Atom-Transfer Radical Addition of Alcohols to Aliphatic Alkynes

Article abstract of DOI:10.1021/acs.joc.9b00804

An intermolecular hydrogen bond-promoted atom-transfer radical addition of simple alcohols to aliphatic alkynes is demonstrated here. Through this strategy, a variety of allyl alcohols can be synthesized in high selectivity and yields. Furthermore, this work reveals the relationship between selectivity and the substrate. ?

Full text of DOI:10.1021/acs.joc.9b00804

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Article
An Atom-Transfer Radical Addition of Alcohol to Aliphatic Alkyne
Yingxia Xiao, and Zhong-Quan Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00804 • Publication Date (Web): 05 Jul 2019
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An Atom-Transfer Radical Addition of Alcohol to Aliphatic Alkyne
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Yingxia Xiao † and Zhong-Quan Liu* †‡
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† State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
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‡ State Key Laboratory Cultivation Base for TCM Quality and Efficacy, College of Pharmacy, Nanjing
University of Chinese Medicine, Nanjing 210023, China
R1
HO
R2
HO
HO
5 mol% KF
OH
H
H
2 eq TBPA
130 C, 3 h
H
H
+
R1 R2
H
H
H
H
O
O
aliphatic alkynes
over 30 examples
scaled up to grams
transition-metal free
yields up to 96%
E/Z up to 20/1
Abstract: An intermolecular hydrogen bond promoted atom-transfer radical addition
of simple alcohol to aliphatic alkyne is demonstrated here. Through this strategy, a
variety of allyl alcohols can be synthesized in high selectivity and yields. Furthermore,
this work reveals the relationship between the selectivity and the substrate.
INTRODUCTION
The construction of a C-C bond by selective cleavage of the α-hydroxy (sp3)C-H
bond in simple aliphatic alcohol is attractive and valuable for organic synthesis.1 In
the past decades, a series of efficient C-C forming methods via atom-transfer radical
addition (ATRA) of alcohols with alkenes have been successfully achieved by Tu,2
Liu,3 Han and Pan4 et al.5 However, ATRA reaction of alcohols with alkynes to
produce allylic alcohols has rarely been investigated. In 2009, a first Ru-catalyzed
alkenylation of alcohols using alkynes was developed by Krische et al.6 Subsequently,
Liu et al. reported an ATRA of simple alcohols and ethers to aryl alkyne in the same
year.3a Nevertheless, there are limitations in both systems. For example, only aryl
alkynes could be amenable to Liu’s system. In addition, the allyl alcohols were
obtained in mixed isomers (E/Z ≈ 1/1). And Krische’s work was limited in primary
alcohols. Hence, efficient strategy for alkenylation of alcohol is highly desirable.
Herein we demonstrated an effective ATRA reaction of simple alcohols with aliphatic
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alkynes (Scheme 1).
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previous works
R1 R2
OH
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OH
R1 R2
TBHP
120 C, 15 h
+
Ar
Liu 2009
Ar
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R1
OH
R'
cat. Ru(O2CCF3)2(CO)(PPh3)2
+
R1
Krische 2009
R
OH
R
200 mol% isopropanol
THF, 95 oC, 9-37 h
R'
this work
aliphatic alkynes
over 30 examples
yields up to 96%
E/Z up to 20/1
5 mol% KF
R1 R2
OH
2 eq TBPA
130 C, 3 h
+
R1 R2
R
R
OH
Scheme 1. Alkenylation of alcohols with alkynes.
RESULTS AND DISCUSSION
As shown in Scheme 2, the rate-determining step (RDS) in this conversion should
be the hydrogen-atom transfer (HAT) from alcohol to the alkenyl radical B and then
regenerating radical A. It might be energetically unfavorable for cleavage of a
relatively strong (sp3)C-H bond (BDE > 91 kcal/mol)(path I).7 Inspired by our
previous resolution for the ATRA of simple alcohol to unactivated alkene,8 we began
to wonder whether an hydrogen-bond donor could facilitate the HAT process. Since
the hydrogen bond (RO-H...A) might strengthen the n-σ*C-H delocalization,9 and thus
the α-hydroxy (sp3)C-H would be weakened. Subsequently the path II would be
favorable to afford the allyl alcohol.
H
R
H
ROOR
+
R1
OH
R1
R
OH
Additive
path II
RDS
hydrogen-bond
R
OH
OH
A
HAT
path I
X
H
R
O
A
R
O
A
acceptor ( )
H
H
or
R
H
R
H
A
R
OH
R1
OH
strengthen
C-H delocalization
A
B
n-
weaken BDE C-H
Scheme 2. Possible resolution by addition of hydrogen-bond acceptors.
In order to evaluate the hypothesis, a set of experiments were carried out. Initially,
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the 2-phenyl-3-butyn-2-ol and ethanol were chosen as the model substrates to
optimize suitable conditions for this reaction (Table 1). Without any additives, no
reaction occurred by using TBPB as the initiator (entry 1). But the desired product
9

was obtained in 38% yield with DTBP at 130 C (entry 2). It is noteworthy that only
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E allylic product was observed. To our delight, the catalytic amount of KF (from 1
mol% to 20 mol%) could dramatically facilitate this reaction (entries 3-10). With 5
mol% KF, 2 equiv. of TBPA afforded the desired product in nearly quantitative yields
(entry 6). The product was isolated in 70% yield even with 1 mol% KF (entry 10).
Table 1. Optimization of the radical addition of alcohols to alkynes a
OH
OH
additive
peroxide
OH
OH
+
Peroxide
Additive
(mol%)
-
Yield b
(%)
-
Temp. (C)
Entry
Sol. (mL)
(equiv)
1
2
TBPB (3)
DTBP (2)
DTBP (2)
TBPB (3)
TBPA (3)
TBPA (2)
TBPA (1)
TBPA (2)
TBPA (2)
TBPA (2)
130
130
130
130
130
130
130
120
130
130
5
5
-
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3
KF (20)
KF (20)
KF (20)
KF (5)
KF (5)
KF (5)
KF (5)
KF (1)
5
87
4
5
67
5
5
91
6
5
96
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5
75
8
5
53
9
3
80
10c
25
70
a
Reaction conditions: Alkynes (1 equiv., 0.20 mmol), ethanol as solvent, sealed tube, 3 h, unless
b
c
otherwise noted. Isolated yield. Alkynes (1 equiv., 1.0 mmol). TBPB = tert-butyl peroxybenzoate;
DTBP = Di-tert-butyl peroxide; TBPA = tert-butyl peroxyacetate.
