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DOI: 10.1039/C8OB00568K
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Metal‐Free α‐Alkylation of Alcohols with para‐Quinone Methides
Jifeng Qi,a Ziyang Deng,a Bo Huanga and Sunliang Cui*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
A metal‐free α‐alkylation of alcohols with para‐quinone methides (p‐QMs) for accessing alcohol‐containing phenols and
dihydroisocoumarins has been developed. The alcohols were converted to α‐oxy radicals in the presence of di‐tert‐butyl
peroxide (DTBP), which added to p‐QMs toward aromatization and C(sp3)‐C(sp3) bond formation
DOI: 10.1039/x0xx00000x
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Introduction
addition. For example, Fan established a catalytic asymmetric
synthesis of functionalized diarylmethines from p‐QMs and
malonates.12 Jørgensen developed another asymmetric
addition between p‐QMs and enamines. 13 Meanwhile, Liao,
Tortosa and Li have independently reported the asymmetric
addition of p‐QMs with the functional incorporation of borane
and thioester.14 Interestingly, Deng, Enders and Fan also
reported the asymmetric addition of p‐QMs with glycine Schiff
base and oxindoles.15 Matsuura reported the Photoinduced
addition of methanol to p‐QMs.16
We recently reported a Fe(III)‐catalyzed hydroalkylation of
alkenes with p‐QMs for accessing phenols, and revealed that p‐QMs
could serve as radical acceptor.17 Therefore, we believed that the
radical addition of p‐QMs could be extended to deliver interesting
compounds. Herein we report a metal‐free α‐alkylation of alcohols
with p‐QMs (Figure 1).
Recently, the C−C bond formaꢀon for the α‐carbon of alcohols has
gained much interests.1 Respecting to the mechanism, most of
these protocols rely on the conversion of alcohols to α‐oxy carbon‐
centered radicals, and the diversified radical transformations
enable the late‐stage C−H funcꢀonalizaꢀon. The seminal work was
Minisci‐Reaction which described the hydroxyalkylation of
heterocycles.2 In the past few years, Tu has established various
cross‐coupling reactions of alcohols with alkenes for accessing
hydroxylation products.3 In 2006, Ishii and co‐workers reported an
N‐hydroxyphthalimide (NHPI) initiated addition of alcohols to
electron‐deficient alkynes catalyzed by Co(II).4 Meanwhile, Liu and
Cheng explored elegant work of tert‐butyl hydroperoxide (TBHP)
mediated generation of α‐oxy radicals and the valuable application
in alcohol functionalizations.5 This protocol has also been extended
by Han in olefin addition and radical cyclization for direct
construction of isoquinolinones.6 Recently, Li reported Pd(II)‐
catalyzed Minisci Reaction of alcohols,7 while Loh reported the Cu‐
catalyzed coupling of sp3 α‐carbon of alcohols with enynes.8 Liu
reported the peroxide mediated radical addition of simple alcohols
to Isocyanides and unactivated alkenes.9
Therefore, the
development of α‐functionalization of alcohols remain continuous
importance and interesting.
para‐Quinone Methides, which are structurally
characterized by assembly of carbonyl and olefinic moieties,
exhibit unique chemical reactivity as a precursor of phenols.10
The early study by Evans concerned an intramolecular
electrophilic cyclization of masked p‐ QMs and the application
in total synthesis of (±)‐Cherylline.11 Recently, p‐QMs have
been widely investigated as Michael acceptor in variou
s
conjugate addition reaction, especially the asymmetric
Figure 1 Metal‐free α‐alkylation of alcohols with p‐QMs.
aInstitute of Drug Discovery and Development, College of Pharmaceutical
Sciences, Zhejiang University, Hangzhou 310058, P. R. China.
E‐mail: slcui@zju.edu.cn
Results and discussion
bState Key Laboratory of Elemento‐Organic Chemistry, Nankai University, Tianjin
300071, China
We commenced our study by investigating p‐QMs 1a and isopr
opanol 2a (Table 1). Initially, we used TBHP as oxidant and i‐PrOH as
solvent under argon protection at 140 oC, and trace amount of α‐al
kylation product 3a was formed (entry 1). The attempt to add cataly
‡
Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available.
DOI: 10.1039/x0xx00000x
See
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tic PivOH failed to afford product (entry 2). We next used PhCl as sol methoxy, cyano, ester, chloro, were well tolerable in this process.
