Cl2·6H2O (3.7 mg, 0.005 mmol) and phenyldiazonium tetrafluoroborate 2a (1.2 mmol),
then MeOH (2 mL) were added and the reaction mixture was irradiation with 4*7W blue led bulb
for 4 hours at room temperature under a N2 atmosphere via several vacuumꢀN2 exchanges. In a 25
mL sealed tube was charged with 1f-1i (0.2 mmol), Pd(OAc)2 (2.2 mg, 0.01 mmol),
Ru(bpy)3Cl2·6H2O (3.7 mg, 0.005 mmol) and phenyldiazonium tetrafluoroborate 2a-2k (1.6
mmol), then MeOH (2 mL) were added and the reaction mixture was irradiation with 4*7W blue
led bulb for 2 hours at room temperature under a N2 atmosphere via several vacuumꢀN2 exchanges.
In a 25 mL sealed tube was charged with 1j-1k (0.2 mmol), Pd(OAc)2 (2.2 mg, 0.01 mmol),
Ru(bpy)3Cl2·6H2O (3.7 mg, 0.005 mmol) and phenyldiazonium tetrafluoroborate 2k (1.6 mmol),
then MeOH (2 mL) were added and the reaction mixture was irradiation with 4*7W blue led bulb
for 2 hours at 0 oC under a N2 atmosphere via several vacuumꢀN2 exchanges. After completion of
the reaction, the mixture was then diluted with brine (10 mL) and extracted with ethyl acetate
(3×10 mL). The organic layer was collected and dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The crude material was purified by column chromatography
on silica gel (VPE/VEA = 1:1 as eluent) to give the desired products 3aa-3kk.
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Deprotection of diacetyl deoxy-purine nucleoside analogues
In the present of NH3/MeOH solution (7 mol/L), the deprotection of the product 3jk (81 mg,
0.15 mmol) could be carried out, affording the biarylꢀpurine nucleoside with free hydroxyl group
4 (66 mg) in 95 % yield.
The background reaction with TEMPO
In a 25 mL sealed tube was charged with 1j (39.6mg, 0.1 mmol), Pd(OAc)2 (1.1 mg, 0.005
mmol), Ru(bpy)3Cl2·6H2O (1.3 mg, 0.0025 mmol) and phenyldiazonium tetrafluoroborate 2k
(158.4mg, 0.6 mmol), TEMPO (93.8 mg, 0.6 mmol), then MeOH (2 mL) were added and the
o
reaction mixture was irradiation with 4*7W blue led bulb for 4 hours at 0 C under a N2
atmosphere via several vacuumꢀN2 exchanges. After completion of the reaction, the mixture was
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then diluted with brine (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was
collected and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The
crude material was purified by column chromatography on silica gel (VPE/VEA = 10:1 as eluent) to
give the desired products 5 (155 mg, 85%).
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Characterization of compounds
6-([1,1'-Biphenyl]-2-yl)-9-benzyl-9H-purine (3aa)
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Light yellow oil. Yield 53 mg (73%) at 0.2 mmol scale. H NMR (400 MHz, CDCl3) δ 8.89 (s,
1H), 7.87 (s, 1H), 7.80 (d, J =8.0 Hz, 1H), 7.57–7.49 (m, 3H), 7.39–7.34 (m, 3H), 7.22–7.20 (dd, J
=8.0 Hz, 2 Hz, 2H), 7.15–7.11 (m, 5H), 5.41 (s, 2H); 13C NMR (151 MHz, CDCl3) δ 159.1, 152.5,
151.6, 144.2, 142.0, 141.3, 135.2, 134.4, 132.2, 130.9, 130.7, 129.9, 129.2, 129.1, 128.6, 127.8,
127.6, 127.4, 126.5, 47.2. HRMS (ESIꢀTOF) m/z: [M+H] + Calcd for C24H19N4 363.1604; Found
363.1609.