Next we began to evaluate the substrate scope under the typical conditions (Scheme
3). A wide range of alkynes afforded the desired allyl alcohols in good to excellent
yields (1-20). Aryl halides such as fluorine, chlorine and iodine as well as heteroarene
can be well tolerated in the system (3-6). Simple cyclic and acyclic alkyl alkynes were
effective substrates (7-9). Furthermore, amide was also compatible with this system
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(10). Gratifyingly, alkynes with complex natural product motif also gave the desired
compound in good yield (11). It is noteworthy that only E-allyl alcohols were
observed in these substrates (1-11). Why is the selectivity so high? Whether is it
related to the size of vicinal substituent on the triple bond? Then we examined other
type of alkynes (12-20). The 1-phenylprop-2-yn-1-ol afforded a mixture of isomers
with E/Z = 4.5/1 (12). But only E-product was isolated with 1-phenylprop-2-yn-1-yl
acetate (13). In addition, substituents with different size of groups were screened
(14-20). As a result, the approximate trend is that the larger substituent on triple bond
is, the higher selectivity would be obtained. As a comparison, several randomly
chosen examples demonstrated that KF facilitates this reaction (9 and 20).
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Scheme 3. Examine the scope of unactivated alkynes a
5 mol% KF
2 eq TBPA
R1 R2
OH
OH
+
R1 R2
R
R
130 C, 3 h
OH
Ph OH
OH
OH
OH
OH
OH
OH
OH
OH
Cl
F
b
1
5
92%
OH
3
2
6
87%
86%
OH
4
66%
HO
OH
N
OH
OH
5
I
8
71%
72%
7
88%
HO
54%
OH
OH
OH
O
OH
OH
OH
H
N
H
H
H
d
c
10
12
91%
OH
63% E/Z = 4.5:1
9
83% (49% )
O
11
52%
OH
OH
OAc
OH
OH
OH
N
Boc
16
75%, E/Z = 3:1
15
69%, E/Z = 2:1
13
60%
14
58%, E/Z = 3:1
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O
OH
OH
OH
Cl
OH
3
O
OH
HO
18
c
19
81%, E/Z = 2.7:1
71%, E/Z = 2.3:1
20
17
71%, E/Z = 1.4:1
75% (49% ), E/Z = 2:1
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a Reaction conditions: Alkynes (1 equiv., 0.20 mmol), KF (0.6 mg, 5 mol%, 0.01 mmol), TBPA (53 mg,
2 equiv., 0.40 mmol), 5 mL of alcohol as solvent, sealed tube, 130 C (measured temperature of the oil
b
c
bath), 3 h, unless otherwise noted. Isolated yield. Isolated yield without KF. d The ratio of the E/Z
isomers was determined by crude 1 H NMR.
Then we tested a series of alcohols, and we found that diverse primary and
secondary alcohols as well as diol were amenable to this system (Scheme 4). Both
linear and cyclic alcohols were effective substrates (21-29). Glycol also gave the
expected product in 25% yield (29). Furthermore we found that this reaction could be
scaled up to gram level without decreasing efficiency. For example, reaction of
1,1-diphenylprop-2-yn-1-ol (1.04 g, 5 mmol) with ethanol produced the
corresponding product (E)-1,1-diphenylpent-2-ene-1,4-diol (30) in 87% yield.
Scheme 4. Scope of alcohols.a
5 mol% KF
2 eq TBPA
R1 R2
OH
OH
+
R1 R2
R
R
130 C, 3 h
HO
HO
HO
OH
OH
OH
b
22
64%
23
89%
21
24
96%
HO
HO
HO
3
HO
OH
OH
26
25
53%
25%
81%
69%
HO
HO
HO
OH
OH
OH
OH
28
27
78%
59%
29
a Typical reaction conditions. b Isolated yield.
Finally, a series of experiments were carried out to verify the mechanism we
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proposed previously (Scheme 5). Firstly, kinetic isotope effect experiments were
conducted. The results showed that it should be a primary isotope effect (kH/kD = 7.0),
which suggested that the cleavage of C-H bond might be involved in the RDS (eq. 1).
Ultimately, an isotopic tracer experiment further confirmed that it should be a typical
ATRA process (eq. 2).
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Scheme 5. Mechanistic studies.
HO
OH
CH3OH
(2.5 mL)
HO
typical reaction
conditions
H
eq (1)
HO
CD3OD
kH/kD = 7.0
OD
D D
(2.5 mL)
H
HO
HO
typical reaction
conditions
OD
eq (2)
CD3OD
D D
D
31
44%
CONCLUSIONS
In summary, we have developed herein a metal-free ATRA reaction of simple
alcohols with aliphatic alkynes. By addition of 5 mol% of KF, a wide range of allylic
alcohols can be facilely synthesized via intermolecular H-bonding. Additionally, this
work revealed that the E/Z selectivity in this type of reaction is not related to alcohol
but the size of substituent on the triple bond. The more sterically crowded alkyne is,
the higher selectivity will be. Hence this method is expected to have wide applications
in material science and medicinal chemistry community.