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vent and DTBP (di‐tert‐butyl peroxide) as oxidant but did not observ Meanwhile, the ortho‐ and meta‐ substitDuOteI:d10p.1‐0Q3M9/sC8wOeBr0e05a6l8sKo
e the product formation (entry 3). Gratifyingly, when i‐PrOH was us applicable in this process to deliver the corresponding phenols in
ed as solvent, we were pleased to find that the product 3a could be good yields (3g and 3h). Additionally, the p‐QMs with valuable
isolated in a remarkable 75% yield (entry 4). The addition of PivOH t polysubstituted aromatic ring, pyridine, thiophene and naphthalene,
o i‐PrOH was also found inferior to suppress the product formation could proceed well with isopropanol to furnish the privileged
(entry 5). The addition of 6 equivalent amount of DTBP did not sho products in good yields (3i‐3m). Furthermore, the structure of
w effect in yield improvement (entry 6). Variation of the solvent to t compound 3j was unambiguously confirmed by X‐ray analysis
oluene, MeCN, t‐BuOH and DCE resulted in no product formation (e (Figure 2).18
ntries 7‐10). Moreover, the argon protection was important to this r
eaction while elimination of argon would lead to trace amount of 3a
Table 2 Substrate scope of p‐QMsa
formation (entry 11). Furthermore, decreasing the temperature to
120 oC would only deliver trace product formation (entry 12).
Table 1 Reaction optimizationa
entry
oxidant
solvent
i‐PrOH
i‐PrOH
PhCl
yield(%)
1
TBHP (4 equiv.)
TBHP (4 equiv.)b
DTBP (3 equiv.)
DTBP (3 equiv.)
DTBP (3 equiv.)b
DTBP (6 equiv.)
DTBP (3 equiv.)
DTBP (3 equiv.)
DTBP (3 equiv.)
DTBP (3 equiv.)
DTBP (3 equiv.)c
DTBP (3 equiv.)d
< 5
0
2
3
0
4
i‐PrOH
i‐PrOH
i‐PrOH
PhCH3
MeCN
t‐BuOH
DCE
75
< 5
76
0
5
6
7
a Reaction condition: p‐QMs
1 (0.2 mmol), DTBP (0.6 mmol), i‐
8
0
PrOH (1 mL), argon, 2 hr, yields refer to isolated products.
9
0
10
11
12
0
i‐PrOH
i‐PrOH
34
trace
Figure 2 ORTEP representation of the X‐ray Crystal Structure of 3j.
a Reaction condition: p‐QMs 1a (0.2 mmol), 2a (0.6 mmol or used as
solvent), argon, 2 hr. b PivOH (10 mol %) was used as additive. c Wit
hout argon protection. d Conducted at 120 oC.
Next, the scope of alcohols was tested to react with p‐QMs 1a
(Table 3). Various primary alcohols, such as methanol, ethanol, n‐pr
opanol, could proceed well and undergo α‐oxy addition to p‐QMs fo
r approach to functionalized alcohols in moderate to good yields (3
n‐3p), and the diastereo ratio of products (3o and 3p) ranged from
1:1 to 1:1.19. Interestingly, when the glycol was applied, this proces
s could furnish the phenolic glycol in good yield (3q, 72%). Moreove
r, the tertiary alcohol like i‐butanol and cyclopentanol could furnish
the corresponding phenolic functionalized tertiary alcohols in mode
With the optimized reaction condition in hand, we next set out
to explore the substrate scope (Table 1). Various p‐QMs were used
as viable radical acceptor to trap the in situ generated α‐oxy radical
to furnish the 2‐hydroxy‐1‐phenylethyl phenols. The electronic
property did not show significant effect on the yield. The functional
group substitutions in the para position of aromatic ring, like methyl,
2 | J. Name., 2012, 00, 1‐3
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rate yields (3r and 3s). Therefore, this method represents a distinct α‐oxy radical B. Then B undergoes a radical addition to p‐QMs to for
View Article Online
DOI: 10.1039/C8OB00568K
approach toward phenol containing alcohols.
m phenol o‐centered radical intermediate C, which abstracts the α
‐(sp3)C‐H from alcohols giving the product 3 and regenerate the radi
cal B. Respecting to p‐QMs 1n, a further lactonization would deliver
the dihydroisocoumarins 4.
Table 3 Substrate Scope of Alcohols
Figure 3 Proposed reaction mechanism.
Conclusions
In summary, a metal‐free α‐alkylation of alcohols with para‐quinon
e methides for accessing phenol containing alcohols and dihydroiso
coumarins has been reported. This protocol not only represents a fa
cile C(sp3)‐C(sp3) bond formation, but also extends the radical additi
on reaction of para‐quinone methides.
a Reaction condition: p‐QMs 1a (0.2 mmol), DTBP (0.6 mmol), alcoh
ol (1 mL), argon, 2 hr., yields refer to isolated products, dr value was
determined by 1HNMR.
