Rate constants for cyclizations of α-hydroxy radical clocks

Article abstract of DOI:10.1039/c0ob00588f

The 1-hydroxy-1-methyl-6,6-diphenyl-5-hexenyl radical (4a) and the 1-hydroxy-1-methyl-7,7-diphenyl-6-heptenyl radical (4b) were prepared from the corresponding PTOC esters (anhydrides of a carboxylic acid and N-hydroxypyridine-2-thione). The key step in the synthetic method for the precursors was a coupling reaction of the respective carboxylic acids with the thiohydroxamic acid, which was conducted for ca. 5 min and followed rapidly by chromatography. Rate constants for cyclizations of radicals 4a and 4b in acetonitrile and in THF were measured directly between -30 and 60 °C by laser flash photolysis methods. The Arrhenius functions in acetonitrile are log k = 9.9-2.6/2.303RT and log k = 8.9-4.4/2.303RT (kcal mol^-1) for 4a and 4b, respectively. Rate constants for cyclizations at room temperature of 9 × 10⁷ s^-1 and 4 × 10⁵ s ^-1 are somewhat larger than the rate constants for cyclizations of analogous alkyl radicals. Crude rate constants at room temperature for H-atom trapping of 4a by thiophenol and 4b by t-butylthiol were k_T = 1.2 × 10⁹ M^-1 s^-1 and k_T = 2 × 10⁷ M^-1 s^-1, respectively, which are modestly larger than rate constants for reactions of alkyl radicals with the same trapping agents.

Full text of DOI:10.1039/c0ob00588f

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PAPER
Rate constants for cyclizations of a-hydroxy radical clocks†‡
Christopher B. DeZutter, John H. Horner and Martin Newcomb*
Received 16th August 2010, Accepted 16th September 2010
DOI: 10.1039/c0ob00588f
The 1-hydroxy-1-methyl-6,6-diphenyl-5-hexenyl radical (4a) and the
1-hydroxy-1-methyl-7,7-diphenyl-6-heptenyl radical (4b) were prepared from the corresponding PTOC
esters (anhydrides of a carboxylic acid and N-hydroxypyridine-2-thione). The key step in the synthetic
method for the precursors was a coupling reaction of the respective carboxylic acids with the
thiohydroxamic acid, which was conducted for ca. 5 min and followed rapidly by chromatography. Rate
constants for cyclizations of radicals 4a and 4b in acetonitrile and in THF were measured directly
between –30 and 60 ◦C by laser flash photolysis methods. The Arrhenius functions in acetonitrile are
log k = 9.9–2.6/2.303RT and log k = 8.9–4.4/2.303RT (kcal mol-1) for 4a and 4b, respectively. Rate
constants for cyclizations at room temperature of 9 ¥ 107 s-1 and 4 ¥ 105 s-1 are somewhat larger than
the rate constants for cyclizations of analogous alkyl radicals. Crude rate constants at room
temperature for H-atom trapping of 4a by thiophenol and 4b by t-butylthiol were kT = 1.2 ¥ 109 M-1 s-1
and kT = 2 ¥ 107 M-1 s-1, respectively, which are modestly larger than rate constants for reactions of
alkyl radicals with the same trapping agents.
a-hydroxy radicals are present in the form of DNA and RNA rad-
Introduction
icals, in both productive and destructive reactions, and in enzyme-
catalyzed reactions of alcohols, polyols, and sugars.6–9 In radical
polymerizations, a-hydroxy radicals are produced in efficient
photochemical cleavages of a-hydroxyketone photo-initiators, and
these nucleophilic radicals rapidly react with acrylates.10–12 In
synthetic applications of radicals, unprotected alcohol groups
are acceptable because the hydroxy group is effectively inert to
radicals due to the high bond energy of the O–H bond, but
synthetic applications of a-hydroxy radicals are uncommon due
to difficulties in preparation of precursors for these species.