6-([1,1'-Biphenyl]-2-yl)-9-methyl-9H-purine (3ba)
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Light yellow oil. Yield 49 mg (86%) at 0.2 mmol scale. H NMR (400 MHz, CDCl3) δ 8.86 (s,
1H), 7.91 (s, 1H), 7.78 (d, J =7.2 Hz, 1H), 7.57–7.50 (m, 3H), 7.16–7.12 (m, 5H), 3.87 (s, 3H);
13C NMR (151 MHz, CDCl3) δ 157.9, 151.2, 150.8, 143.9, 140.9, 140.3, 133.3, 131.2, 130.0,
+
129.8, 128.8, 128.2, 126.8, 126.3, 125.5, 28.8. HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for
C18H14N4Na 309.1111; Found 309.1101.
6-([1,1'-Biphenyl]-2-yl)-9-(sec-butyl)-9H-purine (3ca)
Brown oil. Yield 54 mg (83%) at 0.2 mmol scale. 1H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 7.91
(s, 1H), 7.80 (d, J =7.6 Hz, 1H), 7.56–7.49 (m, 3H), 7.15–7.09 (m, 5H), 4.64 (m, 1H), 2.05–1.88
(m, 2H), 1.59 (d, J =6.8 Hz, 3H), 0.80 (t, J =7.4 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 158.9,
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151.9, 151.4, 142.6, 141.9, 141.3, 134.5, 132.5, 130.9, 130.7, 129.8, 129.2, 127.8, 127.3, 126.4,
53.0, 29.5, 20.4, 10.6. HRMS (ESIꢀTOF) m/z: [M+Na] + Calcd for C21H20N4Na 351.1580; Found
351.1579.
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6-([1,1'-Biphenyl]-2-yl)-9-cyclopentyl-9H-purine (3da)
Brown oil. Yield 53 mg (78%) at 0.2 mmol scale. NMR (600 MHz, ) δ 8.82 (s, 1H), 7.97 (s, 1H),
7.79 (d, J = 7.5 Hz, 1H), 7.55ꢀ7.49 (m, 3.0 Hz), 7.16–7.12 (m, 5H), 4.97 (m, 1H), 2.32–2.29(m,
2H), 2.04–1.99 (m, 2H), 1.95–1.93 (m, 2H), 1.83 – 1.81 (m, 2H).; 13C NMR (151 MHz, CDCl3) δ
157.9, 150.8, 150.6, 141.6, 140.8, 140.3, 133.4, 131.7, 130.0, 129.8, 128.7, 128.2, 126.8, 126.3,
125.4, 55.1, 31.6, 22.9. HRMS (ESIꢀTOF) m/z: [M+H] + Calcd for C22H21N4 341.1761; Found
341.1756.
6-([1,1'-Biphenyl]-2-yl)-9-(2-bromoethyl)-9H-purine (3ea)
Light brown oil. Yield 56 mg (74%) at 0.2 mmol scale. 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H),
7.99 (s, 1H), 7.82 (d, J =7.2 Hz, 1H), 7.58–7.52 (m, 3H), 7.16–7.12 (m, 5H), 4.65 (t, J =5.8 Hz,
2H), 3.79 (t, J =6.0 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ 159.3, 152.3, 151.3, 144.5, 142.0,
141.2, 134.2, 132.4, 131.0, 130.8, 129.9, 129.2, 127.9, 127.4, 126.5, 45.6, 29.6. HRMS (ESIꢀTOF)
m/z: [M+Na] + Calcd for C19H15BrN4Na 401.0372; Found 401.0376.
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Ethyl 2-(6-([1,1'-biphenyl]-2-yl)-9H-purin-9-yl)acetate (3fa)
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Yellow oil. Yield 49 mg (68%) at 0.2 mmol scale. H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H),
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7.99 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.58–7.50 (m, 3H), 7.17–7.13 (m, 5H), 5.01 (s, 2H), 4.27 (q,
J = 7.2 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 166.9, 159.2, 152.4,
151.6, 144.6, 141.9, 141.2, 134.2, 131.8, 131.1, 130.8, 129.9, 129.2, 127.9, 127.4, 126.5, 62.5,
+
44.1, 14.1. HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for C21H18N4O2Na 381.1322; Found
381.1322.