Interestingly, when the ortho‐ester substituted p‐QMs 1n was
subject to this reaction, the addition would occur and take further c
yclization to give the dihydroisocoumarin product 4, albeit in slightl
y low yields. To view insight of the reaction mechanism, a control ex
periment was conducted with the radical scavenger TEMPO, and th
e isomerization product was not observed, indicating a possible radi
cal–mediated reaction pathway (scheme 2).
Experimental
General experimental method
Infrared spectra were obtained on a FTIR spectrometer. 1H NMR an
d 13C NMR spectra were recorded on BRUKER AVANCE III 600 or BR
UKER AVANCE III 400 spectrometer. CDCl3 were used as solvent. Ch
emical shifts were referenced relative to residual solvent. The follo
wing abbreviations are used to describe peak patterns where appro
priate: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, se
pt = septet, m = multiplet, dd = double doublet, td = triple doublet.
Coupling constants (J) are reported in Hertz (Hz). HRMS were perfor
med on Waters GCT Premier Time of Flight Mass Spectrometer (EI).
Melting points were measured with micro melting point apparatus.
The alcohols, Di‐tert‐butyl peroxid (DTBP) were commercial availabl
e, and the para‐Quinone Methides were prepared according the lite
rature.19
Scheme 1 Synthesis of dihydroisocoumarins.
Typical Procedure for Synthesis of 3a. A sealed‐tube containing Qui
none (0.2 mmol), DTBP (0.6 mmol) and isopropanol (1 mL) was evac
uated and purged with Argon three times. The solution was kept at
140 oC for 2 h. After completion, the solution was cooled to room te
mpreture and concerntrated. The purification was performed by fla
sh column chromatography on silica gel using ethyl acetate/petrole
um ether (v/v, 1:50) as eluent to give the product as a pale yellow s
olid.
Scheme 2 Radical scavenger test.
Based on these results, a possible reaction mechanism was propose
d in Figure 3. At the beginning, the DTBP would transform to tert‐bu
tyloxy radical A, which abstracts hydrogen from alcohols to deliver
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2,6‐Di‐tert‐butyl‐4‐(2‐hydroxy‐2‐methyl‐1‐phenylpropyl) phen 54, 1021, 956, 849, 718 cm‐1; HRMS (EI) (m/z): calcd for C24H33ClO2
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DOI: 10.1039/C8OB00568K
ol (3a). Pale yellow solid; m.p. 89‐90 oC, yield: 76 %; Rf = 0.5 (EtOAc/ (M+): 388.2169; Found: 388.2169.
Petroleum ether 1:50); 1H NMR (CDCl3, 400 MHz), δ: 7.54 (d, J = 7.2
2, 6‐Di‐tert‐butyl‐4‐(1‐(2‐chlorophenyl)‐2‐hydroxy‐2‐methylpr
opyl) phenol (3g). Yellow solid; m.p. 134‐135 oC, yield: 62 %; Rf = 0.5
(EtOAc/Petroleum ether 1:50); 1H NMR (CDCl3, 400MHz), δ: 8.16 (d
d, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H), 7.32(dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H), 7.
26‐7.22 (m, 3H), 7.10 (td, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 5.07 (s, 1H), 4.
45 (s, 1H), 1.41 (s, 18H), 1.25 (s, 6H); 13C NMR (CDCl3, 150MHz), δ: 1
52.6, 140.6, 135.6，134.9, 130.7, 130.5, 129.7, 127.3, 126.8, 126.6,
Hz, 2H)，7.31‐7.25 (m, 4H), 7.19 (t, J = 7.2 Hz, 1H), 5.05 (s, 1H), 3.77
(s, 1H), 1.41 (s, 18H), 1.23 (s, 6H); 13C NMR (CDCl3, 150 MHz), δ: 152.
5, 142.8, 135.6, 132.0, 129.8, 128.3, 126.4, 126.3, 73.2, 63.0, 34.5, 3
0.5, 30.1, 29.2; IR (KBr) v: 3640, 2967, 2369, 1593, 1442, 1391, 1240,
1188, 1108, 1022, 941, 885, 809, 702 cm‐1; HRMS (EI) (m/z): calcd f
or C24H34O2 (M+): 354.2559; Found: 354.2556.
2,6‐Di‐tert‐butyl‐‐(2‐hydroxy‐2‐methyl‐1‐(p‐tolyl) propyl) phe 73.5, 56.0, 34.5, 30.9, 30.5, 28.7; IR (KBr) v: 3478, 2966, 2369, 1650,
nol (3b). Pale yellow solid; m.p. 93‐94 oC, yield: 78 %; Rf = 0.5 (EtOAc 1472, 1437, 1371, 1229, 1158, 1021, 946, 813, 763 cm‐1; HRMS (EI)
/Petroleum ether 1:50); 1H NMR (CDCl3, 400MHz), δ: 7.41 (d, J = 8.0 (m/z): calcd for C24H33ClO2 (M+): 388.2169; Found: 388.2169.