EXPERIMENTAL SECTION
General Information: All chemicals were commercially available and used as
received without further purification. Reactions were monitored by thin-layer
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chromatography (TLC). H NMR, C NMR, and F NMR spectra were recorded at
400, 100, and 375 MHz, respectively. Mass spectra were determined on a Hewlett
Packard 5988A spectrometer by direct inlet at 70 eV. High-resolution mass spectral
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analysis (HRMS) data were measured on a Bruker Apex II with a Q-TOF detector. All
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products were identified by H and C NMR, MS or HRMS. The starting materials
were purchased from Energy chemistry, Aldrich, Acros Organics, J&K Chemicals or
TCI and used without further purification. Chemical shifts (δ) are given relative to
internal TMS. The NMR data are presented as follows: chemical shift (ppm),
multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, br = broad), coupling
constant J (Hz), and integration.
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Typical Experimental Procedure for the Synthesis of 1-31.
A mixture of alkynes (1 equiv., 0.20 mmol), alcohols (5 mL), KF (0.6 mg, 5 mol%,

0.01 mmol), and TBPA (53 mg, 2 equiv., 0.40 mmol) was heated at 130 C (the
measured temperature of the oil bath) for 3 h in a sealed tube (35 mL). After the
reaction finished, the mixture was evaporated under vacuum and purified by column
chromatography to afford the desired product.
A scaled-up experimental procedure: A mixture of 1,1-diphenylprop-2-yn-1-ol
(1.04 g, 1 equiv., 5.0 mmol), ethanol (125 mL), KF (14.5 mg, 5 mol%, 0.25 mmol),

and TBPA (1.32 g, 2 equiv., 10.0 mmol) was heated at 130 C (the measured
temperature of the oil bath) for 3 h in a sealed tube (300 mL). After the reaction
finished, the mixture was evaporated under vacuum and purified by column
chromatography
to
afford
the
desired
product
(30,
(E)-1,1-diphenylpent-2-ene-1,4-diol, 1.04 g, isolated yield: 87%).
(E)-4-phenylpent-2-ene-1,4-diol10 (1). A colorless liquid after purification by flash
1
column chromatography (petroleum ether/ethyl acetate = 1/1, 32.7 mg, 92%). H
NMR (400 MHz, CDCl3) δ 7.47 (m, 2H), 7.35 (m, 2H), 7.26 (m, 1H), 6.04 (dt, J =
15.6, 1.2 Hz, 1H), 5.88 (dt, J = 15.6, 5.2 Hz, 1H), 4.19 (dd, J = 5.2, 1.3 Hz, 2H), 1.98
(s, 1H), 1.68 (s, 3H), 1.26 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 146.5, 138.2,
128.3, 127.2, 127.0, 125.1, 74.2, 63.0, 29.7. MS(EI): m/z(%): 178(0.05), 160(10.8),
147(67.4), 117(100.0), 43(50.1).
(E)-1,1-diphenylbut-2-ene-1,4-diol (2). A colorless liquid after purification by
flash column chromatography (petroleum ether/ethyl acetate = 2/1, 41.3 mg, 86%). 1H
NMR (400 MHz, CDCl3) δ 7.31 – 7.17 (m, 10H), 6.30 (dt, J = 15.6, 1.6 Hz, 1H), 5.81
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(dt, J = 15.6, 5.2 Hz, 1H), 4.16 (dd, J = 5.2, 1.2 Hz, 2H), 2.35 (s, 1H), 1.52 (s, 1H).
13C{1H} NMR (101 MHz, CDCl3) δ 145.9, 136.6, 128.9, 128.2, 127.3, 126.8, 78.8,
63.0. HRMS (ESI, m/z): Calculated for C16H17O2 (M+H)+ 241.1233, found 241.1231.
(E)-4-(2-fluorophenyl)pent-2-ene-1,4-diol (3). A colorless liquid after purification
by flash column chromatography (petroleum ether/ethyl acetate = 1/1, 34.1 mg, 87%).
1H NMR (400 MHz, CDCl3) δ 7.55 (t, J = 8.0 Hz, 1H), 7.28 – 7.22 (m, 1H), 7.13 (t, J
= 7.6 Hz, 1H), 7.01 (dd, J = 12.0, 8.0 Hz, 1H), 6.13 (d, J = 15.6 Hz, 1H), 5.81 (dt, J =
15.6, 5.2 Hz, 1H), 4.15 (d, J = 5.2 Hz, 2H), 2.52 (s, 1H), 1.87 (s, 1H), 1.71 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 161.1, 158.7, 136.9, 136.8, 133.3, 133.2, 129.0,
128.9, 127.5, 126.8, 126.7, 124.1, 124.0, 116.2, 115.9, 73.1, 73.0, 62.9, 28.5, 28.5. 19F
NMR (376 MHz, CDCl3) δ -112.05, -112.08, -112.10, -112.12. HRMS (ESI, m/z):
Calculated for C11H14FO2 (M+H)+ 197.0972, found 197.0975.
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(E)-4-(2-chlorophenyl)pent-2-ene-1,4-diol (4). A colorless liquid after purification
by flash column chromatography (petroleum ether/ethyl acetate = 1/1, 30.0 mg, 66%).
1H NMR (400 MHz, CDCl3) δ 7.69 (dd, J = 7.8, 1.6 Hz, 1H), 7.34 (dd, J = 7.8, 1.6 Hz,
1H), 7.29 – 7.25 (m, 1H), 7.21 (td, J = 7.6, 1.6 Hz, 1H), 6.15 (dt, J = 15.6, 1.6 Hz,
1H), 5.76 (dt, J = 15.6, 5.4 Hz, 1H), 4.17 (dd, J = 5.4, 1.6 Hz, 2H), 2.95 (s, 1H), 1.78
(s, 3H), 1.75 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 142.9, 136.8, 131.7, 131.2,
128.6, 128.6, 127.4, 126.9, 74.4, 63.0, 27.9. HRMS (ESI, m/z): Calculated for
C11H14ClO2 (M+H)+ 213.0677, found 213.0675.
(E)-4-(2-iodophenyl)pent-2-ene-1,4-diol (5). A colorless liquid after purification
by flash column chromatography (petroleum ether/ethyl acetate = 1/1, 32.8 mg, 54%).
