Design, Synthesis, and Evaluation of Novel 2,6-Disubstituted Phenol Derivatives as General Anesthetics

Article abstract of DOI:10.1021/acs.jmedchem.7b00254

A novel series of optically active 2,6-disubstituted alkylphenols with improved anesthetic profiles compared to widely used propofol were synthesized. The incorporation of the cyclopropyl group not only increased the steric effect but also introduced ster

Full text of DOI:10.1021/acs.jmedchem.7b00254

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Article
Design, Synthesis and Evaluation of Novel 2,6-
Disubstituted Phenol Derivatives as General Anesthetics
Linlin Qin, Lei Ren, Songlin Wan, Guoliang Liu, Xinfeng Luo,
Zhenhong Liu, Fangqiong Li, Yan Yu, Jianyu Liu, and Yonggang Wei
J. Med. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Apr 2017
Downloaded from http://pubs.acs.org on April 22, 2017
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Design, Synthesis and Evaluation of Novel 2,6ꢀ
Disubstituted Phenol Derivatives as General
Anesthetics
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Linlin Qin*, Lei Ren, Songlin Wan, Guoliang Liu, Xinfeng Luo, Zhenhong Liu, Fangqiong Li,
Yan Yu, Jianyu Liu and Yonggang Wei
Haisco Pharmaceuticals Group Co. Ltd., 136 Baili Road, Wenjiang district, Chengdu, 611130,
China
KEYWORDS anesthetics, GABAA, 2,6ꢀdisubstituted phenol derivatives, water soluble prodrug,
stereoselectivity
ABSTRACT A novel series of optically active 2,6ꢀdisubstituted alkylphenols with improved
anesthetic profiles compared to widely used propofol were synthesized. The incorporation of the
cyclopropyl group not only increased the steric effect but also introduced stereoselective effects
over their anesthetic properties. Compounds 1, 2 and 6 were selected as potential candidates for
further preꢀclinical development including studies of their waterꢀsoluble prodrugs. Clinical
studies of candidate compound 6 (Haisco HSK3486) as a general anesthetic are performed in
Australia and China.
INTRODUCTION
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2,6ꢀDisubstituted alkylphenols are well known for their anesthetic activities. Propofol
(compound 33), with a chemical name of 2,6ꢀdiisopropylphenol, working through γꢀ
aminobutyric acid type A (GABAA)ꢀmediated inhibition of synaptic transmission, and the
inhibition of glutamate release,1,2 has gained wide acceptance as a central intravenous anesthetic
in current clinical practice. It possesses favorable pharmacokinetic properties which allow rapid
onꢀset and return of consciousness with little residual effects. 1,2 Compound 33 can be clinically
used for induction and maintenance of general anesthesia, endoscopic procedural sedation and
sedation of patients in intensive care.1 Despite being an excellent anesthetic agent, compound 33
is associated with some limitations and disadvantages, such as injection pain, blood pressure
decrease, respiratory depression caused apnea and ICU syndrome.3ꢀ5 Thus, in clinical practice,
sedation with compound 33 is restricted under certain circumstances. Many anesthetics
undergoing clinical development are modified to overcome the shortcomings of compound 33.
However, an ideal drug that is entirely satisfactory has not been discovered.
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Inspired by the improved sedative potency of a previously reported compound 33 analog (R,
R)ꢀ2,6ꢀdiꢀsecꢀbutylphenol (compound 34) (PF0713),6 we incorporated cyclopropyl group(s) into
the 2, 6 side chains of compound 33 to decrease its lipophilicity, in the meantime breaking the
symmetry of the compound 33 molecule by introducing one or more chiral centers. Therefore,
we synthesized a series of 2,6ꢀdisubstituted phenol derivatives and evaluated the
pharmacological features of these compounds in contrast to compound 33. Several compounds
were identified as potent general anesthetics that possess better properties than compound 33.
To circumvent problems associated with a lipidꢀbased formulation of compound 337, several
waterꢀsoluble derivatives and prodrugs have been developed.8,9 Efficacy and safety assessment
of compound 35 (fospropofol) proved it to be the most suitable prodrug of compound 33 for
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clinical development thus far.10 However, compound 35 was reported to suffer from slow onꢀ
set11 and itching side effect12. This same modification was also evaluated for our selected
compounds and proved to be able to overcome some of the existed drawbacks of compound 35.
RESULTS AND DISCUSSION
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Chemistry. A series of 2,6ꢀdisubstituted phenols were designed and prepared by the following
methods (according to the following routes: Schemes 1 and 2). As shown in Scheme 1, most of
the compounds were synthesized from the key intermediate 20. 2ꢀBromophenol 17 reacted with
1ꢀchlorobutꢀ2ꢀene and NaOH to give compound 18, which was subjected to thermal Claisen
rearrangement in the presence of K2CO3 to produce compound 19. Key intermediate 20 was
synthesized via cyclopropanation. Intermediate 20 reacted with nꢀBuLi and 2ꢀbutanone to give
alcohol 21 followed by dehydroxylation to produce compound 1. Treatment of intermediate 20
with Weinreb amide in the presence of nꢀBuLi produced ketone 22. Ketone 22 was treated with a
Grignard reagent, which was followed by dehydroxylation in the presence of Et3SiH and TFA to
afford compounds 2 and 14ꢀ16. Intermediate 20 was converted to compound 3 via orthoꢀ
lithiation and workup by protonic solvents. Hydroxymethylphenol 24 was obtained when
intermediate 20 was treated with nꢀBuLi and paraformaldehyde. Dehydroxylation of compound
24 was carried out to give compound 4. Alkylation of intermediate 20 produced compound 25
followed by Claisen rearrangement to give compounds 7 and 8.
Scheme 1. Synthesis of derivatives of 2,6-disubstituted phenols from 2-bromophenola
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OH
OH
HO
d
e
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7
8
1
21
O
N
OH
22
O
OH R2
OH R2
O
OH
g
h
9
f
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23
2,14-16
R2 = Me; Et; i-Pr; cyclopropyl
23a R2 = Me
23b R2 = Et
23c R2 = i-Pr
OH
i
23d R2 = cyclopropyl
OH
Br
3
OH
OH
20
k
HO
j
24
O
4
R'
OH
Br
l
R1
m
R1 = H, CH3
7,8
25
25a R'=H
25b R'=Me
aReagents and conditions:(a)1ꢀchlorobutꢀ2ꢀene, NaOH, DMF; (b) K2CO3, 200oC; (c) AlEt3,
CH2I2, DCM; (d) 2ꢀbutanone, nꢀBuLi, THF; (e) Et3SiH, TFA, DCM; (f) Weinreb amide, nꢀBuLi,
THF; (g) R2MgBr, THF; (h) Et3SiH, TFA, DCM; (i) nꢀBuLi, THF; (j) nꢀBuLi, (HCHO)n, THF;
(k) Et3SiH, TFA, DCM; (l) allyl bromide, K2CO3, CH3CN; (m) nꢀBuLi, TMEDA, Et2O.