((3aR,4R,6R,6aR)-6-(6-([1,1'-Biphenyl]-2-yl)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)methanol (3ga)
Light rellow oil. Yield 56 mg (63%) at 0.2 mmol scale. 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H),
8.02 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.58–7.50 (m, 3H), 7.16 (s, 5H), 5.91 (d, J = 4.8 Hz, 1H),
5.76 (d, J = 9.6, 1H), 5.24 (t, J = 5.2 Hz, 1H), 5.11 (d, J = 5.2, 1H), 4.54 (s, 1H), 3.96 (d, J = 12.4
Hz, 1H), 3.78 (t, J = 11.0 Hz, 1H), 1.65 (s, 3H), 1.38 (s, 3H); 13C NMR (151 MHz, CDCl3) δ
160.4, 151.6, 150.2, 144.1, 142.0, 141.0, 133.9, 133.8, 131.2, 131.0, 130.1, 129.2, 128.0, 127.4,
126.7, 114.3, 94.1, 86.1, 82.9, 81.6, 63.3, 27.6, 25.3. HRMS (ESIꢀTOF) m/z: [M+H] + Calcd for
C25H25N4O4 445.1870; Found 445.1875.
((3aR,4R,6R,6aR)-2,2-Dimethyl-6-(6-(4'-methyl-[1,1'-biphenyl]-2-yl)-9H-purin-9-yl)tetrahyd
rofuro[3,4-d][1,3]dioxol-4-yl)methanol (3gb)
Light brown oil. Yield 62 mg (68%) at 0.2 mmol scale. 1H NMR (600 MHz, CDCl3) δ 8.80 (s, 1H),
8.01 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.57–7.53 (m, 2H), 7.49 (t, J = 7.2 Hz, 1H), 7.03 (d, J = 7.8
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Hz, 2H), 6.97 (d, J = 7.8 Hz, 2H), 5.91 (d, J = 4.8 Hz, 1H), 5.79 (d, J = 10.8 Hz, 1H), 5.25 (t, J =
5.1 Hz, 1H), 5.13 (d, J = 6.0 Hz, 1H), 4.56 (s, 1H), 3.99 (d, J = 12.6 Hz, 1H), 3.81 (t, J = 12.0 Hz,
1H), 2.28 (s, 3H), 1.66 (s, 3H), 1.39 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 160.8, 151.7, 150.3,
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144.2, 142.1, 138.2, 136.5, 134.2, 133.9, 131.3, 131.1, 130.3, 129.2, 128.9, 127.3, 114.4, 94.4,
+
86.2, 83.0, 81.8, 63.5, 27.8, 25.4, 21.2. HRMS (ESIꢀTOF) m/z: [M+Na]
C26H26N4NaO4 481.1846; Found 481.1851.
Calcd for
((3aR,4R,6R,6aR)-6-(6-(4'-Methoxy-[1,1'-biphenyl]-2-yl)-9H-purin-9-yl)-2,2-dimethyltetrahy
drofuro[3,4-d][1,3]dioxol-4-yl)methanol (3gc)
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Light yellow oil. Yield 62 mg (65%) at 0.2 mmol scale. H NMR (400 MHz, CDCl3) δ 8.82 (s,
1H), 8.00 (s, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.57–7.46 (m, 3H), 7.07 (d, J = 8.8 Hz, 2H), 6.70 (d, J
= 8.8 Hz, 2H), 5.90 (d, J = 4.8 Hz, 1H), 5.76 (d, J = 10.0 Hz, 1H), 5.25 (t, J = 5.4 Hz, 1H), 5.13 (d,
J = 5.6 Hz, 1H), 4.56 (s, 1H), 3.99 (d, J = 12.4 Hz, 1H), 3.81 (t, J = 11.2 Hz, 1H), 3.75 (s, 3H),
1.66 (s, 3H), 1.39 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 159.7, 157.5, 150.6, 149.1, 143.0, 140.6,
133.0, 132.7, 132.5, 130.1, 129.8, 129.3, 129.1, 126.0, 113.3, 112.5, 93.2, 85.1, 81.8, 80.6, 62.3,
54.1, 26.6, 24.2. HRMS (ESIꢀTOF) m/z: [M+Na] + Calcd for C26H26N4NaO5 497.1795; Found
497.1795.