In the past few decades, a rapidly increasing knowledge of
radical kinetics has been linked to fundamental advances in
applications of radicals in organic synthesis and in understanding
radical reactions in biology. Many of the practical applications
of radical kinetics have relied on indirect kinetic studies using
radical clock methodology,1,2 where a reaction of interest competes
with a calibrated (typically first-order) radical clock reaction, and
the rate constant of interest is calculated from product ratios
determined after the reaction and the known rate constant for
the clock reaction. Often, radical clocks involve intramolecular
rearrangement reactions such as radical cyclizations, and early
radical clock calibrations were reported by pioneers in organic
radical chemistry such as Walling3 and Beckwith.4,5
Results and Discussion
The kinetics method used in this work is similar to that previously
reported by our group for a number of direct kinetic studies
using laser flash photolysis (LFP) methods,13 and the technique
was previously applied for kinetic studies of related a- and
b-methoxy-substituted radicals.14,15 The radical precursors were
Barton PTOC esters 1.16,17 These precursors contain a long
wavelength chromophore centered at about 360 nm, and they are
readily cleaved by photolysis with 355 nm light from a Nd-YAG
laser (Scheme 1). The initial photochemical reaction cleaves the
N–O bond of the precursor to give the pyridine-2-thiyl radical
(2) and acyloxyl radicals 3. The acyloxyl radicals decarboxylate
rapidly to give a-hydroxy radicals 4. Cyclizations of radicals 4
give diphenylalkyl radicals 5, which have a strong long wavelength
chromophore centered at ca. 335 nm. In LFP applications with
Nd-YAG lasers and fast photomultiplier tubes, first-order rate
constants in excess of 1 ¥ 108 s-1 can be measured.
A wide range of radical clocks exists, but the number of
calibrated clocks for substituted carbon-centered radicals is some-
what limited. In this work, we report absolute kinetic studies
of cyclizations of two a-hydroxy-substituted radicals that can
serve as clocks. a-Hydroxy radicals are produced in a number
of contexts, and perhaps the two most important are in biology
and in commercial radical polymerization chemistry. In biology,
Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor
St., Chicago, IL, 60607, USA
† This work is dedicated to the memory of Athel Beckwith, a teacher and
scientist from whom we learned how to study chemistry by example. His
pioneering advances in radical chemistry laid the foundation for much of
the current radical clock methodology.
‡ Electronic supplementary information (ESI) available: Kinetic results
and NMR spectra. See DOI: 10.1039/c0ob00588f
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and ester (11). The ketal enolate alkylation reaction giving 10
was attempted first. Due to the modest yield of that reaction,
we conducted the second alkylation with the enolate from ethyl
lactate,22 but the yield of 11 was similar to the yield of 10.
Hydrolyses of 10 and 11 gave acids 12 that were converted to the
PTOC esters. Acids 12 were characterized by NMR spectroscopy
and high resolution mass spectrometry.
As noted, we are unaware of previous preparations of PTOC
esters from a-hydroxy acids. In our initial attempts to couple
acids 12 with N-hydroxypyridine-2-thione, unidentified products
were obtained when the reactions were conducted under typical
reactions conditions of room temperature and reaction times of
ca. 30 min to 3 h. Acceptable yields of 1 were obtained when
the reaction time was reduced to 5 min, the reaction mixture
was poured directly onto a chromatography column, and the
product was rapidly eluted from the column. We used 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide as the coupling agent to avoid
precipitation of the urea by-product, which would complicate
the rapid chromatography step. The PTOC esters were obtained
in 45–50% yields in about 95% purity as judged from NMR
spectroscopy, which was acceptable for our studies. In our hands,
these compounds decomposed on standing at room temperature
or when stored at ca. 0 ◦C for more than a day. The samples used
in the kinetic studies were stored at -78 ◦C and used within a
few days of preparation.
The conception of our kinetic studies was that radicals 4 would
cyclize rapidly to give product radicals that are readily detected by
fast UV-visible spectroscopy. We conducted preparative reactions
with PTOC esters 1 to ensure that the overall reaction sequence
was as expected. Thus, PTOC esters 1 were allowed to react in
radical chain reactions in the presence of thiols. The thiols can
trap the initially formed a-hydroxy radicals 4 by H-atom transfer
in competition with the cyclization reactions to give acyclic
alcohols 13, and they also will react with cyclic radicals 5 to give
hydrocarbon products 14 (Scheme 3). We used thiophenol as the
trapping agent for the reaction of radical 4a because the cyclization
reaction is fast enough to compete with this trapping agent. For
Scheme 1
Barton PTOC esters17 were originally designed for synthetic
applications of radicals and are seldom isolated when applied
in synthesis.16 The preparative methods we used were generally
routine, but isolation of the precursors was necessary, and PTOC
esters from a-hydroxy acids have not been reported previously
to our knowledge. Precursors 1 proved to be unstable when
stored for short periods at room temperature, as one might expect
for compounds containing the reactive PTOC moiety, a mixed
anhydride of the thiohydroxamic acid and a carboxylic acid, and
an unprotected hydroxy group. Nonetheless, they could be isolated
in acceptably pure form when they were prepared in short duration
reactions and purified quickly. We note that the PTOC ester entry
for unprotected tertiary a-hydroxy radicals such as those prepared
here might have synthetic utility.