Other phenol analogs were synthesized by the approach outlined in Scheme 2. Substituted
phenol 26 was treated with DHP in the presence of pyridinium 4ꢀtoluenesulfonate to afford
protected phenol 27, which reacted with nꢀBuLi and Weinreb amides, followed by hydrolysis to
give compound 28. Tertiary alcohol 29 was generated from the reaction of ketones 28 and
Grignard reagents. Dehydroxylation of alcohol 29 was carried out in the presence of Et3SiH and
TFA to yield the desired series of compounds 5, compound 6 (HSK3486)13 and 9-13.
Scheme 2. Syntheses of derivatives of 2,6-disubstituted phenols from 2-substituted phenols a
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aReagents and conditions:(a) DHP, Pyridinium 4ꢀtoluenesulfonate, DCM; (b) Weinreb amides,
nꢀBuLi, THF; (c) HCl, MeOH; (d) R5MgBr,Toluene; (e) Et3SiH, TFA, DCM.
PhosphonoꢀOꢀmethyl prodrugs of compounds 1, 2 and 6 were prepared following the synthetic
route depicted in Scheme 3. Compounds 1, 2 or 6 reacted with bromochloromethane to form the
corresponding phenol chloromethyl ethers. This intermediate was then treated with phosphorous
acid, followed by treatment with NaOH to afford the target prodrug.
Scheme 3. Syntheses of Prodrugs of compound 1, 2 and 6a
aReagents and conditions: (a) Bromochloromethane, NaOH, THF; (b) Phosphorous acid, TEA;
(c) NaOH.
Biological Evaluation.
2,6ꢀDisubstituted phenol derivatives as well as their proꢀdrugs have been extensively studied
for their pharmacological actions especially in the anesthetic area.14 As a generally accepted
anesthesia, compound 33 is well known for its fast onꢀset and clean recovery from anesthesia,
which is preferred by many anesthetists and clinicians. Compound 34, a single diastereoisomer
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bearing two defined chiral centers of the Rꢀconfiguration drew our attention.6 Compound 34 not
only resembles the structure of compound 33 but also displays a similar anesthetic potency.
However, it shows a slower onꢀset and longer duration of anesthetic action. It is well known that
individual enantiomers usually give significantly different pharmacological performance
compared to their racemic mixtures.
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A validated rodent model of general anesthesia15,16 was used to provide a measure of onꢀset
and duration of anesthesia as demonstrated by loss of righting reflex (LORR) experiments. These
results allowed us to easily record and compare the onꢀset and recovery time of the compounds,
which are the essential features of a general anesthetic for clinical usage. All compounds were
prepared with 5% of dimethyl sulfoxide, 5ꢀ10% of Solutol HSꢀ15 and 85ꢀ90% of saline, and
administered to fasted ICR mice at a series of dosages (7ꢀ9 dosages per compound) by
intravenous injection (n=10 per dose group), which required approximately 10 seconds per dose.
Immediately following injection, the mice were placed on their backs continually until they
stopped righting themselves. Anesthetic effect was assessed using onꢀset of LORR. And duration
was monitored as the time it took until the mice regained the righting reflex while recovery time
recorded as the time interval from return of righting reflex until the mouse was able to grip and
climb a steel frame and ambulated normally, as assessed subjectively from behavioral
observations. Therefore, the onꢀset, anesthetic duration and recovery time data were collected
(Table 1) at doses could produce 100% lost of righting reflex of the mice. Most of the
compounds (especially compounds with higher potency) possessed a fast onꢀset and quick
recovery on mice, and they generally provided moderate to long anesthetic duration. It is well
known that compound 33 may cause significant hypotension and respiratory depression.3,4,17,18
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As compound 33 analogues, the designed molecules may also associate with side effects such as
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respiratory and cardiovascular depression which may be the cause of mortality in high doses.
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Table 1. Evaluation studies on sedation profiles of compound 33, compound 34 and
compounds 1ꢀ1613
Onꢀset
(sec)
Duration
(sec)
Recovery time
(sec)
Compound Structure
ꢀ
<10
303.2±97.82
50.00±10.37
33
18.00±3.46
459.83±71.04
39.83±18.84
34
R,R
mix
<10
<10
418.14±63.77
471.88±109.66
130.71±32.37
391.29±65.05
R,R
R,S
S,R
S,S
OH
<10
<10
545.00±79.68
418.00±65.27
363.67±91.20
192.33±41.81
1
<10
<10
<10
643.40±100.94
563.63±127.92
318.43±56.00
224.00±55.96
233.83±37.98
61.67±17.42
mix
R,R
2
R,S
S,S
<10
492.17±49.81
567.33±69.46
24.50±7.42
7.00±1.41
150.80±37.51
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mix
<10
<10
598.00±165.64
329.60ꢀ43.83
122.00±58.17
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4
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mix
198.33±53.50
mix
mix
<10
<10
409.57±33.86
518.50±48.47
226.57±81.01
78.00±37.60
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R
S
21.86±9.04
5.71±1.38
313.43±43.65
344.00±68.96
64.80±14.57
168.33±71.71
6
mix
mix
mix
mix
<10
9.50±2.07
<10
500.67±46.89
365.75±124.40
364.14±27.84
193.63±144.59
306.13±97.81
79.00±17.40
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8
9
13.60±8.26
523.57±23.16
364.00±21.44
50.38±42.52
46.00±21.53
10
mix
43.50±25.56
R
<10
443.50±62.70
450.43±50.32
89.11±59.96
191.80±4.38
11
S
15.63±2.67
mix
ꢀ
5.00±0.71
<10
737.33±182.65
2616.4±311.81
670.13±185.18
NA
441.60±88.05
220.17±38.91
205.8±65.30
NA
12
13
14
15
mix
mix
7.50±1.05
NA
mix
<10
761.33±189.10
326.50±73.22
16
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Using this LORR data, ED50 (50 % of the mice to lose righting reflex), LD50 (median lethal
dose) and HD10 min (the dose required to produce 10 min of anesthesia) were calculated by nonꢀ
linear fitting using Graph Pad Prism5 to evaluate the relative efficacy of tested compounds.
Compounds 1 and 2 and their diastereoisomers were synthesized and studied for their anesthetic
properties (Table 2). They all show much lower ED50 which equates to a higher potency than
compound 33.