((3aR,4R,6R,6aR)-6-(6-(4'-Chloro-[1,1'-biphenyl]-2-yl)-9H-purin-9-yl)-2,2-dimethyltetrahydr
ofuro[3,4-d][1,3]dioxol-4-yl)methanol (3gd)
Brown oil. Yield 68 mg (71%) at 0.2 mmol scale. 1H NMR (600 MHz, CDCl3) δ 8.81 (s, 1H), 8.02
(s, 1H), 7.80–7.78 (m, 1H), 7.60–7.50 (m, 3H), 7.15 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H),
5.92 (d, J = 4.8 Hz, 1H), 5.66 (d, J = 10.4 Hz, 1H), 5.26 (t, J = 5.4 Hz, 1H), 5.13 (d, J = 6.0 Hz,
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1H), 4.56 (s, 1H), 3.99 (d, J = 12.8 Hz, 1H), 3.81 (d, J = 11.2 Hz, 1H), 1.66 (s, 3H), 1.39 (s, 3H).
13C NMR (151 MHz, CDCl3) δ 158.9, 150.6, 149.2, 143.2, 139.8, 138.6, 132.8, 132.7, 131.8,
130.4, 129.8, 129.5, 129.2, 129.0, 127.7, 127.2, 126.7, 113.3, 93.1, 85.1, 81.9, 80.6, 62.3, 26.6,
24.2. HRMS (ESIꢀTOF) m/z: [M+H] + Calcd for C25H24ClN4O4 479.1481; Found 479.1481.
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((3aR,4R,6R,6aR)-6-(6-(2'-Bromo-[1,1'-biphenyl]-2-yl)-9H-purin-9-yl)-2,2-dimethyltetrahydr
ofuro[3,4-d][1,3]dioxol-4-yl)methanol (3ge)
Light brown oil. Yield 55 mg (53%) at 0.2 mmol scale. 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H),
8.07 (s, 1H), 8.05–8.01 (m, 1H), 7.60–7.56 (m, 2H), 7.46–7.42 (m, 2H), 7.26–7.23 (m, 1H), 7.19 (t,
J = 7.6 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 5.93 (d, J = 4.9 Hz, 1H), 5.68 (t, J = 11.2 Hz, 1H), 5.24
(q, J =5.2 Hz, 1H), 5.13–5.10 (m, 1H), 4.55 (s, 1H), 4.00–3.91 (m, 1H), 3.79 (t, J = 11.2 Hz, 1H),
1.66 (s, 3H), 1.39 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 159.1, 151.1, 150.3, 144.1, 142.0, 141.1,
132.3, 131.8, 131.5, 129.9, 128.4, 128.0, 126.8, 114.3, 94.3, 94.2, 81.6, 63.4, 27.7, 25.2. HRMS
(ESIꢀTOF) m/z: [M+Na] + Calcd for C25H23BrN4NaO4 545.0795; Found 545.0791.
((3aR,4R,6R,6aR)-6-(6-(3'-Bromo-[1,1'-biphenyl]-2-yl)-9H-purin-9-yl)-2,2-dimethyltetrahydr
ofuro[3,4-d][1,3]dioxol-4-yl)methanol (3gf)
Brown oil. Yield 73 mg (70%) at 0.2 mmol scale. 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.02
(s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.57–7.53 (m, 3H), 7.27 (d, J = 7.2 Hz, 1H), 7.04ꢀ6.94 (m, 2H),
5.92 (d, J = 4.8 Hz, 1H), 5.56 (d, J = 10.4 Hz, 1H), 5.25 (t, J = 5.2 Hz,1H), 5.13 (d, J = 6.0 Hz,
1H), 4.55 (s, 1H), 3.98 (d, J = 12.4 Hz, 1H), 3.81 (t, J = 11.4 Hz, 1H), 1.66 (s, 3H), 1.39 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 159.9, 151.7, 150.3, 144.3, 140.8, 140.1, 133.7, 131.4, 131.2,
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130.8, 130.8, 130.3, 128.7, 128.3, 127.7, 126.5, 121.1, 114.3, 94.2, 86.1, 82.9, 81.6, 63.4, 27.6,