1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 7.8
Hz, 1H), 7.05 (t, J = 7.8 Hz, 1H), 5.96 (d, J = 15.6 Hz, 1H), 5.84 (dt, J = 15.6, 7.8 Hz,
13
1H), 4.14 (dd, J = 5.2, 1.2 Hz, 2H), 2.39 (s, 1H), 2.28 (s, 1H), 1.61 (s, 3H). C{1H}
NMR (101 MHz, CDCl3) δ 149.0, 137.4, 136.0, 134.2, 130.0, 127.7, 124.5, 94.42,
73.7, 62.7, 29.7. HRMS (ESI, m/z): Calculated for C11H14IO2 (M+H)+ 305.0033,
found 305.0032.
(E)-2-(pyridin-2-yl)hex-3-ene-2,5-diol (6). A colorless solid after purification by
flash column chromatography (petroleum ether/ethyl acetate = 1/2, 27.8 mg, 72%). 1H
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NMR (400 MHz, CDCl3) δ 8.34 (dd, J = 5.6, 4.4 Hz, 2H), 7.30 (dd, J = 5.6, 1.2 Hz,
2H), 5.89 (d, J = 15.6 Hz, 1H), 5.77 (ddd, J = 15.6, 7.6, 5.6 Hz, 1H), 4.31 (p, J = 6.4
Hz, 1H), 3.80 (s, 2H), 1.58 (d, J = 1.2 Hz, 3H), 1.24 (dd, J = 6.4, 2.4 Hz, 4H). 13C{1H}
NMR (75 MHz, CDCl3) δ 156.9, 148.7, 134.6, 133.4, 120.6, 73.1, 67.6, 29.19, 23.27.
HRMS (ESI, m/z): Calculated for C11H16NO2 (M+H)+ 194.1176, found 194.1175.
(E)-2-methylhex-3-ene-2,5-diol (7). A colorless liquid after purification by flash
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column chromatography (petroleum ether/ethyl acetate = 1/1, 20.4 mg, 88%). H
NMR (400 MHz, CDCl3) δ 5.85 (d, J = 15.6 Hz, 1H), 5.79 (dd, J = 15.6, 4.4 Hz, 1H),
4.14 (d, J = 4.4 Hz, 2H), 2.05 (s, 1H), 2.03 (s, 1H), 1.32 (s, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ 139.4, 125.8, 70.5, 63.0, 29.6. HRMS (ESI, m/z): Calculated for
C6H13O2 (M+H)+ 117.0910, found 117.0912.
(E)-4-methyldec-2-ene-1,4-diol (8). A colorless liquid after purification by flash
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column chromatography (petroleum ether/ethyl acetate = 1/1, 18.5 mg, 71%). H
NMR (400 MHz, CDCl3) δ 5.88 – 5.80 (m, 1H), 5.78 (d, J = 15.6 Hz, 1H), 4.18 (d, J
= 4.4 Hz, 2H), 1.53 (m, 2H), 1.44 (s, 1H), 1.28 (m, 11H), 0.88 (t, J = 6.4 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 138.7, 126.4, 72.7, 63.2, 42.7, 31.8, 29.7, 27.9,
23.9, 22.6, 14.0. HRMS (ESI, m/z): Calculated for C11H23O2 (M+H)+ 187.1693, found
187.1694.
(E)-1-(3-hydroxyprop-1-en-1-yl)cyclohexan-1-ol (9). A colorless liquid after
purification by flash column chromatography (petroleum ether/ethyl acetate = 2/1,
25.9 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 5.87 (dd, J = 15.6, 4.4 Hz, 1H), 5.81 (d,
J = 15.6 Hz, 1H), 4.15 (d, J = 4.0 Hz, 2H), 1.81 (s, 2H), 1.63 – 1.24 (m, 10H). 13C{1H}
NMR (101 MHz, CDCl3) δ 139.3, 126.5, 71.2, 63.2, 37.8, 25.4, 22.0. HRMS (ESI,
m/z): Calculated for C9H17O2 (M+H)+157.1223, found 157.1224.
(E)-N-(5-hydroxy-2-methylpent-3-en-2-yl)acetamide (10). A colorless liquid after
purification by flash column chromatography (petroleum ether/ethyl acetate = 1/1,
28.6 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 5.88 (d, J = 15.6 Hz, 1H), 5.69 (dt, J =
15.6, 5.6 Hz, 2H), 4.12 (dd, J = 5.6, 0.8 Hz, 2H), 2.80 (s, 1H), 1.93 (s, 3H), 1.42 (s,
6H). 13C{1H} NMR (101 MHz, CDCl3) δ 139.4, 125.8, 70.5, 63.0, 29.6. HRMS (ESI,
m/z): Calculated for C8H16NO2 (M+H)+ 158.1176, found 158.1174.
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(8R,9S,10R,13S,14S,17R)-17-hydroxy-17-((E)-3-hydroxyprop-1-en-1-yl)-10,13-di
methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenan
thren-3-one (11). A white solid after purification by flash column chromatography
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(petroleum ether/ethyl acetate = 1/2, 34.7mg, 53%). H NMR (400 MHz, CDCl3) δ
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5.89 (d, J = 15.6 Hz, 1H), 5.77 (dt, J = 15.6, 5.2 Hz, 1H), 5.72 (s, 1H), 4.25 – 4.15 (m,
2H), 2.43 – 2.24 (m, 4H), 2.03 – 1.94 (m, 2H), 1.86 (m, 2H), 1.68 – 1.47 (m, 6H),
1.43 – 1.35 (m, 2H), 1.25 – 1.20 (m, 2H), 1.18 (s, 3H), 0.95 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 199.5, 171.2, 136.1, 127.1, 123.8, 83.3, 63.2, 53.6, 49.6, 46.4,
38.6, 36.6, 36.3, 35.7, 33.9, 32.8, 32.0, 31.6, 23.4, 20.6, 17.4, 14.0. HRMS (ESI, m/z):
Calculated for C22H33O3 (M+H)+ 345.2424, found 345.2423
(E)-4-methyl-1-phenylpent-2-ene-1,4-diol (12). A colorless liquid after purification
by flash column chromatography (petroleum ether/ethyl acetate = 1/1, 19.8 mg, 51%).