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In order to further evaluate the effects of the steric bulk and potency, one side chain was
modified while keeping one cyclopropyl ethyl side chain unchanged. Unsubstituted, methyl,
ethyl, isopropyl, cyclopropyl and methoxy substituted cyclopropylethylphenol were evaluated
accordingly. Sharing the same isopropyl group with compound 33, compound 6 and its
enantiomers presented the highest potency among this series of modified derivatives. The results
from compounds 10 to 16 (Table 2) revealed that the increase of the steric bulk of the side chain
may play a role in the decrease of potency.
10 min of anesthesia is a suitable time period for certain surgical operations or gastroscopy19.
Therefore, HD10 min is employed for the head to head evaluation between designed molecules and
compound 33. Among the evaluated diastereoisomers, (R, R)ꢀconfigured diastereoisomers were
found to have even higher potency than the other isomers.
Table 2. SAR study of compound 33, compound 34 and designed 2,6-disubstituted phenol
derivatives (compounds 1-16)13
ED50
LD50
HD10 min
mg/Kg
Entry
Structure
mg/Kg mg/Kg
ꢀ
11.70
31.3
25.0
33
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2.69
4.5
23.8
38.1
14.3
10.0
20.0
7.5
34
R,R
mix
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2.0
R,R
R,S
S,R
OH
10.1
1.3
65.4
8.3
20.0
4.0
1
5.3
36.8
10.0
S,S
mix
3.6
1.5
>15.0
~6.3
NA
5.0
R,R
R,S
S,S
2
5.9
43.6
20.0
40.0
19.5
149.0
mix
mix
mix
14.0
7.4
64.8
54.9
57.1
30.0
NA
NA
3
4
5
7.7
mix
R
3.7
1.5
7.9
22.7
9.9
10.0
4.8
6
S
50.0
30.0
mix
mix
14.6
10.5
80.0
40.0
NA
7
8
45.0
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mix
mix
7.4
6.2
67.0
53.2
NA
NA
9
10
7
8
9
mix
R
7.1
40.0
38.2
107.0
NA
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6.6
NA
11
S
46.1
100.0
mix
ꢀ
19.9
30.1
9.0
115.0
>100.0
74.7
40.0
50.0
20.0
NA
12
13
14
15
mix
mix
NA
NA
mix
9.8
98.2
20.0
16
Due to its aqueous insolubility, compound 33 was formulated as an oilꢀinꢀwater emulsion.20
The concentration of compound 33 in the aqueous phase is responsible for the pain upon
injection, and previous research has demonstrated that the pain would be reduced when patients
were injected with compound 33 with lower concentration in the aqueous phase of the emulsion3.
The higher potencies of these modified compounds (Table 2) compared to compound 33
definitely give the potential to formulate at a lower concentration, which leads to less risk of
injection pain.
In an attempt to make better sense of the influence of lipophilicity and steric bulk on the
anesthetic effect of discussed phenol derivatives, we investigated their SAR by graphically
relating their CLogP values with relative steric bulk. To better understand the general trend of
steric hindrance, the 16 alkylphenols were divided into two groups, namely modification of both
isopropyl side chains (Figure 1-(a)) and modification of one isopropyl side chain (Figure 1-(b)
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and Figure 1-(c)). The CLogP values showed a general increasing trend along with the increase
of steric bulk. In general, compounds at the middle range of the graph possess both medium
liphophilicity and suitable steric bulk resulting in better anesthetic potencies over compound 33.
Figure 1-(a) (compound 6) shows that a minor structural change can produce a modest increase
in CLogP with a dramatic effect on potency.
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Figure 1-(a). General activity map according to steric bulk and CLogP of compound 33
and selected compounds.
CLogP: data were calculated using Chemdraw/CLogP(Biobyte).
Figure 1-(b). General activity map according to steric bulk and CLogP of compound 33
and selected compounds.
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CLogP: data were calculated using Chemdraw/CLogP(Biobyte).
Figure 1-(c). General activity map according to steric bulk and CLogP of compound 33 and
selected compounds.
CLogP: data were calculated using Chemdraw/CLogP(Biobyte).
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The systematic evaluation of the anesthetic properties of compounds 1, 2 and 6 reveals their
possible clinical usage as potential candidates to replace compound 33. Molecular
pharmacological studies have established that compound 33 is an allosteric potentiator and
agonist of GABAA receptors.21 To further evaluate the activity of above three compounds, a
radioligand binding assay method was employed in this study. According to Maksay and
Simonyi’s study22, crude synaptosomal membranes of cerebral cortex from male Wistar rats
were used to test the selected compounds. Tested compounds with membrane suspensions in 20
mM TrisꢀHCl (pH 7.4) containing 200 mM NaCl were incubated with 2.0 nM [35S]TBPS at 25°C
for 3 hours. The resulted mixture was then filtered under vacuum and washed with 3 x 3 ml of
iceꢀcold buffer. A scintillation counter was employed to measure the radioactivity of the filters.
Nonspecific binding was determined in the presence of 200 µM picrotoxin. Concentrationꢀ
dependent effects of tested compounds on [35S]TBPS binding were expressed as % inhibition of
control specific TBPS binding. The binding assay results (Table 3) are consistent with the in
vivo LORR results. The Rꢀconfigured enantiomers proved to have much higher potency than
other isomers as well as compound 33. This type of preference also demonstrated the
stereoselectivity of GABAA receptor.
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Table 3. GABAA receptor binding assay results of compound 33, compound 34 and
compounds 1, 2 and 6.
Binding assay
(% inhibition)
(10µM) (1µM)
Entry
Structure
23
ꢀ
~10
33
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R,R
29
0
34
5
6
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mix
74
87
ꢀ3
23
R,R
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R,S
S,R
S,S
34
63
47
ꢀ9
ꢀ1
5
1
mix
R,R
R,S
S,S
mix
R
91
96
78
35
3
13
64
ꢀ5
2
6
ꢀ11
ꢀ12
34
3
85
ꢀ9
S
Selected Rꢀconfigured diastereoisomers were administered to fasted rats at 1mg/kg
intravenously (n=3 per group). The i.v. dose was formulated in 10% of dimethylacetamide, 20%
Soltul HSꢀ15 (30%，w/v) and 70% saline. Blood samples were collected into heparinized tubes
predose and at 2, 4, 8, 12, 15 and 30 min, and at 1, 1.5 and 2 h via jugular vein after
administration, then centrifuged at 5500 rpm for 10 min to obtain plasma samples. Plasma
samples were stored at ꢀ40oC until analysis. All compound concentrations were determined by
liquid chromatography–tandem mass spectrometry (LC–MS/MS). Pharmacokinetic parameters
were estimated by nonꢀcompartmental model using WinNonlin 6.3.