Hz, 2H), 7.25 (s, 2H), 7.09 (d, J = 8.0 Hz, 2H), 5.03 (s, 1H), 3.74 (s, 1H),
2.30 (s, 3H), 1.41(s, 18H), 1.22 (s, 6H); 13C NMR (CDCl3, 150MHz), δ:
2,6‐Di‐tert‐butyl‐4‐(2‐hydroxy‐1‐(3‐methoxyphenyl)‐2‐methyl
propyl) phenol (3h). Yellow oil; yield: 87 %; Rf = 0.5 (EtOAc/Petroleu
m ether 1:20); H NMR (CDCl3, 400MHz), δ: 7.27 (s, 2H), 7.25‐7.11
(m, 3H), 6.74 (dd, J1 = 8.0 Hz, J2 = 2.4 Hz, 1H), 5.05 (s, 1H), 3.79 (s, 3
H), 3.74 (s, 1H), 1.42 (s, 18H), 1.24 (s, 3H), 1.22 (s, 3H); 13C NMR (CD
Cl3, 150MHz), δ: 159.5, 152.5, 144.3, 135.5, 131.9, 129.2, 126.4, 122.
152.4, 139.7, 135.8, 135.5, 132.2, 129.6, 129.0, 126.3, 73.2, 62.7, 3
4.5, 30.5, 29.9, 29.2, 21.1; IR (KBr) v: 3625, 2967, 2359, 1508, 1437,
1366, 1239, 1143, 1142, 1032, 809, 718 cm‐1; HRMS (EI) (m/z): calcd
for C25H36O2 (M+): 368.2715; Found: 368.2710.
1
2,6‐Di‐tert‐butyl‐4‐(2‐hydroxy‐1‐(4‐methoxyphenyl)‐2‐me‐thy 3, 115.7, 111.7，73.2, 63.0，55.2, 34.5, 30.5, 30.0, 29.2; IR (film) v:
lpropyl) phenol (3c). Yellow solid; m.p. 97‐98 oC, yield: 83 %; Rf = 0. 3635, 2957, 2359, 1594, 1432, 1259, 1153, 1118, 1041, 951, 869, 8
5 (EtOAc/Petroleum ether 1:30); 1H NMR (CDCl3, 400MHz), δ: 7.45 08, 773 cm‐1; HRMS (EI) (m/z): calcd for C25H36O3 (M+): 384.2664; Fo
(d, J = 8.4 Hz, 2H), 7.24 (s, 2H), 6.84 (d, J = 8.8 Hz, 2H), 5.04 (s, 1H), 3. und: 384.2664.
78 (s, 3H), 3.73(s, 1H), 1.41(s, 18H), 1.22 (s, 6H); 13C NMR (CDCl3, 15
2,6‐Di‐tert‐butyl‐4‐(1‐(3,4‐dimethoxyphenyl)‐2‐hydroxy‐2‐me
thylpropyl) phenol (3i). Yellow oil, yield: 85 %; Rf = 0.3 (EtOAc/Petro
leum ether 1:10); 1H NMR (CDCl3, 400MHz), δ: 7.26 (s, 2H), 7.21 (s,
1H), 7.01 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 6.79(d, J = 8.4 Hz, 1H), 5.0
6 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.71(s, 1H), 1.42 (s, 18H), 1.24 (s,
0MHz), δ: 158.1, 152.4, 135.5, 135.0, 132.3, 130.7, 126.3, 113.7, 73.
3, 62.1, 55.3, 34.5, 30.5, 30.0, 29.1; IR (KBr) v: 3630, 2971, 2359, 16
04, 1502, 1442, 1285, 1123, 1032, 956, 839, 813 cm‐1; HRMS (EI) (m
/z): calcd for C25H36O3 (M+): 384.2664; Found: 384.2660 .
4‐(1‐(3,5‐Di‐tert‐butyl‐4‐hydroxyphenyl)‐2‐hydroxy‐2‐methylp 3H); 1.22（s, 3H）13C NMR (CDCl3, 150MHz), δ: 152.4, 148.6, 147.5,
ropyl) benzonitrile (3d). Yellow solid; m.p. 135‐136 oC, yield: 82 %;
135.5, 135.4, 132.1, 126.2, 122.0, 113.0, 111.0, 73.3, 62.3, 55.92, 5
Rf = 0.4 (EtOAc/Petroleum ether 1:50); 1H NMR (CDCl3, 400MHz), δ: 5.87, 34.5, 30.5, 30.0, 29.1; IR (film) v: 3640, 2952, 2363, 1589, 1512,
7.71 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.17 (s, 2H), 5.12 (s, 1 1431, 1260, 1143, 1123, 1026, 982, 823, 736 cm‐1; HRMS (EI) (m/z):
H), 3.79 (s, 1H), 1.41 (s, 18H), 1.23 (s, 3H), 1.21 (s, 3H); 13C NMR (CD calcd for C26H38O4 (M+): 414.2770; Found: 414.2775.