25.2. HRMS (ESIꢀTOF) m/z: [M+H] + Calcd for C25H24BrN4O4 523.0975; Found 523.0979.
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((3aR,4R,6R,6aR)-6-(6-(4'-Bromo-[1,1'-biphenyl]-2-yl)-9H-purin-9-yl)-2,2-dimethyltetrahydr
ofuro[3,4-d][1,3]dioxol-4-yl)methanol (3gg)
Light brown oil. Yield 76 mg (73%) at 0.2 mmol scale. 1H NMR (600 MHz, CDCl3) δ 8.81 (s, 1H),
8.02 (s, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.59–7.50 (m, 3H), 7.30 (d, J = 7.8 Hz, 2H), 7.03 (d, J = 7.8
Hz, 2H), 5.92 (d, J = 4.8 Hz, 1H), 5.54 (d, J = 10.8 Hz, 1H), 5.26 (t, J = 5.4 Hz, 1H), 5.13 (d, J =
6.0 Hz, 1H), 4.56 (s, 1H), 3.99 (d, J = 12.6 Hz, 1H), 3.81 (t, J = 11.4 Hz, 1H), 1.66 (s, 3H), 1.39 (s,
3H). 13C NMR (151 MHz, CDCl3) δ 159.9, 151.7, 150.3, 140.8, 140.1, 133.9, 133.7, 131.4, 131.2,
130.8, 130.8, 130.3, 127.8, 121.1, 114.3, 94.2, 86.1, 82.9, 63.4, 27.6, 25.2. HRMS (ESIꢀTOF) m/z:
[M+H] + Calcd for C25H24BrN4O4 523.0975; Found 523.0973.
((3aR,4R,6R,6aR)-6-(6-(4'-Fluoro-[1,1'-biphenyl]-2-yl)-9H-purin-9-yl)-2,2-dimethyltetrahydr
ofuro[3,4-d][1,3]dioxol-4-yl)methanol (3gh)
Brown oil. Yield 62 mg (67%) at 0.2 mmol scale. 1H NMR (600 MHz, CDCl3) δ 8.81 (s, 1H), 8.00
(s, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.52 (t, J = 7.2 Hz, 2H), 7.11 (dd, J =
8.2, 5.6 Hz, 2H), 6.86 (t, J = 8.4 Hz, 2H), 5.91 (d, J = 4.8 Hz, 1H), 5.59 (d, J = 10.8 Hz, 1H), 5.25
(t, J = 5.4 Hz, 1H), 5.12 (d, J = 6.0 Hz, 1H), 4.55 (s, 1H), 3.98 (d, J = 12.6 Hz, 1H), 3.80 (t, J =
11.7 Hz, 1H), 1.65 (s, 3H), 1.39 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 162.7, 161.1, 160.1, 151.6,
150.2, 144.2, 141.0, 137.1, 133.9, 133.8, 131.3, 130.9, 130.8, 130.7, 130.2, 129.2, 128.0, 127.5,
115.0, 114.3, 94.2, 86.1, 82.9, 81.6, 63.3, 27.6, 25.2. HRMS (ESIꢀTOF) m/z: [M+H] + Calcd for
C25H24FN4O4 463.1776; Found 463.1779.