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The pharmacokinetic profiles of selected analogues are shown in Table 4.
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Table 4. Pharmacokinetic parameters of compound 33 and selected R-/R,R- configured
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optical isomers
Cmax
AUC(0ꢀt)
(ng.h/mL)
T1/2
Vdss
CL
Compounds Structure
(mg/
mL)
(min)
(L/kg)
(mL/kg.min)
384
575
76.9
42
22
31
28
5.23
3.23
1.92
2.02
204
208
95
33
78.1
(R,R)-1
(R,R)-2
(R)-6
713
834
170.0
164.0
100
The same phosphonoꢀOꢀmethyl modification, as evidenced in compound 35, was also
introduced into our previously discussed compounds. Results from their evaluation studies on
sedation profiles are shown in Tables 5-7 which included experiments in mouse, rat, beagle dogs
and minipigs.
In the mouse model (Table 5), phosphate prodrugs of compounds 1, 2 and 6 (referring as Pro-
1, Pro-2 and Pro-6) showed better efficacy than compound 35. In accordance with previous
results from their active compounds, prodrugs of Rꢀ and (R,R)ꢀ optical isomers displayed even
higher TI up to twice the value of compound 35. Studies in the rat model (Table 6) also proved
that Pro-6 and Pro-2 had higher efficacy than compound 35 by four to six times.
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Table 5. Evaluation studies on anesthesia profiles of compound 35 and prodrugs of
compounds 1, 2 and 6 in mouse
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9
ED50
LD50
Compound Structure
TI
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(mg/Kg) (mg/Kg)
ꢀ
94.97
220
2.3
35
R,R
15.89
24.27
11.67
63.68
91.78
42.46
4.0
3.8
3.6
Pro-1
S,R
R,R
R,S
S,S
35.79
94.67
142.8
274.3
4.0
2.9
Pro-2
Pro-6
R
S
20.39
82.66
86.47
369.8
4.2
4.5
TI = LD50/ED50
Table 6. Evaluation studies on anesthesia profiles of compound 35 and prodrugs of
compounds 2 and 6 in rat
ED50
LD50
Compound Structure
TI
(mg/Kg)
(mg/Kg)
ꢀ
40.98
189.0
4.61
35
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R,R
R
7.34
40.44
61.36
5.51
4.74
Pro-2
Pro-6
12.94
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Potent compounds Pro-(R,R)-2 and Pro-(R)-6 were selected for further evaluation in beagle
dog and minipig model studies (Table 7). To perform a similar sedation effect, which includes
similar sedation level and duration, Pro-(R,R)-2 and Pro-(R)-6 not only showed much shorter
onꢀset and recovery time properties than compound 35, but also required much lower dosages,
down to one fifth of the amount required for compound 35.
Table 7. Anesthetic effects following compounds 35, Pro-(R,R)-2 and Pro-(R)-6 bolus in
beagle dogs or minipigs
Beagle dogs
Minipigs
Dosage
Dosage
Recovery
time
Recovery
time
Compound
Onꢀset Duration
Onꢀset Duration
(mg/Kg)
(mg/Kg)
min
min
min
min
min
min
75
2.1±0.2 80.4±4.4 7.3±4.5
22.5
1.6±0.6 72.6±15.6 6.0±2.5
35
12.5
25
0.9±0.1 70.2±10.7 3.3±2.7
0.7±0.1 72.2±10.6 11.2±6.8
4
5
3.0±0.7 65.8±13.1 9.6±4.5
1.6±0.1 68.2±13.8 4.8±1.1
Pro-(R,R)-2
Pro-(R)-6
CONCLUSION
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In conclusion, we have developed a novel series of 2,6ꢀdisubstituted phenol analogs, which
have proved to possess promising anesthetic properties. As potential candidates of general
anesthetics, some of the analogs have much higher potency and tighter binding towards GABAA
receptor while maintaining a fast onꢀset and recovery time compared to compound 33. The
sedation evaluation of waterꢀsoluble prodrugs of compounds 1, 2 and 6 also demonstrated their
better potency than compound 35 as well as their faster onꢀset and recovery time sedative
profiles. Following the Phase I clinical studies in Australia and China, Phase II clinical trial with
selected candidate, compound 6, is now ongoing in China. And related clinical data will be
reported in a separate paper.
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EXPERIMENTAL SECTION
General procedures in Animal studies:
SpragueꢀDawley rats (200ꢀ250g, male) and ICR mice (18ꢀ22g, male and female) involved in
biology experiments were purchased from Vital River Co. LTD. Male and female beagle dogs
and minipigs were purchased from Chengdu Dossy Experimental Animals Co., LTD. Animal
facilities, animal care and study programs were conducted in conformity with inꢀhouse
guidelines of Institute of Laboratory Animal Resources, Commission on Life Science, National
Research Coulncil (National Academy Press, Washington, D.C., 2010). All animals were housed
in cages at 21 ± 2oC and provided free access to food and water. Rooms with constant
temperature and humidity, were in a cycle of 12 h of light (8:00–20:00 h) and 12 h of dark (from
20:00 to 8:00 h).
Synthetic procedures in Chemistry:
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All purchased reagents and starting materials were used without further purification. NMR
spectra were recorded with a Bruker Avance 400 spectrometer (400 and 100 MHz for 1H and 13C
NMR, respectively), with tetramethylsilane (TMS) as the internal standard; chemical shifts are
expressed in parts per million (ppm, δ units). Mass spectra were acquired on FinniganLCQAd
instrument (ESI). Most masses were reported as those of the protonated parent ions. Preparative
column chromatography was performed using 200ꢀ300 mesh silica. All Rf values involved are
from TLC. The title compounds were over 95% purity by HPLC.
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2-(1-Cyclopropylethyl)-6-sec-butyl-phenol (1): To
a
solution of 2ꢀbromo ꢀ6ꢀ(1ꢀ
cyclopropylethyl)phenol (20) (10.00 g, 0.04 mol) in anhydrous THF (50.0 mL) was added
dropwise nꢀBuLi (2.5 M in nꢀhexane, 50 mL, 0.12 mol) below 0oC under nitrogen atmosphere.
Upon completion of the addition, the reaction mixture was stirred for 40 min at 0oC. nꢀButanone
(4.50 g, 0.06 mol) was added to the above mixture at ꢀ10oC. After removing the cooling bath, the
mixture was stirred at room temperature overnight and then quenched with water (20 mL) and
extracted with ethyl acetate (40 mL×3). The combined organic layers were washed with brine
(50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The
residue was purified by flash chromatography to give the crude dihydroxyl product 21 (6.80 g) as
a yellow oil. Rf = 0.8 (petroleum ether/ethyl acetate = 50/1). This was used directly in the next
step without further purification.