Cl3, 150MHz), δ:152.8, 148.6, 135.9, 132.0, 130.6, 126.3, 119.2, 110.
2,6‐Di‐tert‐butyl‐4‐(2‐hydroxy‐2‐methyl‐1‐(2,4,5‐trimetho‐xyp
1, 73.0, 62.6, 34.5, 30.5, 30.4, 29.1; IR (KBr) v: 3645, 2947, 2338, 22
23, 1599, 1508, 1371, 1239, 1123, 855, 809, 768 cm‐1; HRMS (EI) (m
/z): calcd for C25H33NO2 (M+): 379.2511; Found: 379.2510.
o
henyl) propyl) phenol (3j). Yellow solid, m.p. 130‐131 C, yield: 79
%; Rf = 0.5 (EtOAc/Petroleum ether 1:10); 1H NMR (CDCl3, 400MHz),
δ: 7.50 (s, 1H), 7.28 (s, 2H), 6.50 (s, 1H), 5.03 (s, 1H), 4,32 (s, 1H), 3.
4‐(1‐(3,5‐Di‐tert‐butyl‐4‐hydroxyphenyl)‐2‐hydroxy‐2‐methylp 86 (s, 6H), 3.77 (s, 3H), 1.41 (s, 18H), 1.22 (s, 3H), 1.21 (s, 3H); 13C N
ropyl) methylbenzoate (3e). Yellow solid; m.p. 119‐120 oC, yield: 87 MR (CDCl3, 150MHz), δ: 152.3, 151.4, 147.7, 143.0, 135.3, 132.3, 12
%; Rf = 0.3 (EtOAc/Petroleum ether 1:10); 1H NMR (CDCl3, 400MHz), 6.6, 123.4, 114.1, 98.3, 73.6, 57.1, 56.5, 56.1, 52.3, 34.4, 30.5, 30.2,
δ: 7.96 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.22 (s, 2H), 5.09 29.2; IR (KBr) v: 3604, 2971, 2379, 1604, 1518, 1462, 1326, 1219, 11
(s, 1H), 3.89 (s, 3H), 3.82 (s, 1H), 1.41 (s, 18H), 1.24 (s, 3H), 1.22 (s, 3 81, 1031, 940, 854, 819, 768 cm‐1; HRMS (EI) (m/z): calcd for C27H40
H); 13C NMR (CDCl3, 150MHz), δ: 167.3, 152.7, 148.4, 135.8, 131.0, 1 O5 (M+): 444.2876, Found: 444.2876.
29.9, 129.6, 128.1, 126.4, 73.1, 62.7, 52.1, 34.5, 30.5, 30.4, 29.0; IR
2,6‐Di‐tert‐butyl‐4‐(2‐hydroxy‐2‐methyl‐1‐(pyridin‐3‐ylpropyl)
phenol (3k). Yellow solid, m.p. 86‐87 oC, yield: 59 %; Rf = 0.5 (EtOAc
/Petroleum ether 1:100); 1H NMR (CDCl3, 400MHz), δ: 8.67 (s, 1H), 8.
42 (s, 1H), 8.05 (td, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 7.25‐7,23 (m, 1H), 7.
(KBr) v: 3630, 2946, 2374, 1715, 1604, 1442, 1371, 1285, 1118, 102
1, 869, 819 cm‐1; HRMS (EI) (m/z): calcd for C26H36O4 (M+): 412.2614;
Found: 412.2616.
2,6‐Di‐tert‐butyl‐4‐(1‐(4‐chlorophenyl)‐2‐hydroxy‐2‐methylpr 21 (s, 2H), 5.14 (s, 1H), 3.76 (s, 1H), 1.41 (s, 18H), 1.25 (s, 3H), 1.22
opyl) phenol (3f). Yellow solid; m.p. 107‐108 oC, yield: 80 %; Rf = 0.5 (s, 3H); 13C NMR (CDCl3, 150MHz), δ: 152.8, 151.0, 147.6, 137.0, 135.
(EtOAc/Petroleum ether 1:50); 1H NMR (CDCl3, 400MHz), δ: 7.49 (d, 9, 131.0, 126.3, 123.3, 73.2, 60.2, 34.5, 30.5, 30.4, 29.2; IR (KBr) v: 3
J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.20 (s, 2H), 5.08 (s, 1H), 3.73 645, 2941, 2369, 1731, 1599, 1437, 1366, 1254, 1067, 1026, 804, 74
(s, 1H), 1.41 (s, 18H), 1.22 (s, 6H); 13C NMR (CDCl3, 150MHz), δ: 152. 8 cm‐1; HRMS (EI) (m/z): calcd for C23H33NO2 (M+): 355.2511; Found:
6, 141.4, 135.7, 132.1, 131.4, 131.1, 128.4, 126.3, 73.1, 62.1, 34.5, 3 355.2518.