1H NMR (400 MHz, CDCl3) δ 7.38 – 7.26 (m, 5H), 5.94 (d, J = 15.6 Hz, 1H), 5.86
(dd, J = 15.6, 6.0 Hz, 1H), 5.21 (d, J = 6.0 Hz, 1H), 2.04 (s, 1H), 1.33 (d, J = 1.6 Hz,
6H), 1.25 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 142.9, 139.1, 129.0, 128.6,
127.7, 126.2, 74.6, 70.6, 29.7. HRMS (ESI, m/z): Calculated for C12H17O2 (M+H)+
193.1223, found 193.1223.
(E)-4-hydroxy-4-methyl-1-phenylpent-2-en-1-yl acetate (13). A colorless liquid
after purification by flash column chromatography (petroleum ether/ethyl acetate =
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2/1, 28.1 mg, 60%). H NMR (400 MHz, CDCl3) δ 7.41 – 7.31 (m, 5H), 6.27 (d, J =
4.7 Hz, 1H), 5.88 (d, J = 15.6 Hz, 1H), 5.83 (dd, J = 15.6, 4.8 Hz, 1H), 2.10 (s, 3H),
1.31 (d, J = 4.4 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.9, 140.9, 139.3,
128.5, 128.1, 127.0, 125.2, 75.6, 70.5, 29.6, 21.3. HRMS (ESI, m/z): Calculated for
C14H19O3 (M+H)+ 235.1329, found 235.1328
(Z)-5-methyl-1-phenylhex-3-ene-1,5-diol (14’). A colorless liquid after purification
by flash column chromatography (petroleum ether/ethyl acetate = 1/1, 4.5 mg, 14.5%).
1H NMR (400 MHz, CDCl3) δ 7.37 – 7.29 (m, 4H), 7.27 – 7.24 (m, 1H), 5.64 (d, J =
12.0 Hz, 1H), 5.37 (ddd, J = 12.0, 9.2, 7.6 Hz, 1H), 4.73 (dd, J = 8.4, 3.6 Hz, 1H),
3.01 – 2.94 (m, 1H), 2.80 (s, 1H), 2.62 – 2.55 (m, 1H), 1.33 (d, J = 2.0 Hz, 6H), 1.23
(s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 144.4, 140.1, 128.4, 127.4, 125.7, 124.8,
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73.1, 72.0, 37.3, 32.0, 31.2. HRMS (ESI, m/z): Calculated for C13H19O2 (M+H)+
207.1038, found 207.1036.
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(E)-5-methyl-1-phenylhex-3-ene-1,5-diol (14). A colorless liquid after purification
by flash column chromatography (petroleum ether/ethyl acetate = 1/1, 17.9 mg,
43.5%). 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.29 (m, 4H), 7.26 – 7.22 (m, 1H), 5.68
(d, J = 15.6 Hz, 1H), 5.60 (dt, J = 15.6, 6.4 Hz, 1H), 4.68 (dd, J = 7.2, 5.6 Hz, 1H),
2.46 – 2.38 (m, 2H), 2.19 (d, J = 6.8 Hz, 1H), 1.69 (s, 1H), 1.26 (s, 6H). 13C{1H}
NMR (101 MHz, CDCl3) δ 143.9, 141.9, 128.4, 127.5, 125.8, 122.6, 73.7, 70.6, 42.1,
29.8, 29.7. HRMS (ESI, m/z): Calculated for C13H19O2 (M+H)+ 207.1038, found
207.1037.
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tert-butyl (E)-4-(3-hydroxy-3-methylbut-1-en-1-yl)piperidine-1-carboxylate (15’).
A colorless liquid after purification by flash column chromatography (petroleum
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ether/ethyl acetate = 1/1, 12.4 mg, 23%). H NMR (400 MHz, CDCl3) δ 5.44 (d, J =
12.0 Hz, 1H), 5.1 (t, J = 6.4 Hz,1H), 4.07 (s, 2H), 3.02 (dt, J = 15.0, 11.2 Hz, 1H),
2.73 (s, 2H), 1.60 (d, J = 10.4 Hz, 2H), 1.45 (s, 9H), 1.37 (s, 6H), 1.22 (dd, J = 13.6,
5.3 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 154.8, 136.0, 135.2, 79.3, 71.7,
43.23, 34.9, 32.3, 31.6, 28.5. HRMS (ESI, m/z): Calculated for C15H28NO3 (M+H)+
270.2064, found 270.2062
tert-butyl (E)-4-(3-hydroxy-3-methylbut-1-en-1-yl)piperidine-1-carboxylate (15).
A colorless liquid after purification by flash column chromatography (petroleum
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ether/ethyl acetate = 1/1, 24.8 mg, 46%). H NMR (400 MHz, CDCl3) δ 5.59 (d, J =
15.6 Hz, 1H), 5.54 (d, J = 15.6 Hz, J = 6.4 Hz, 1H), 4.07 (s, 2H), 2.71 (t, J = 11.6 Hz,
2H), 2.12 – 2.01 (m, 1H), 1.64 (d, J = 12.8 Hz, 2H), 1.58 (d, J = 10.7 Hz, 1H), 1.44 (s,
9H), 1.28 (s, 6H), 1.27 – 1.20 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 154.8,
136.6, 130.8, 79.3, 70.5, 43.9, 38.4, 31.8, 29.8, 28.4. HRMS (ESI, m/z): Calculated
for C15H28NO3 (M+H)+ 270.2064, found 270.2065.
(Z)-2,6,6-trimethylhept-3-ene-2,5-diol (16’). A colorless liquid after purification by
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flash column chromatography (petroleum ether/ethyl acetate = 1/1, 6.5 mg, 19%). H
NMR (400 MHz, CDCl3) δ 5.62 (dd, J = 12.4, 1.2 Hz, 1H), 5.50 (dd, J = 12.4, 6.8 Hz,
1H), 4.40 (dd, J = 6.8, 1.2 Hz, 1H), 2.93 (s, 1H), 1.39 (d, J = 4.2 Hz, 6H), 1.25 (s, 1H),
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0.94 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 140.3, 126.3, 80.2, 70.5, 34.8, 29.8,
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25.5.