To a stirred solution of the crude dihydroxyl product 21 (6.80 g) and triethylsilane (6.00 g, 0.05
mol) in DCM (30 mL), TFA (11.70 g, 0.10 mol) was added dropwise below 0oC under a nitrogen
atmosphere. Upon completion of the addition, the reaction mixture was stirred for 3 h at 0oC,
quenched with iceꢀwater (30 mL) and extracted with DCM (30 mL×2). To the combined organic
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layers was added TBAF·3H2O (4.00 g，0.01 mol) and the mixture was stirred for 30 min at
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room temperature. The mixture was stirred with water (20 mL), extracted with DCM (20 mL×3).
The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was purified by flash
chromatography to give 2ꢀ(1ꢀcyclopropylethyl)ꢀ6ꢀsecꢀbutylꢀphenol (1) (2.80 g, 32.06% yield
over 2 steps, HPLC: 98.08%) as a pale yellow oil. Rf = 0.3 (petroleum ether/ethyl acetate = 50/1).
1H NMR (400 MHz, CDCl3): δ 7.18ꢀ7.14 (m, 1H), 7.09ꢀ7.06 (m, 1H), 6.97ꢀ6.12 (m, 1H), 4.95 (s,
1H), 2.99ꢀ2.94 (m, 1H), 2.61ꢀ2.54 (m, 1H), 1.77ꢀ1.61 (m, 2H), 1.38ꢀ1.35 (m, 3H), 1.32ꢀ1.29 (m,
3H), 1.14ꢀ1.09 (m, 1H), 0.98ꢀ0.93 (m, 3H), 0.65ꢀ0.59 (m, 1H), 0.54ꢀ0.48 (m, 1H), 0.30ꢀ0.20 (m,
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13
2H). C NMR (100 MHz, CDCl3): δ 150.70, 132.84, 132.81, 132.00, 131.89, 124.90, 124.36,
120.49, 37.31, 37.19, 34.20, 34.14, 30.18, 30.07, 20.51, 20.09, 20.06, 17.01, 12.27, 4.37, 4.33,
+
3.82, 3.68. HRMS (ESI) Calcd. for C15H22O [M+H] : 219.17042. Found: 219.17425. Anal.
Calcd. for C15H22O: C, 82.52; H, 10.16. Found: C, 81.49; H, 10.31.
2-[(1S)-1-Cyclopropylethyl]-6-sec-butyl-phenol [(S)-1] and 2-[(1R)-1-cyclopropylethyl]-6-
sec-butyl-phenol [(R)-1] were prepared from 2ꢀbromoꢀ6ꢀ[(1R)ꢀ1ꢀcycloꢀpropylethyl]phenol [(S)-
20] and 2ꢀbromoꢀ6ꢀ[(1R)ꢀ1ꢀcycloꢀpropylethyl]phenol [(R)-20], referring to racemic mixture 1.
The HRMS spectra of (R)-1 and (S)-1 are the same as 1. (S)-1 and (R)-1: 1H NMR (400 MHz,
CDCl3): δ 7.12ꢀ7.09 (m, 1H), 7.01 (dd, J = 1.6, 7.6 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H), 4.88 (s,
1H), 2.93ꢀ2.87 (m, 1H), 2.56ꢀ2.46 (m, 1H), 1.69ꢀ1.55 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H), 1.24 (d,
J = 6.8 Hz, 3H), 1.08ꢀ1.02 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H), 0.58ꢀ0.53 (m, 1H), 0.49ꢀ0.43 (m,
1H), 0.23ꢀ0.16 (m, 2H) . 13C NMR (100 MHz, CDCl3): δ 150.63, 132.77, 132.75, 131.94, 131.83,
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124.85, 124.83, 124.31, 120.41, 37.25, 37.14, 34.14, 34.08, 30.11, 30.00, 20.45, 20.03, 20.00,
16.95, 16.93, 12.22, 4.30, 4.27, 3.77, 3.63.
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2-[(1S)-1-Cyclopropylethyl]-6-[(1R)-1-methylpropyl]phenol [(S,R)-1] and 2-[(1S)-1-
cyclopropylethyl]-6-[(1S)-1-methylpropyl]phenol [(S,S)-1]:
2ꢀ(1ꢀCyclopropylethyl)ꢀ6ꢀsecꢀ
butylꢀphenol (1) (0.50 g) was separated by chiral HPLC to afford two optical isomers.
Preparative condition: (instrument: Agilent 1260/ LHꢀYꢀJ0371(4ꢀ1); Column: CHIRALCEL
OJHS (0.46 cm I.D. × 15 cm L); Mobile phase: iꢀPrOH/hexane=1/100; flow rate: 1.0 mL/min;
backpressure: 100 bar; temperature: 35oC; Wave length: 214 nm; time: 10 min).
Peak 1 [(S,R)-1]: 0.19 g, HPLC: 95.90%, pale yellow oil, chiral HPLC retention time = 3.61
min. HRMS m/z (ESI) is the same as 1. 1H NMR (400 MHz, CDCl3): δ 7.10 (dd, J = 1.6, 7.6 Hz,
1H), 7.01 (dd, J = 1.6, 7.6 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H), 4.88 (s, 1H), 2.93ꢀ2.87 (m, 1H),
2.56ꢀ2.49 (m, 1H), 1.69ꢀ1.55 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H), 1.24 (d, J = 6.8 Hz, 3H), 1.08ꢀ
1.02 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H), 0.58ꢀ0.53 (m, 1H), 0.49ꢀ0.43 (m, 1H), 0.24ꢀ0.13 (m, 2H) .
13C NMR (100 MHz, CDCl3): δ 150.63, 132.77, 131.84, 124.83, 124.28, 120.41, 37.12, 34.06,
30.11, 20.44, 20.00, 16.92, 12.20, 4.26, 3.61.
Peak 2 [(S,S)-1]: 0.20 g, HPLC: 98.66%, pale yellow oil, chiral HPLC retention time = 4.21
min. HRMS m/z (ESI) is the same as 1. 1H NMR (400 MHz, CDCl3): δ 7.11 (dd, J = 1.6, 7.6 Hz,
1H), 7.02 (dd, J = 1.6, 7.6 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H), 2.94ꢀ2.86 (m, 1H), 2.54ꢀ2.46 (m,
1H), 1.71ꢀ1.55 (m, 2H), 1.30 (d, J = 7.0 Hz, 3H), 1.25 (d, J = 6.9 Hz, 3H), 1.09ꢀ1.01 (m, 1H),
0.89 (t, J = 7.4 Hz, 3H), 0.60ꢀ0.53 (m, 1H), 0.45ꢀ0.43 (m, 1H), 0.24ꢀ0.13 (m, 2H). 13C NMR
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(100 MHz, CDCl3): δ 150.62, 132.75, 131.94, 124.83, 124.30, 120.41, 37.25, 34.14, 29.99,
20.45, 20.03, 16.95, 12.21, 4.30, 3.76.