0.49, 30.47, 30.3, 29.0; IR (KBr) v: 3640, 2936, 2364, 1482, 1431, 12
4 | J. Name., 2012, 00, 1‐3
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2,6‐Di‐tert‐butyl‐4‐(2‐hydroxy‐2‐methyl‐1‐(thiophen‐2‐yl)‐pro 1:5); 1H NMR (CDCl3, 400MHz), δ: 741‐7.22 (m, 5H), 7.17 (s, 1H), 7.0
View Article Online
DOI: 10.1039/C8OB00568K
pyl) phenol (3l). Yellow oil, yield: 69 %; Rf = 0.5 (EtOAc/Petroleum e 5 (s, 1H), 5.12 and 5.07 (s, 1H), 4.41‐4.36 (m, 1H), 3.91 (q, 1H), 3.63‐
ther 1:50); 1H NMR (CDCl3, 400MHz), δ: 7.28 (s, 2H), 7.18 (d, J = 5.2 3.42 (m, 2H), 1.42 (s, 9H), 1.39 (s, 9H); 13C NMR (CDCl3, 150MHz), δ:
Hz, 1H), 7.02 (s, 1H), 6.96‐6.93 (m, 1H), 5.10 (s, 1H), 4.17 (s, 1H), 1.4 150.3 and 152.7, 142.0 and 141.6, 136.5 and 136.1, 131.8 and 131.2,
4 (s, 18H), 1.26 (s, 3H), 1.21 (s, 3H); 13C NMR (CDCl3, 150MHz), δ: 15 129.0 and 128.9, 128.8 and 128.2, 127.0 and 126.8, 125.1 and 124.
2.7, 144.6, 135.6, 131.2, 126.6, 126.2, 124.3, 73.1, 59.0, 34.5, 30.5, 7, 74.7 and 74.5, 65.1 and 64.7, 55.22 and 55.15, 34.53 and 34.47, 3
28.8, 28.6; IR (film) v: 3645, 2966, 2363, 1437, 1366, 1234, 1118, 10 0.4; IR (film) v: 3645, 2961, 2369, 1438, 1356, 1239, 1092, 1026, 885,
53, 1021, 950, 900, 803 cm‐1; HRMS (EI) (m/z): calcd for C22H32O2S
(M+): 360.2123; Found: 360.2125.
748 cm‐1; HRMS (EI) (m/z): calcd for C23H32O3 (M+): 356.2351; Foun
d: 356.2358.
2,6‐Di‐tert‐butyl‐4‐(2‐hydroxy‐2‐methyl‐1‐(naphthalen‐2‐yl) p
2,6‐Di‐tert‐butyl‐4‐(2‐hydroxy‐2‐methyl‐1‐phenylbutyl) pheno
ropyl) phenol (3m). Yellow solid, m.p. 143‐144 oC, yield: 59 %; Rf = 0. l (3r). Pale yellow oil, yield: 54 %; Rf = 0.5 (EtOAc/Petroleum ether 1:
4 (EtOAc/Petroleum ether 1:20); 1H NMR (CDCl3, 400MHz), δ: 8.29 50); 1H NMR (CDCl3, 400MHz), δ: 7.55 (m, 2H), 7.30‐7.26 (m, 4H), 7.
(d, J = 7.2 Hz, 1H), 8,21 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7,7 18 (t, J = 7.6 Hz, 1H), 5.04 (s, 1H), 3.78 and 3.77 (s, 1H), 1.51‐1.46 (m,
1 (d, J = 8.4 Hz, 1H), 7.50‐7.40 (m, 3H), 7.31 (s, 2H), 5.03 (s, 1H), 4.72 2H), 1.41 (s, 18H), 1.13 (s, 3H), 0.94‐0.87 (m, 3H); 13C NMR (CDCl3, 1
(s, 1H), 1.39 (s, 18H), 1.34 (s, 3H), 1.29 (s, 3H), 13C NMR (CDCl3, 150 50MHz), δ: 152.5 and 152.4, 142.9 and 142.6, 135.6, 132.0 and 131.