HRMS (ESI, m/z): Calculated for C10H21O2 (M+H)+ 173.1536, found
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173.1537.
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(E)-2,6,6-trimethylhept-3-ene-2,5-diol (16). A colorless liquid after purification by
flash column chromatography (petroleum ether/ethyl acetate = 1/1, 19.4 mg, 56%). 1H
NMR (400 MHz, CDCl3) δ 5.82 (d, J = 15.6 Hz, 1H), 5.73 (dd, J = 15.6, 6.8 Hz, 1H),
3.75 (d, J = 6.8 Hz, 1H), 1.51 (s, 1H), 1.49 (s, 1H), 1.33 (s, 6H), 0.90 (s, 9H). 13C{1H}
NMR (101 MHz, CDCl3) δ 140.5, 126.4, 80.4, 70.7, 35.0, 29.9, 29.8, 25.6. HRMS
(ESI, m/z): Calculated for C10H21O2 (M+H)+ 173.1536, found 173.1537.
(Z)-2-methylhex-3-ene-2,5-diol (17’). A colorless liquid after purification by flash
column chromatography (petroleum ether/ethyl acetate = 1/1, 7.7 mg, 30%). 1H NMR
(400 MHz, CDCl3) δ 5.50 (dd, J = 12.4, 1.2 Hz, 1H), 5.38 (dd, J = 12.4, 6.4 Hz, 1H),
4.87 (pd, J = 6.4, 1.2 Hz, 1H), 3.63 (s, 2H), 1.39 (s, 6H), 1.30 (d, J = 6.4 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 138.2, 132.7, 71.8, 64.0, 31.9, 30.8, 23.8. HRMS
(ESI, m/z): Calculated for C7H15O2 (M+H)+ 131.1067, found 131.1065.
(E)-2-methylhex-3-ene-2,5-diol (17). A colorless liquid after purification by flash
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column chromatography (petroleum ether/ethyl acetate = 1/1, 10.7 mg, 41%). H
NMR (400 MHz, CDCl3) δ 5.80 (d, J = 16.0 Hz, 1H), 5.70 (dd, J = 15.6, 6.0 Hz, 1H),
4.32 (p, J = 6.4 Hz, 1H), 2.35 (s, 2H), 1.32 (s, 6H), 1.28 (d, J = 6.4 Hz, 3H). 13C{1H}
NMR (75 MHz, CDCl3) δ 137.6, 130.7, 70.4, 68.3, 29.7, 29.5, 23.4. HRMS (ESI,
m/z): Calculated for C7H15O2 (M+H)+ 131.1067, found 131.1066.
(Z)-4-methylpent-2-ene-1,4-diol (18’). A colorless liquid after purification by flash
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column chromatography (petroleum ether/ethyl acetate = 5/1, 5.1 mg, 21.9%). H
NMR (400 MHz, CDCl3) δ 5.59 (d, J = 12.0 Hz, 1H), 5.51 (dd, J = 12.0, 4.8 Hz, 1H),
4.31 (d, J = 4.2 Hz, 2H), 3.14 (s, 1H), 3.13 (s, 1H), 1.38 (s, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ 139.4, 127.5, 71.9, 59.0, 31.2. HRMS (ESI, m/z): Calculated for
C6H13O2(M+H)+ 117.0910, found 117.0908.
(E)-4-methylpent-2-ene-1,4-diol (18). A colorless liquid after purification by flash
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column chromatography (petroleum ether/ethyl acetate = 5/1, 13.7 mg, 59%). H
NMR (400 MHz, CDCl3) δ 5.83 (d, J = 15.6 Hz, 1H), 5.77 (dd, J = 15.6, 4.8 Hz, 1H),
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4.11 (d, J = 4.4 Hz, 2H), 2.66 (s, 1H), 2.52 (s, 1H), 1.31 (s, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ 139.4, 125.8, 70.5, 62.8, 29.5. HRMS (ESI, m/z): Calculated for
C6H13O2(M+H)+ 117.0910, found 117.0909.
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(E)-7-chloro-2-methylhept-3-en-2-ol (19). A colorless liquid after purification by
flash column chromatography (petroleum ether/ethyl acetate = 1/1, 14.8 mg, 49.5%).
1H NMR (400 MHz, CDCl3) δ 5.67 (d, J = 15.6 Hz, 1H), 5.59 (dt, J = 15.6, 6.4 Hz,
1H), 3.53 (t, J = 6.4 Hz, 2H), 2.19 (q, J = 1 6.4 Hz, 2H), 1.82 – 1.89 (m, 2H), 1.38 (s,
1H), 1.31 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 139.4, 125.1, 70.6, 44.3, 32.0,
29.9, 29.2. HRMS (ESI, m/z): Calculated for C8H15ClO (M+H)+ 163.0884, found
163.0883.
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(Z)-4-hydroxy-4-methylpent-2-en-1-yl benzoate (20’). A colorless liquid after
purification by flash column chromatography (petroleum ether/ethyl acetate = 5/1, 11
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mg, 25%). H NMR (400 MHz, CDCl3) δ 8.11 – 8.00 (m, 2H), 7.60 – 7.52 (m, 1H),
7.48 – 7.41 (m, 2H), 5.67 (dt, J = 12.0, 1.2 Hz, 1H), 5.50 (dt, J = 12.0, 6.8 Hz, 1H),
5.25 (dd, J = 6.8, 1.2 Hz, 2H), 2.85 (s, 1H), 1.39 (s, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ 166.9, 140.8, 133.0, 130.3, 129.6, 128.3, 123.0, 72.2, 61.6, 31.0. HRMS
(ESI, m/z): Calculated for C13H17O3 (M+H)+ 221.1172, found 221.1171.