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2-[(1R)-1-Cyclopropylethyl]-6-[(1S)-1-methylpropyl]phenol [(R,S)-1] and 2-[(1R)-1-cyclo
propylethyl]-6-[(1R)-1-methylpropyl]phenol [(R,R)-1] : 2ꢀ[(1R)ꢀ1ꢀCyclopropylethyl]ꢀ6ꢀsecꢀ
butylꢀphenol (1.00 g) was separated by chiral HPLC to afford two optical isomers. Preparative
condition: (Instrument: GXꢀ281/CHꢀYꢀC0630; Column: CHIRALPAK OJꢀH (4.6 mm×150
mmL, 5ꢁm); Mobile phase: iꢀPrOH/hexane=0/100; flow rate: 1.0 mL/min; backpressure: 100
bar; temperature: 35oC; Wave length: 210 nm; time: 8 min).
Peak 1 [(R,R)-1]: 0.35 g, HPLC: 97.75%, pale yellow oil, chiral HPLC retention time = 4.98
min. 1H NMR, 13C NMR and HRMS spectra are the same as its enantiomer [(S,S)-1].
Peak 2 [(R,S)-1]: 0.32 g, HPLC: 95.77%, pale yellow oil, chiral HPLC retention time = 5.28
min. 1H NMR, 13C NMR and HRMS spectra are the same as its enantiomer [(S,R)-1].
2,6-Bis(1-cyclopropylethyl)phenol (2) : To a stirred solution of 2ꢀ(1ꢀcyclopropylethyl)ꢀ6ꢀ
(1ꢀcyclopropylꢀ1ꢀhydroxyꢀethyl)phenol (23a) (3.20 g, 12.99 mmol) and triethylsilane (4.53 g,
38.97 mmol) in 30 mL dichloromethane was added dropwise TFA (11.85 g, 103.92 mmol) below
0oC under a nitrogen atmosphere. Upon completion of the addition, the reaction mixture was
stirred for 3h at 0oC. The reaction solution was quenched with 100 mL iceꢀwater and extracted
with dichloromethane (50 mL×2). To the combined organic layers was added TBAF·3H2O
(12.27 g，38.97 mmol) and the mixture stirred for 30 min at ambient temperature. The mixture
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was added to 500 mL water and extracted with dichloromethane (50 mL×3). The combined
organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified by flash chromatography to give
the title compound 2 (2.75 g, 91.91% yield, HPLC: 95.56%) as a pale yellow oil. Rf = 0.6
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(petroleum ether/ethyl acetate = 50/1). H NMR (400 MHz, CDCl3): δ 7.14 (d, J = 7.6 Hz, 1H),
7.13 (d, J = 7.6 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 5.07 (s, 1H), 2.55ꢀ2.47 (m, 2H), 1.31 (d, J =
7.2 Hz, 6H), 1.10ꢀ1.02 (m, 2H), 0.61ꢀ0.43 (m, 4H), 0.26ꢀ0.14 (m, 4H). HRMS (ESI): Calcd. for
C16H22O [M+H] +: 231.17042. Found: 231.17425. Anal. Calcd. for C16H22O: C, 83.43; H, 9.63.
Found: C, 83.45; H, 9.60.
2,6-Bis[(1R)-1-cyclopropylethyl]phenol (R,R)-2, 2-[(1R)-1-cyclopropylethyl]-6-[(1S)-1-
cyclopropylethyl]phenol (R,S)-2 and 2,6-bis[(1S)-1-cyclopropylethyl]phenol (S,S)-2: The
compound 2,6ꢀbis(1ꢀcyclopropylethyl)phenol (2) (4.80 g，20.84 mmol) was separated on Chiral
Column (CHIRALPAK OZꢀH, hexane/isopropanol(v/v) = 100/0, 1.0 mL/min, UV = 214 nm，
temperature：35°C) to obtain the compound (R,R)-2 (0.71 g, 59.17% yield, HPLC: 98.48%) as a
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white solid. H NMR (400 MHz, CDCl3): δ 7.14 (d, J = 7.6 Hz, 2H), 6.89 (t, J = 7.6 Hz, 1H),
5.05 (s, 1H), 2.54ꢀ2.46 (m, 2H), 1.30 (d, J = 6.8 Hz, 6H), 1.09ꢀ1.03 (m, 2H), 0.60ꢀ0.54 (m,2H),
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0.49ꢀ0.43 (m, 2H), 0.25ꢀ0.14 (m, 4H). C NMR (100 MHz, CDCl3): δ 150.76, 132.13, 125.15,
120.37, 37.12, 20.07, 16.98, 4.35, 3.79. Compound (R,S)-2 (1.30 g, 54.16% yield, HPLC:
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97.23%) was obtained as a pale yellow oil. H NMR (400 MHz, CDCl3): δ 7.14 (d, J = 7.6 Hz,
2H), 6.91 (t, J = 7.6 Hz, 1H), 5.07 (s, 1H), 2.56ꢀ2.48 (m, 2H), 1.31 (d, J = 6.8 Hz, 6H), 1.09ꢀ1.02
(m, 2H), 0.60ꢀ0.54 (m, 2H), 0.50ꢀ0.43 (m, 2H), 0.26ꢀ0.15 (m, 4H). 13C NMR (100 MHz,
CDCl3): δ 150.77, 132.11, 125.15, 120.36, 37.16, 20.04, 17.03, 4.33, 3.76. Compound (S,S)-2
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(0.72 g, yield 60.0%, HPLC: 98.25%) was obtained as a white solid. H NMR (400 MHz,
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CDCl3): δ 7.14 (d, J = 7.6 Hz, 2H), 6.90 (t, J = 7.6 Hz, 1H), 5.05 (s, 1H), 2.54ꢀ2.47 (m, 2H), 1.30
(d, J = 6.8 Hz, 6H), 1.09ꢀ1.02 (m, 2H), 0.60ꢀ0.54 (m, 2H), 0.49ꢀ 0.42 (m, 2H), 0.25ꢀ0.14 (m,
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4H). C NMR (100 MHz, CDCl3): δ 150.75, 132.12, 125.15, 120.36, 37.21, 20.06, 16.97, 4.34,
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3.78.