MHz), δ: 152.5, 138.8, 135.6, 134.3, 132.7, 131.4, 129.2, 126.8, 126. 8, 129.95 and 129.91, 128.3, 126.5 and 126.4, 126.3, 75.4 and 75.3,
6, 126.5,125.9, 125.1, 123.6, 73.7, 54.8, 34.5, 31.3, 30.5, 28.8; IR (KB 60.9 and 60.8, 34.5, 34.3 and 33.6, 30.53, 26.1 and 25.2, 8.8 and 8.7;
r) v: 3640, 2961, 2359, 2328, 1593, 1512, 1437, 1396, 1239, 1118, 9 IR (film) v: 3651, 2957, 2369, 1442, 1239, 1153, 1118, 900, 703 cm‐1;
45, 879, 804 cm‐1; HRMS (EI) (m/z): calcd for C28H36O2 (M+): 404.271 HRMS (EI) (m/z): calcd for C25H36O2 (M+): 368.2715; Found: 368.271
5; Found: 404.2715.
5.
2,6‐Di‐tert‐butyl‐4‐(2‐hydroxy‐1‐phenylethyl) phenol (3n). ello
2,6‐Di‐tert‐butyl‐4‐((1‐hydroxycyclopentyl) (phenyl)methyl) p
w solid, m.p.143‐144 oC, yield: 52 %; Rf = 0.5 (EtOAc/Petroleum ethe henol (3s). Pale yellow oil, yield: 53 %; Rf = 0.3 (EtOAc/Petroleum et
r 1:20); 1H NMR (CDCl3, 400MHz), δ: 7.33‐7.22 (m, 5H), 7,05 (s, 2H), her 1:50); 1H NMR (CDCl3, 400MHz), δ: 7.53 (d, J = 7.2 Hz, 2H), 7.30‐
5.11 (s, 1H), 4.12 (s, 1H), 1.41 (s, 18H), 13C NMR (CDCl3, 150MHz), δ: 7.26 (m, 2H), 7.24 (s, 2H), 7.19 (t, J = 7.2 Hz, 1H), 5.05 (s, 1H), 3.88 (s,
152.8, 142.0, 136.2,131.7，128.8, 128.4, 126.8, 124.9, 66.8, 54.0, 3 1H), 1.81‐1.61 (m, 8H), 1.40 (s, 18H); 13C NMR (CDCl3, 150MHz), δ:
4.5, 30.4; IR (KBr) v: 3650, 3012, 2961, 2895, 2369, 1659, 1599, 144 152.4, 143.2, 135.5, 132.5, 129.7, 128.3, 126.3, 126.1, 85.0, 61.4, 40.
2, 1396, 1265, 1122, 1037, 895, 844, 819 cm‐1; HRMS (EI) (m/z): calc 9, 39.7, 34.5，30.5，24.0, 23.9; IR (film) v: 3554, 2952, 2566, 2369,
d for C22H30O2 (M+): 326.2246; Found: 326.2249.
1999, 15834, 1452, 1371, 1234, 1031, 956, 889, 814, 773 cm‐1; HRM
S (EI) (m/z): calcd for C26H36O2 (M+): 380.2715; Found: 380.2710.
2,6‐Di‐tert‐butyl‐4‐(2‐hydroxy‐1‐phenylpropyl) phenol (3o). P
ale yellow oil, yield: 71 %; Rf = 0.5 (EtOAc/Petroleum ether 1:20); 1H
4‐(3,5‐Di‐tert‐butyl‐4‐hydroxyphenyl)‐3,3‐dimethylisochr‐om
NMR (CDCl3, 400MHz), δ: 7.39 (d, J = 7.2 Hz, 1H), 7.33‐7.19 (m, 4H), an‐1‐one (4a). Yellow solid, m.p. 161‐162 oC, yield: 42 %; Rf = 0.5 (Et
7.17 (s, 1H), 7.05 (s, 1H), 5.10 and 5.04 (s, 1H), 4.48‐4.44 (m, 1H), 3. OAc/Petroleum ether 1:20); 1H NMR (CDCl3, 400MHz), δ: 8.17 (d, J =
72‐3.66 (m, 1H), 1.42 (s, 9H), 1.40 (s, 9H), 1.17 (t, J = 6.4 Hz, 3H), 13
C
8.2 Hz, 1H), 7.50 (td, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H), 7.39 (t, J = 7.6 Hz,
NMR (CDCl3, 150MHz), δ: 152.9 and 152.5, 143.3 and 142.2, 136.7 a 1H), 7.18 (d, J = 7.6 Hz, 1H), 6.88 (s, 2H), 5.16 (s, 1H), 4.04 (s, 1H), 1.
nd 135.9, 131.9 and 128.9, 128.91 and 128.88, 128.7 and 128.2, 126. 45 (s, 3H), 1.39 (s, 18H), 1.25 (s, 3H); 13C NMR (CDCl3, 150MHz), δ: 1
8 and 126.5, 125.1 and 124.8, 70.8 and 70.5, 61.2 and 60.6, 34.53 a 65.5, 153.2, 142.3, 135.9, 134.1, 129.9, 128.9, 128.8, 127.5, 126.2, 1
nd 34.48, 30.47 and 30.43; IR (film) v: 3544, 2961, 2369, 1442, 1366, 24.9, 83.6, 53.9, 34.4, 30.4, 28.6, 25.5; IR (KBr) v: 3635, 3594, 2369,
1244, 1122, 1082, 1026, 748 cm‐1; HRMS (EI) (m/z): calcd for C23H32 1711, 1609, 1468, 1447, 1239, 1122, 1087, 950, 854, 809 cm‐1; HRM
O2 (M+): 340.2402; Found: 340.2400.