(E)-4-hydroxy-4-methylpent-2-en-1-yl benzoate (20). A colorless liquid after
purification by flash column chromatography (petroleum ether/ethyl acetate = 2/1, 22
mg, 50%). 1H NMR (400 MHz, CDCl3) δ 8.12 – 8.00 (m, 2H), 7.55 (d, J = 7.4 Hz,
1H), 7.44 (t, J = 7.7 Hz, 2H), 6.00 (d, J = 15.7 Hz, 1H), 5.89 (dd, J = 13.7, 7.8 Hz,
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1H), 4.82 (dd, J = 5.8, 0.9 Hz, 2H), 1.69 (s, 1H), 1.35 (s, 6H). C{1H} NMR (101
MHz, CDCl3) δ 166.3, 142.3, 132.9, 130.2, 129.6, 128.3, 120.9, 70.5, 64.9, 29.6.
HRMS (ESI, m/z): Calculated for C13H17O3 (M+H)+ 221.1172, found 221.1170.
(E)-4-phenylpent-2-ene-1,4-diol3a (21). A colorless liquid after purification by
flash column chromatography (petroleum ether/ethyl acetate = 1/1, 36.9 mg, 96%). 1H
NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 7.6 Hz, 2H), 7.26 –
7.21 (m, 1H), 5.98 (ddd, J = 15.6, 4.0, 0.8 Hz, 1H), 5.72 (ddd, J = 15.6, 6.5, 3.0 Hz,
1H), 4.12 – 3.98 (m, 1H), 2.26 (d, J = 16.8 Hz, 1H), 1.87 (s, 1H), 1.64 (t, J = 3.2 Hz,
3H), 1.62 – 1.51 (m, 2H), 0.91 (td, J = 7.4, 2.8 Hz, 3H). 13C{1H} NMR (101 MHz,
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CDCl3) δ 146.6, 136.6, 132.1, 128.2, 126.9, 125.1, 74.1, 68.3, 29.7, 23.3. MS (EI):
m/z (%): 192(0.1), 177(5.3), 147(100.0),131(79.5), 105(42.8), 91(37.0), 43(88.5).
(E)-2-phenylhept-3-ene-2,5-diol (22). A colorless liquid after purification by flash
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column chromatography (petroleum ether/ethyl acetate = 1/1, 26.4 mg, 64%). H
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NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 8.0 Hz, 2H), 7.26 –
7.22 (m, 1H), 5.98 (ddd, J = 15.6, 4.0, 0.8 Hz, 1H), 5.72 (ddd, J = 15.6, 6.4, 3.2 Hz,
1H), 4.05 (dd, J = 6.4, 3.6 Hz, 1H), 2.26 (d, J = 16.8 Hz, 1H), 1.87 (s, 1H), 1.65 (d, J
= 2.8 Hz, 3H), 1.61 – 1.52 (m, 2H), 0.91 (td, J = 7.2, 2.8 Hz, 3H). 13C{1H} NMR (75
MHz, CDCl3) δ 146.6, 137.7, 130.6, 128.2, 126.9, 125.0, 74.1, 73.7, 30.0, 29.7, 9.8.
HRMS (ESI, m/z): Calculated for C13H19O2 (M+H)+ 207.1380, found 207.1380.
(E)-2-methyl-5-phenylhex-3-ene-2,5-diol11 (23). A white solid after purification by
flash column chromatography (petroleum ether/ethyl acetate = 1/1, 36.7 mg, 89%). 1H
NMR (400 MHz, CDCl3) δ 7.43 (d, J = 7.6 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.23 (t, J
= 7.2 Hz, 1H), 5.95 (d, J = 15.8 Hz, 1H), 5.83 (d, J = 15.8 Hz, 1H), 2.30 (s, 1H), 2.03
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(s, 1H), 1.62 (s, 3H), 1.30 (s, 6H). C{1H} NMR (75 MHz, CDCl3) δ 146.8, 135.8,
133.4, 128.1, 126.8, 125.1, 74.1, 70.6, 29.8, 29.7, 29.6. MS (EI): m/z(%): 206(0.02),
191(5.5), 171(16.6), 145(100.0), 105(73.5).
(E)-5-methyl-2-phenylhept-3-ene-2,5-diol (24). A colorless liquid after purification
by flash column chromatography (petroleum ether/ethyl acetate = 1/1, 30.4 mg, 69%).
1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.2 Hz, 2H), 7.34 (d, J = 7.2 Hz, 2H), 7.25
(d, J = 6.8 Hz, 1H), 5.98 (dd, J = 15.6, 1.2 Hz, 1H), 5.76 (d, J = 15.6 Hz, 1H), 2.03 (s,
1H), 1.65 (s, 3H), 1.60 – 1.54 (m, 2H), 1.28 (d, J = 1.6 Hz, 3H), 0.87 (td, J = 7.6, 4.4
Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 146.8, 134.7, 134.5, 128.2, 126.9, 125.1,
74.2, 73.0, 35.2, 29.9, 27.4, 8.3. HRMS (ESI, m/z): Calculated for C14H21O2 (M+H)+
221.1536, found 221.1539.
(E)-2-phenyloct-3-ene-2,5-diol (25). A colorless liquid after purification by flash
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column chromatography (petroleum ether/ethyl acetate = 1/1, 35.7 mg, 81%). H
NMR (400 MHz, CDCl3) δ 7.8 (d, J = 7.6 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.29 –
7.24 (m, 1H), 6.00 (ddd, J = 15.6, 3.6, 0.8 Hz, 1H), 5.75 (ddd, J = 15.6, 6.4, 3.0 Hz,
1H), 4.16 (q, J = 6.4 Hz, 1H), 2.29 (s, 1H), 2.13 (s, 1H), 1.67 (d, J = 2.8 Hz, 1H), 1.60
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– 1.48 (m, 2H), 1.45 – 1.33 (m, 2H), 0.95 (td, J = 7.2, 3.0 Hz, 3H). 13C{1H} NMR (75
MHz, CDCl3) δ 146.6, 137.5, 131.0, 128.2, 126.9, 125.1, 74.1, 72.2, 39.3, 29.7, 18.6,