2-(1-Cyclopropylethyl)phenol (3): To a solution of 2ꢀbromoꢀ6ꢀ(1ꢀcyclopropylethyl)phenol
(20) (1.40g, 5.8 mmol) in 10 mL anhydrous THF was added dropwise nꢀBuLi solution (2.5M in
nꢀhexane, 20 mL, 50 mmol) below 0oC under a nitrogen atmosphere. Upon completion of the
addition, the reaction mixture was stirred for 3h at 0oC. The mixture was quenched with 10 mL
saturated aqueous NH4Cl and extracted with ethyl acetate (20 mL×3). The combined organic
layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated
under reduced pressure. The residue was purified by flash chromatography to give the title
product 3 (0.80 g, HPLC: 97.36%, 80% yield) as a pale yellow oil. Rf = 0.5 (petroleum ether/
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ethyl acetate = 10/1). H NMR: (400 MHz，CDCl3): δ 7.30 (dd, J = 1.6, 7.6 Hz, 1H), 7.11ꢀ7.07
(m, 1H), 6.95ꢀ9.91 (m, 1H), 6.75 (dd, J = 1.2, 8.0 Hz, 1H), 4.79 (s, 1H), 2.50ꢀ2.43 (m, 1H), 1.32
(d, J = 6.8 Hz, 3H ), 1.11ꢀ1.03 (m, 1H), 0.62ꢀ0.55 (m, 1H), 0.48ꢀ0.42 (m, 1H), 0.28ꢀ0.16 (m,
2H). 13C NMR (100 MHz, CDCl3): δ 152.93, 133.98, 127.77, 126.80, 120.86, 115.35, 37.43,
+
20.16, 17.06, 4.49, 3.79. HRMS (ESI) Calcd. for C11H14O [M+H] : 163.10782. Found:
163.11173. Anal. Calcd. for C11H14O: C, 81.44; H, 8.70. Found: C, 80.74; H, 8.82.
2-(1-Cyclopropylethyl)-6-methyl-phenol (4): 2ꢀ(1ꢀCyclopropylethyl)ꢀ6ꢀ(hydroxymethyl)ꢀ
phenol (24) (1.50 g, 7.80 mmol) was dissolved in 8 mL of DCM. Triethylsilane (1.93 g, 16.73
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mmol) and TFA (2.40 mL, 33.45 mmol) were added to the previous solution at ꢀ15oC. The
reaction was kept at room temperature overnight before being quenched with ice water. The
aqueous phase was extracted with DCM (10 mL×2). The combined organic layers were washed
with saturated sodium bicarbonate solution (20 mL×2). To the organic phase was added
TBAF·3H2O (1.23 g，3.90 mmol), the mixture stirred for 1 h, washed with water (30 mL × 3),
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brine (30 mL), dried with anhydrous sodium sulfate and concentrated. The residue was purified
by chromatography on silica gel to afford 2ꢀ(1ꢀcyclopropylethyl)ꢀ6ꢀmethylꢀphenol (4) as a
colorless oil (0.51 g，37% yield, HPLC: 95.41%). Rf = 0.3 (petroleum ether/ethyl acetate = 40/1).
1H NMR (400 MHz, CDCl3): δ 7.16 (dd, J = 1.6, 7.6 Hz, 1H), 7.02ꢀ7.00 (m, 1H), 6.86 (t, J = 7.6
Hz, 1H), 4.77 (s, 1H), 2.52ꢀ2.45 (m, 1H), 2.28 (s, 3H), 1.32 (d, J = 7.2 Hz, 3H), 1.09ꢀ1.05 (m,
1H), 0.60ꢀ0.55 (m, 1H), 0.48ꢀ0.44 (m, 1H), 0.29ꢀ0.24 (m, 1H), 0.23ꢀ0.16 (m, 1H).13C NMR (100
MHz, CDCl3): δ 151.39, 132.16, 128.35, 125.48, 123.02, 120.35, 37.52, 20.14, 17.07, 16.01,
4.45, 3.88. HRMS (ESI): Calcd. for C14H18O [M+H] +: 177.12347. Found: 177.12735.
2-(1-Cyclopropylethyl)-6-ethyl-phenol (5) ： 2ꢀ(1ꢀCyclopropylꢀ1ꢀhydroxyꢀethyl)ꢀ6ꢀethylꢀ
phenol (29a) (1.00 g, 4.85 mmol) was dissolved in 8 mL of DCM at ꢀ15oC. Triethylsilane (1.20
g, 10.4 mmol) and TFA (1.5 mL, 20.80 mmol) were added to the reaction solution which was
stirred at ꢀ10oC for 1 hr. The reaction was kept at room temperature overnight before being
quenched with ice water. The aqueous phase was extracted with DCM (10 mL×2) and washed
with saturated sodium bicarbonate solution (20 mL×2). To the organic phase was added
TBAF·3H2O (0.75 g, 2.43 mmol), the mixture stirred for 1 hr, washed with water (30 mL × 3),
brine (30 mL), dried with anhydrous sodium sulfate, then concentrated and purified by flash
chromatography on silica gel to afford the desired product 5 as a colorless oil (0.68 g, 70% yield,
HPLC: 96.27%). Rf = 0.3 (petroleum ether). 1H NMR (400 MHz, CDCl3): δ 7.16 (dd, J = 1.6, 7.6
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Hz, 1H), 7.03 (dd, J = 1.6, 7.6 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H), 4.85 (s, 1H), 2.65 (q, J = 7.6 Hz,
2H), 2.54ꢀ2.47 (m, 1H), 1.32 (d, J = 6.8 Hz, 3H), 1.28 (t, J = 7.6 Hz, 3H), 1.11ꢀ1.03 (m, 1H),
0.60ꢀ0.55 (m, 1H), 0.47ꢀ0.44 (m, 1H), 0.28ꢀ0.22 (m, 1H), 0.21ꢀ0.16 (m, 1H). HRMS (ESI):
Calcd. for C13H18O [M+H] +: 191.13912. Found: 191.14304.