S (EI) (m/z): calcd for C25H32O3 (M+): 380.2351; Found: 380.2351.
2,6‐Di‐tert‐butyl‐4‐(2‐hydroxy‐1‐phenylbutyl) phenol (3p). Pal
4‐(3,5‐Di‐tert‐butyl‐4‐hydroxyphenyl)‐3‐methylisochroma‐n‐1
e yellow oil, yield: 51 %; Rf = 0.3 (EtOAc/Petroleum ether 1:20); 1H N ‐one (4b). Yellow solid, m.p. 127‐128 oC, yield: 22 %; Rf = 0.5 (EtOAc
MR (CDCl3, 400MHz), δ: 7.40 (d, J = 7.2 Hz, 1H), 7.30‐7.21 (m, 4H), 7. /Petroleum ether 1:20); 1H NMR (CDCl3, 400MHz), δ: 8.16 (dd, J1 = 7.
16 (s, 1H ), 7.07 (s, 1H), 5.09 and 5.05 (s, 1H), 4.20‐4.18 (m, 1H), 3.8 6 Hz, J2 = 1.6 Hz, 1H), 7.47 (td, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H), 7.39 (t, J =
1‐3.70 (m, 1H), 1.62‐ 1.57 (m, 2H), 1.41 (s, 18H), 0.97 (t, J =7.2 Hz, 3
7.6 Hz, 1H), 6.91‐6.89 (m, 3H), 5.21 (s, 1H), 4.78‐4.74 (m, 1H), 3.96
H); 13C NMR (CDCl3, 150MHz), δ: 152.9 and 152.4, 143.3 and 141.1, (d, J = 9.6 Hz, 1H), 1.41 (s, 18H), 1.29‐1.23 (m, 3H); 13C NMR (CDCl3,
136.3 and 135.9, 133.1 and 131.9, 129.1 and 128.8, 128.7 and 128.3, 150MHz), δ: 165.5, 153.4, 143.7, 136.7, 133.8, 130.2, 129.2, 127.9,
126.7 and 126.4, 125.2 and 124.8, 75.9 and 75.4, 59.3 and 58.3, 34. 127.6, 125.6, 125.1, 80.0, 50.6, 34.5, 30.5, 30.3, 20.0; IR (KBr) v: 365
52 and 34.48, 30.5 and 30.4, 27.9 and 27.8, 10.4 and 10.3; IR (film) v: 2, 3445, 2956, 2369, 1711, 1604, 1431, 1361, 1290, 1123, 1057, 966,
3645, 2961, 2369, 1497, 1442, 1361, 1239, 1118, 966, 763, 702 cm‐ 879, 804, 758 cm‐1; HRMS (EI) (m/z): calcd for C24H30O3 (M+): 366.21
1; HRMS (EI) (m/z): calcd for C24H34O2 (M+): 354.2559; Found: 354.25 95; Found: 366.2193.
56.
Radical scavenger test. A sealed‐tube containing 1a (0.2 mmol), DT
3‐(3,5‐Di‐tert‐butyl‐4‐hydroxyphenyl)‐3‐phenylpropane‐1,2‐di BP (0.6 mmol), TEMPO (0.4 mmol) and 2a (1 mL) was evacuated and
ol (3q). Pale yellow oil, yield: 72 %; Rf = 0.3 (EtOAc/Petroleum ether
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purged with Argon three times. The solution was kept at 140 oC for 17 Y. Shen, J. Qi, Z. Mao, S. Cui, Org. Lett. 2016, 18, 27V2i2ew. Article Online
DOI: 10.1039/C8OB00568K
2 h. And the product (3a) was not observed.
18 CCDC 1490040.
19 (a) W. Chu, L. Zhang, X. Bao, X. Zhao, C. Zeng, J. Du, G. Zhang, F.
Wang, X. Ma, C. Fan, Angew, Chem. Int. Ed. 2013, 52, 9229. (b)
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Chem. 2009, 19, 3203.
Conflicts of interest
There are no conflicts to declare
Acknowledgements
We acknowledge for the financial support from NSFC (21472163).
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