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((3aR,4R,6R,6aR)-2,2-Dimethyl-6-(6-(4'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)-9H-purin-9-yl
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)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (3gi)
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Light yellow oil. Yield 71 mg (69%) at 0.2 mmol scale. H NMR (400 MHz, CDCl3) δ 8.76 (s,
1H), 8.01 (s, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.61–7.49 (m, 3H), 7.41 (d, J = 8.0 Hz, 2H), 7.24 (s,
2H), 5.90 (d, J = 5.2 Hz, 1H), 5.46 (d, J = 10.0 Hz, 1H), 5.22 (t, J = 5.2 Hz, 1H), 5.10 (d, J = 5.2
Hz, 1H), 4.53 (s, 1H), 3.97 (d, J = 12.8 Hz, 1H), 3.79 (t, J = 11.2 Hz, 1H), 1.63 (s, 3H), 1.37 (s,
3H). 13C NMR (151 MHz, CDCl3) δ 159.5, 151.6, 150.4, 144.9, 144.3, 140.7, 133.9, 133.8, 131.6,
131.0, 130.4, 129.5, 128.1, 125.0, 124.9, 114.4, 94.2, 86.1, 82.9, 81.6, 63.3, 27.6, 25.2. HRMS
(ESIꢀTOF) m/z: [M+H] + Calcd for C26H24F3N4O4 513.1744; Found 513.1747.
2'-(9-((3aR,4R,6R,6aR)-6-(Hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-y
l)-9H-purin-6-yl)-[1,1'-biphenyl]-4-carbonitrile (3gj)
Yellow oil. Yield 70 mg (75%) at 0.2 mmol scale. 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H),
8.02 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.64–7.57 (m, 2H), 7.51 (dd, J = 7.6, 2.0 Hz, 1H), 7.47 (d, J
= 8.4 Hz, 2H), 7.27 (s, 1H), 7.25 (s, 1H), 5.92 (d, J = 4.8 Hz, 1H), 5.43 (d, J = 9.6 Hz, 1H), 5.24 (t,
J = 5.2 Hz, 1H), 5.12 (d, J = 4.8 Hz, 1H), 4.55 (s, 1H), 3.98 (d, J = 12.8 Hz, 1H), 3.81 (t, J = 11.2
Hz, 1H), 1.66 (s, 3H), 1.39 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 159.1, 151.7, 150.4, 146.1,
144.4, 140.2, 133.8, 131.8, 131.8, 130.8, 130.5, 129.9, 128.5, 118.9, 114.4, 110.5, 94.1, 86.1,
63.33. HRMS (ESIꢀTOF) m/z: [M+H] + Calcd for C26H24N5O4 470.1823; Found 470.1826.
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Ethyl 2'-(9-((3aR,4R,6R,6aR)-6-(Hydroxymethyl)-2,2-dimethyltetrahydrofuro
[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl)-[1,1'-biphenyl]-4-carboxylate (3gk)
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Light brown oil. Yield 85 mg (82%) at 0.2 mmol scale. 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H),
8.01 (s, 1H), 7.86–7.81 (m, 3H), 7.62–7.53 (m, 3H), 7.22 (d, J = 8.4 Hz, 2H), 5.91 (d, J = 4.8 Hz,
1H), 5.61 (d, J = 9.6 Hz, 1H), 5.25 (t, J = 5.4 Hz, 1H), 5.12 (d, J = 6.0 Hz, 1H), 4.55 (s, 1H), 4.33
(q, J = 7.2 Hz, 2H), 3.98 (d, J = 12.8 Hz, 1H), 3.80 (t, J = 11.2 Hz, 1H), 1.65 (s, 3H), 1.39–1.35(m,
6H). 13C NMR (151 MHz, CDCl3) δ 166.6, 159.7, 151.6, 150.3, 145.9, 144.2, 141.1, 133.9, 132.1,
132.1, 132.0, 131.4, 130.8, 130.3, 129.3, 129.2, 128.7, 128.6, 128.5, 128.0, 114.3, 94.2, 86.2, 82.9,
63.3, 60.9, 27.6, 25.2, 14.3. HRMS (ESIꢀTOF) m/z: [M+Na] + Calcd for C28H28N4NaO6 539.1901;
Found 539.1900.