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2-(1-Cyclopropylethyl)-6-isopropylphenol (6): To a stirred solution of 2ꢀ(1ꢀcycloprop lꢀ1ꢀ
hydroxyꢀethyl)ꢀ6ꢀsopropylꢀphenol (29b) (3.00 g, 13.62 mmol) and triethylsilane (6.40 g, 55.04
mmol) in DCM (25 mL) was added TFA (12.60 g, 110.51 mmol) dropwise at 0oC. Upon
completion of the addition, the reaction mixture was stirred at 0oC for 2 hrs. The mixture was
washed sequentially with water (50 mL) and saturated NaHCO3 (50 mL). To the organic phase
was added TBAF·3H2O (2.20 g, 6.97 mmol), the mixture stirred for 1 h, washed with water (30
mL × 3), brine (30 mL), dried over anhydrous sodium sulfate, evaporated, and purified by
column chromatography to afford 2ꢀ(1ꢀcyclopropylethyl)ꢀ6ꢀisopropylphenol (6) as a colorless oil
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(2.0 g, 71.6% yield, HPLC: 98.42%). Rf = 0.5 (petroleum ether/ethyl acetate = 100/1). H NMR
(400 MHz, CDCl3): δ 7.13 (dd, J = 1.6, 7.6 Hz, 1H), 7.08 (dd, J = 1.6, 7.6 Hz, 1H), 6.90 (t, J =
7.6 Hz, 1H), 4.93 (s, 1H), 3.16 (hept, J = 6.9 Hz, 1H), 2.50 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H),
1.26 (d, J = 6.9 Hz, 6H), 1.07ꢀ1.05 (m, 1H), 0.58ꢀ0.45 (m, 2H), 0.24ꢀ0.16 (m, 2H). 13C NMR
(100 MHz, CDCl3): δ 150.37, 133.83, 131.94, 124.99, 123.65, 120.49, 37.27, 27.13, 22.73,
+
20.04, 16.97, 4.33, 3.81. HRMS (ESI): Calcd. for C14H20O [M+H] : 205.15477. Found:
205.15865. Anal. Calcd. for C14H20O: C, 82.30; H, 9.87. Found: C, 81.86; H, 9.91.
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(S)-2-(1-cyclopropylethyl)-6-isopropylphenol [(S)-6] or (R)-2-(1-cyclopropyl ethyl)-6-
isopropylphenol [(R)-6]: 2ꢀ(1ꢀcyclopropylethyl)ꢀ6ꢀisopropylphenol (6) (0.50 g) was separated
by chiral HPLC to afford two optical isomers.
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Preparative condition: (instrument: Agilent 1260/ LHꢀYꢀJ0371(4ꢀ1); Column: Chiralpak OJꢀ
H (4.6 mm × 25 cm, 5 micron particles); Mobile phase: n-hexane; flow rate: 1.0 mL /min;
backpressure: 100 bar; temperature: 35oC; Wave length: 275 nm; time: 30 min)
Peak 1 [(R)-6]: 0.21 g, HPLC: 98.43%, pale yellow oil, chiral HPLC retention time = 11.48
min. 1H NMR, 13C NMR and HRMS spectra are the same as 6.
Peak 2 [(S)-6]: 0.20 g, HPLC: 97.28%, pale yellow oil, chiral HPLC retention time = 14.46
min. 1H NMR, 13C NMR and HRMS spectra are the same as 6.
2-Cyclopropyl-6-(1-cyclopropylethyl)phenol (7) ：2ꢀ(Allyloxy)ꢀ1ꢀbromoꢀ3ꢀ(1ꢀcyclopropylꢀ
ethyl)benzene (25a) (10.00 g, 35.81 mmol) and anhydrous diethyl ether (200 mL) were added to
the flask under nitrogen protection. The mixture was cooled to ꢀ75 oC. nꢀButyllithium (30 mL,
2.5 M) was then added, following by 1hr of stirring before the addition of N,N,N,Nꢀ
tetramethylethylenediamine (9.57 g ，82.37 mmol). The system was warmed up to room
temperature and stirred for another 10 hrs before saturated ammonium chloride (100 mL) was
added to quench the reaction. The mixture was extracted with ethyl acetate (200 mL×2). The
combined organic phases were washed with saturated NaCl (200 mL×2) solution, dried with
anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel to afford 2ꢀcyclopropylꢀ6ꢀ(1ꢀ
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cyclopropylethyl)phenol (7) as a yellow oil (0.48 g, 6.6 % total yield, HPLC: 99.73%). Rf = 0.2
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(petroleum ether). H NMR (400 MHz, CDCl3): δ 7.21 (dd, J = 1.6, 7.6 Hz, 1H), 6.99 (dd, J =
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1.33 (d, J = 7.2 Hz, 1H), 1.14ꢀ1.03 (m, 1H), 1.01ꢀ0.96 (m, 2H), 0.69ꢀ0.65 (m, 2H), 0.58ꢀ0.54 (m,
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1H), 0.44ꢀ0.38 (m, 1H), 0.27ꢀ0.16 (m, 2H). C NMR (100 MHz, CDCl3): δ 152.92, 132.67,
126.65, 126.55, 125.98, 119.85, 37.71, 20.43, 17.27, 9.56, 5.14, 4.64, 3.92. HRMS (ESI): Calcd.
for C14H18O [M+H] +: 203.13912. Found: 203.14307.
2-(1-Cyclopropylethyl)-6-(1-methylcyclopropyl)phenol (8): 1ꢀBromoꢀ3ꢀ(1ꢀcyclopropylꢀ
ethyl)ꢀ2ꢀ((2ꢀmethylallyl)oxy)benzene (25b) (10.57 g，35.81 mmol) and anhydrous ether (200
mL) was added to the flask. The mixture was cooled to ꢀ75oC followed by the slow addition of nꢀ
butyllithium (30 mL, 2.5 M). The reaction mixture was stirred below ꢀ75oC for 1 hr. before the
addition of N,N,N,Nꢀ tetramethylethylenediamine (9.57 g，82.37 mmol). Then the system was
warmed up to room temperature and stirred for another 10 hrs before saturated ammonium
chloride (100 mL) was added to quench the reaction. The mixture was extracted with ethyl
acetate (200 mL×2), the combined organic phases were washed with saturated NaCl (200
mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel to afford 2ꢀ(1ꢀcyclopropylethyl)ꢀ
6ꢀ (1ꢀmethylcyclopropyl)phenol (8) as a yellow oil (0.60 g, 8.01 % total yield, HPLC: 99.22%).
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Rf = 0.2 (petroleum ether). H NMR (400 MHz, CDCl3): δ 7.21 (dd, J = 1.6, 7.6 Hz, 1H), 7.09
(dd, J = 1.6, 7.6 Hz, 1H), 6.85 (t, J = 7.6 Hz, 1H), 5.75 (s, 1H), 2.54ꢀ2.46 (m, 1H), 1.34 (s, 3H),
1.31 (d, J = 7.2 Hz, 3H), 1.09ꢀ1.00 (m, 1H), 0.84ꢀ0.79 (m, 4H), 0.58ꢀ0.52 (m, 1H),0.42ꢀ0.36 (m,
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