The preparative route for radical precursors 1 is shown in
Scheme 2. 5-Bromopentanoyl chloride (6a) and 6-bromohexanoyl
chloride (6b), prepared from reaction of the acids with oxalyl
chloride, were treated with excess phenylmagnesium bromide to
give the diphenyl-substituted alcohols 7 that were dehydrated to
give the known bromoalkenes 8.18–20 The bromides were converted
to iodides 9; 9a is a known and characterized compound.21 Iodides
9 were used in enolate alkylation reactions that gave derivatives
of the desired a-hydroxy acids (12) in the form of the ketal (10)
Scheme 2
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Scheme 3
Fig. 1 Time-resolved spectrum from reaction of radical 4a at room
temperature. The traces show absorbances at 24, 36, 56, 89, and 223 ns
after the laser pulse. The inset shows the kinetic trace recorded at 335 nm
and solved for a single exponential growth function.
the 6-exo cyclization of radical 4b, we used tert-butylthiol as the
trapping agent.
In practice, radical chain reactions of PTOC esters 1 gave
mixtures of 13 and both diastereomers of 14. For the reaction
of radical 4a in the presence of thiophenol, we obtained 13a and
a ca. 2 : 1 mixture of diastereomers of 14a that were partially
purified by chromatography. From 1H 1-D NOE experiments,
the major diastereomer in the mixture was assigned as the
(1R,2R) and (1S,2S) mixture. Specifically, irradiation of the
protons of the methyl groups in the diastereomers of 14a
resulted in enhanced absorptions from the benzhydryl C–H for
the (1S,2R) diastereomer and from the C2-H for the (1R,2R)
diastereomer.
For the reaction of radical 4b in the presence of t-butylthiol,
a mixture of 13b and diatereromers 14b was obtained. Products
14b were again approximately a 2 : 1 mixture as determined from
NMR spectroscopy, but the diastereomers were not separated.
The reaction of 4b with t-butylthiol also gave some 8,8-diphenyl-
7-octen-2-one from disproportionation of radical 4b. This type
of behavior was seen previously in kinetic studies of alkyl radical
cyclizations in the presence of t-butylthiol,13 which does not react
fast enough in chain reactions to prevent accumulation of relatively
high radical concentrations.
exo cyclization of 4b was fast enough such that reaction with
residual oxygen would not be appreciable. Reactions of radicals
with the PTOC precursors have second-order rate constants on
the order of 106 M-1 s-1,24 and these reactions cannot compete
with the cyclizations given the low concentrations of precursors
used in LFP studies. Therefore, the measured rate constants for
cyclizations of radicals 4 were not corrected, and these values are
listed in Tables S1 and S2 in the ESI.‡ The results are shown
in the form of Arrhenius functions in Fig. 2, and the Arrhenius
parameters are collected in Table 1. Within experimental limits,
the cyclization reactions displayed no solvent effects.
Rate constants for cyclizations of radicals 4 were measured
directly in laser flash photolysis (LFP) studies.13 Dilute solutions
of PTOC ester precursors 1 were sparged with helium in a
temperature controlled addition funnel and allowed to flow
through the reaction cell. Fresh samples were irradiated with
355 nm light from a Nd-YAG laser, and signal growth or decay
was monitored over the range 300–560 nm.
Fig. 1 shows a time-resolved spectrum observed from reaction of
radical 4a. A strong signal with lmax ª 335 nm growing in with time
is attributed to the diphenylalkyl radical 5a formed by cyclization
of 4a.13 A broad signal with lmax ª 490 nm is decaying with time;
this signal is due to the pyridine-2-thiyl radical (2), for which the
UV-visible spectrum has been reported.23 On the time scale of
this kinetic measurement, only a small amount of decay of 2 was
observed. The inset in Fig. 1 shows the kinetic trace recorded at
335 nm, which was solved for first-order exponential growth.
Kinetic studies for radicals 4 were performed i◦n acetonitrile
and in THF over the temperature range -30 to 60 C. Each rate
constant was determined from the average of ten independent
kinetic measurements. The 5-exo cyclizations of radical 4a were
so fast that essentially no competing reaction occurred. The 6-
Fig. 2 Temperature-dependent kinetics of cyclizations of radicals 4. Rate
constants for the 5-exo cyclizations of 4a are squares, and those for 6-exo
cyclizations of 4b are circles. Reactions in acetonitrile are filled symbols,
and reactions in THF are unfilled symbols. The lines are regression fits.
Table 1 Arrhenius parameters for cyclizations of radicals 4a
◦
Radical
Solvent
log Ab
EAc/kcal mol-1
k20 C/s-1d
4a
CH3CN
THF
9.9 0.1
10.0 0.1
2.6 0.1
2.7 0.2
9.1 ¥ 107
9.7 ¥ 107
4b
CH3CN
THF
8.9 0.2
9.2 0.2
4.4 0.3
4.9 0.3
4.1 ¥ 105
3.5 ¥ 105
a From analysis of the rate constants in ESI;‡ errors are 2s. b Pre-
exponential factor. c Activation energy. d Rate constant at 20 ◦C calculated
from the Arrhenius function.