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Ethyl 2'-(9-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro
[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl)-5'-methyl-[1,1'-biphenyl]-4-carboxylate (3hk)
Brown oil. Yield 76 mg (72%) at 0.2 mmol scale. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 7.98
(s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 6.8 Hz, 2H), 7.22 (d, J =
8.4 Hz, 2H), 5.90 (d, J = 4.8 Hz, 1H), 5.58 (d, J = 10.8 Hz, 1H), 5.25 (t, J = 5.4 Hz, 1H), 5.12 (d, J
= 6.0 Hz, 1H), 4.54 (s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 3.97 (d, J = 12.8 Hz, 1H), 3.80 (t, J = 11.4
Hz, 1H), 2.48 (s, 3H), 1.65 (s, 3H), 1.39–1.35 (m, 6H). 13C NMR (151 MHz, CDCl3) δ 166.6,
159.8, 151.6, 150.2, 146.1, 144.0, 141.0, 140.5, 133.9, 131.6, 131.5, 131.1, 129.2, 129.2, 128.8,
128.6, 114.3, 94.2, 86.1, 82.8, 81.6, 63.4, 60.9, 27.6, 25.2, 21.5, 14.3. HRMS (ESIꢀTOF) m/z:
[M+H] + Calcd for C29H31N4O6 531.2238; Found 531.2237.
Diethyl 6-(9-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro
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[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl)-[1,1'-biphenyl]-3,4'-dicarboxylate (3ik)
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Light yellow oil. Yield 74 mg (63%) at 0.2 mmol scale. H NMR (600 MHz, CDCl3) δ 8.81 (s,
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1H), 8.22–8.21 (s, 2H), 8.01 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.25 (d, J
= 7.8 Hz, 2H), 5.91 (d, J = 4.8 Hz, 1H), 5.36 (d, J = 11.4 Hz, 1H), 5.24 (t, J = 5.1 Hz, 1H), 5.12 (d,
J = 6.0 Hz, 1H), 4.55 (s, 1H), 4.44 (q, J = 7.2 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.97 (d, J = 12.6
Hz, 1H), 3.80 (t, J = 11.7 Hz, 1H), 1.65 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H), 1.39–1.36 (m, 6H). 13C
NMR (151 MHz, CDCl3) δ 166.4, 165.9, 158.6, 151.7, 150.4, 144.9, 144.5, 141.4, 137.9, 133.9,
129.4, 129.2, 114.4, 94.1, 86.2, 82.9, 81.6, 63.3, 61.4, 61.0, 30.9, 27.6, 25.2, 14.3. HRMS
(ESIꢀTOF) m/z: [M+H] + Calcd for C31H33N4O8589.2293; Found 589.2295.
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Ethyl 2'-(9-((2R,4S,5R)-4-acetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-9H
-purin-6-yl)-[1,1'-biphenyl]-4-carboxylate (3jk)
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Colorless oil. Yield 85 mg (78%) at 0.2 mmol scale. H NMR (600 MHz, CDCl3) δ 8.82 (s, 1H),
8.11 (s, 1H), 7.83 (t, J = 7.8 Hz, 3H), 7.60–7.54 (m, 3H), 7.23 (d, J = 7.8 Hz, 2H), 6.48 (t, J = 7.2
Hz, 1H), 5.44 (d, J = 6.0 Hz, 1H), 4.40 (q, J = 6.0 Hz, 1H), 4.36–4.31 (m, 4H), 3.00–2.95 (m, 1H),
2.67–2.63 (m, 1H), 2.14 (s, 3H), 2.06 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H). 13C NMR (151 MHz,
CDCl3) δ 170.4, 170.3, 166.6, 158.8, 152.3, 151.1, 146.0, 142.6, 140.9, 134.2, 132.9, 131.3, 130.8,
130.1, 129.2, 129.2, 128.6, 128.0, 84.7, 82.7, 74.5, 63.7, 60.9, 37.5, 20.9, 20.7, 14.3. HRMS
(ESIꢀTOF) m/z: [M+Na] + Calcd for C29H28N4NaO7 567.1850; Found 567.1849.