14.0. HRMS (ESI, m/z): Calculated for C14H21O2 (M+H)+ 221.1536, found 221.1537.
(E)-2-phenylnon-3-ene-2,5-diol (26). A colorless liquid after purification by flash
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column chromatography (petroleum ether/ethyl acetate = 1/1, 21.8 mg, 53%). H
NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.0 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.26 –
7.22 (m, 1H), 5.98 (dd, J = 15.6, 3.2 Hz, 1H), 5.74 (dd, J = 15.6, 6.4 Hz, 1H), 4.13 (q,
J = 6.4 Hz, 1H), 2.12 (s, 1H), 2.03 (s, 1H), 1.66 (d, J = 2.8 Hz, 3H), 1.60 – 1.51 (m,
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2H), 1.35 – 1.32 (m, 4H), 0.90 (td, J = 6.8, 2.4 Hz, 3H). C{1H} NMR (75 MHz,
CDCl3) δ 146.5, 137.5, 131.1, 128.2, 127.0, 125.1, 74.1, 72.5, 36.9, 29.7, 27.6, 22.6,
14.0. HRMS (ESI, m/z): Calculated for C15H23O2 (M+H)+ 235.1393, found 235.1391.
(E)-5-ethyl-2-phenylhept-3-ene-2,5-diol (27). A colorless liquid after purification
by flash column chromatography (petroleum ether/ethyl acetate = 1/1, 27.6 mg, 59%).
1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.6 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.26
– 7.23 (m, 1H), 5.98 (d, J = 15.8 Hz, 1H), 5.67 (d, J = 15.8 Hz, 1H), 1.94 (s, 1H), 1.66
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(s, 3H), 1.59 – 1.52 (m, 4H), 1.39 (s, 1H), 0.86 (q, J = 7.2 Hz, 6H). C{1H} NMR
(75 MHz, CDCl3) δ 146.8, 135.5, 133.4, 128.2, 126.9, 125.2, 75.3, 74.4, 33.2, 30.0,
7.9. HRMS (ESI, m/z): Calculated for C15H23O2 (M+H)+ 235.1393, found 235.1392.
(E)-1-(3-hydroxy-3-phenylbut-1-en-1-yl)cyclopentan-1-ol (28). A colorless liquid
after purification by flash column chromatography (petroleum ether/ethyl acetate =
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1/1, 36.2 mg, 78%). H NMR (400 MHz, CDCl3) δ 7.48 – 7.44 (m, 2H), 7.33 (t, J =
7.6 Hz, 2H), 7.26 – 7.22 (m, 1H), 6.05 (d, J = 15.6 Hz, 1H), 5.88 (d, J = 15.6 Hz, 1H),
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1.87 – 1.84 (m, 2H), 1.67 (s, 8H), 1.66 (s, 3H). C{1H} NMR (75 MHz, CDCl3) δ
146.8, 134.2, 133.8, 128.2, 126.9, 125.1, 81.7, 74.2, 40.6, 40.5, 30.0, 23.6. HRMS
(ESI, m/z): Calculated for C15H21O2 (M+H)+ 233.1536, found 233.1535.
(E)-5-phenylhex-3-ene-1,2,5-triol (29). A colorless liquid after purification by
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flash column chromatography (ethyl acetate, 10.4 mg, 25%). H NMR (400 MHz,
CDCl3) δ 7.45 (d, J = 7.6 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H),
6.12 (d, J = 15.6 Hz, 1H), 5.74 (ddd, J = 15.6, 12.0, 6.0 Hz, 1H), 4.28 (s, 1H), 3.66
(dd, J = 7.2, 4.0 Hz, 1H), 3.51 (dd, J = 17.2, 9.2 Hz, 1H), 2.77 (br, 2H), 1.88 (s, 1H),
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1.66 (d, J = 2.8 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ146.3, 139.4, 128.3,
127.1, 126.7, 125.1, 74.2, 72.4, 66.3, 29.7. HRMS (ESI, m/z): Calculated for
C12H17O3 (M+H)+ 209.1172, found 209.1175.
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(E)-1,1-diphenylpent-2-ene-1,4-diol (30).A colorless liquid after purification by
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flash column chromatography (petroleum ether/ethyl acetate = 2/1, 1.04 g, 87%). H
NMR (300 MHz, CDCl3) δ 7.39 – 7.19 (m, 10H), 6.28 (dd, J = 15.6, 1.2 Hz, 1H), 5.75
(dd, J = 15.6, 6.0 Hz, 1H), 4.42 – 4.26 (m, 1H), 3.02 (s, 2H), 1.25 (d, J = 6.4 Hz, 3H).
13C{1H} NMR (75 MHz, CDCl3) δ 145.9, 135.2, 133.6, 128.1, 127.2, 126.8, 78.6,
68.2, 23.3.HRMS (ESI, m/z): Calculated for C17H19O2 (M+H)+ 255.1380, found
255.1382
(E)-4-phenylpent-2-ene-1,1,3-d3-1,4-diol-d (31). A colorless liquid after
purification by flash column chromatography (petroleum ether/ethyl acetate = 1/1, 16
mg, 44%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 7.2 Hz,
2H), 7.30 – 7.22 (m, 1H), 5.87 (s, 1H), 1.68 (s, 3H), 1.59 (s, 1H). 13C{1H} NMR (101
MHz, CDCl3) δ 146.5, 138.2, 128.3, 127.2, 127.0, 125.1, 74.2, 63.0, 29.7. HRMS
(ESI, m/z): Calculated for C11H10D4O2Na (M+Na)+ 205.1137, found 205.1139.
AUTHOR INFORMATION
Corresponding Author:
E-mail: liuzhq@lzu.edu.cn
Notes
The authors declare no competing financial interest.
Supporting Information
Modification of the conditions, mechanistic studies, and copies of spectra. This
material is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
This project is supported by National Natural Science Foundation of China (No.
21672089).
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