(2R,3R,4S,5R)-2-(Acetoxymethyl)-5-(6-(4'-(ethoxycarbonyl)-[1,1'-biphenyl]-2-yl)-9H-purin-9
-yl)tetrahydrofuran-3,4-diyl diacetate (3kk)
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Colorless oil. Yield 98 mg (81%) at 0.2 mmol scale. H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H),
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8.08 (s, 1H), 7.83–7.79 (m, 3H), 7.60–7.53 (m, 3H), 7.23 (s, 1H), 7.21 (s, 1H), 6.62 (d, J = 4.4 Hz,
1H), 5.48 (t, J = 3.8 Hz, 1H), 5.43 (t, J = 3.6 Hz 1H), 4.45 (t, J = 4.8 Hz, 2H), 4.31 (q, J = 7.2 Hz,
2H), 4.26 (m, 1H), 2.17 (s, 3H), 2.10 (s, 3H), 1.78 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H). 13C NMR (151
MHz, CDCl3) δ 170.5, 169.6, 168.5, 166.5, 158.7, 152.6, 150.9, 146.0, 143.3, 140.9, 134.1, 131.9,
129.2, 128.6, 128.1, 83.1, 80.0, 75.8, 74.9, 62.9, 60.9, 20.8, 20.7, 20.1, 14.3. HRMS (ESIꢀTOF)
m/z: [M+Na] + Calcd for C31H30N4NaO9 625.1905; Found 625.1903.
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Ethyl 2'-(9-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-9H-
purin-6-yl)-[1,1'-biphenyl]-4-carboxylate (4)
o
1
White solid. Yield 68 mg (95%) at 0.2 mmol scale of 3j. M.p. 62ꢀ64 C H NMR (600 MHz,
CDCl3) δ 8.78 (s, 1H), 8.00 (s, 1H),7.84 (m, 3H), 7.61–7.54 (t, J = 8.4 Hz , 3H), 7.23 (d, J = 7.8
Hz, 2H), 6.36 (q, J = 5.2 Hz, 1H), 5.62 (s, 1H), 4.80 (d, J = 4.8 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H),
4.23 (s, 1H), 3.98 (dd, J = 13.2, 5.4 Hz, 1H), 3.88 (s, 1H), 3.80 (d, J = 11.4 Hz, 1H), 3.12–3.08 (m,
1H), 2.35 (q, J = 5.4 Hz, 1H), 1.37 (t, J = 7.2 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 166.6,
159.6, 151.4, 150.4, 145.9, 144.3, 141.1, 134.1, 134.0, 131.4, 130.8, 130.3, 129.3, 129.2, 128.7,
+
128.0, 89.6, 87.7, 73.5, 63.4, 61.0, 40.7, 14.3. HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for
C25H24N4NaO5 483.1639; Found 483.1632.
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Ethyl 4-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)benzoate (5)
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Browm solid. Yield 155 mg (85%) at 0.6 mmol scale.1H NMR (600 MHz, CDCl3) δ 7.94 (d, J =
9.0 Hz, 2H), 7.20 (br, 2H), 4.33 (q, J = 7.2 Hz, 2H), 4.06 (br, 1H), 1.94–1.91 (m, 3H), 1.63 (t, J =
12.0 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H), 1.27 (s, 6H), 1.01 (s, 6H). 13C NMR (101 MHz, CDCl3) δ
167.1, 166.6, 131.1, 122.6, 113.7, 62.9, 60.9, 60.6, 48.2, 32.5, 21.3, 14.4. HRMS (ESIꢀTOF) m/z:
[M+H] + Calcd for C18H28NO3 306.2064; Found 306.2067.
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ASSOCIATED CONTENT
Supporting Information
Verification test, copies of all spectral and full characterization for all new compounds. This
information is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: ghm@htu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful for the financial support from the National Natural Science Foundation of China (Nos. U1604283，
21472037, 21372066, U1604182，and 21402041), the Plan for Scientific Innovation Talent of Henan Province
(164200510008), and Program for Innovative Research Team in Science and Technology in University of Henan
Province (15IRTSTHN003).
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