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Table 2 Rate constants for 5-exo cyclizations of radicals 4a and 15 in
was determined to be equal to that of the unsubstituted 5-
hexenyl radical.26 From that observation and the fact that radical
4a cyclizes about 1.5 times as fast as radical 15e, one should
expect that the 1-hydroxy-5-hexenyl radical will cyclize with rate
constants similar to or somewhat larger than those of the 5-hexenyl
radical.27 At room temperature, the predicted rate constant for
cyclization of the 1-hydroxy-5-hexenyl radical is 2–3 ¥ 105 s-1.
The results of the trapping reactions we conducted provide
approximate second-order rate constants for reactions of the thiols
with radicals 4. As indicated in Scheme 3, the cyclization rate
constant and ratio of products can be used to calculate a trapping
rate constant by indirect competition kinetics methods.2 This
method does not give highly precise rate constants when only one
competition reaction is studied, but a single competition study
does give approximate kinetic values. For reaction of radical 4a in
the presence of thiophenol at room temperature, we calculate an
approximate rate constant for trapping of kT = 1.2 ¥ 109 M-1 s-1.
For reaction of 4b with t-butylthiol, we calculate a rate constant
of kT = 2 ¥ 107 M-1 s-1. We estimate that the errors in these values
are on the order of 20%.
Although admittedly low precision, the second-order rate
constants for reactions of the thiols with radicals 4 are larger than
those for reactions of the same thiols with unsubstituted primary
alkyl radicals. Thiophenol reacts with a primary alkyl radical at
25 ◦C with a rate constant kT = 1.4 ¥ 108 M-◦1 s-1,28,29 and t-butylthiol
reacts with a primary alkyl radical at 25 C with a rate constant
of 8 ¥ 106 M-1 s-1.30 That is, the thiophenol reaction with 4a is
nearly an order of magnitude faster than with an alkyl radical,
and the t-butylthiol reaction with 4b is about a factor of 2.5 times
faster than reaction with an alkyl radical. The increased reactivity
of the hydroxy-substituted radicals presumably reflects favorable
polarization in the transition state for the H-atom transfer reaction
where the H-atom of the thiol has relatively positive charge
and the hydroxy-substituted radicals have nucleophilic character
even greater than that of simple alkyl radicals. Such nucleophilic
behavior for an a-hydroxy radical was observed by Fischer
and co-workers for addition reactions of hydroxy-substituted
radicals to alkenes.10 Previously, the rate constants for reactions
of an alkanethiol with a methoxy-substituted radical and an
unsubstituted analog were found to be approximately equal,15 and
the assumption was made then that rate constants for hydroxy-
substituted radicals with thiols would be similar to those of alkyl
radicals, but we now suggest that the reactions of the thiols with
a-hydroxy radicals are faster than those with alkyl radicals.
acetonitrile at 20 ◦
C
Radical
R1
R2
k/s-1
Ref
4a
15a
OH
H
CH3
H
9.2 ¥ 107
4 ¥ 107
this work
13
19
19
14
25
19
19
15b
15c
15d
15e
15f
15g
H
CH3
CH3
H
2 ¥ 107
1 ¥ 107
3.6 ¥ 107
6.1 ¥ 107
2 ¥ 105
4 ¥ 105
CH3
OCH3
OCH3
CN
CH3
CH3
CH3
CO2Et
Rate constants for 5-exo and 6-exo cyclizations of several
terminal diphenylethene radicals with various substituents at
the radical center have been measured directly.13,14,19,25 Table 2
lists the rate constants at 20 ◦C for 5-exo cyclizations for
radical 4a and radicals 15 (Scheme 4). Radical stabilizing groups
typically have small effects on rate constants for cyclizations
because the substituent group has counterbalancing effects on
both the reactant and product radical. Thus, the rate constants
for cyclizations of the hydroxy-substituted radical (4a) and the
methoxy-substituted radicals (15d, 15e) are similar to those for the
primary (15a), secondary (15b), and tertiary (15c) radicals. Note
that a substituent can have a major effect on the rate of cyclization
when it is conjugated with the radical center (giving a planar
structure) such that increased steric compression is present in the
transition state for the cyclizations, and this effect is seen in radicals
15f and 15g.19 The hydroxy radical substituent in radical 4a does
not give a planar radical center, and the cyclization reaction is
faster than that of the unsubstituted parent radical (15a).
Scheme 4
Although the data set is not as complete, similar conclusions can
be made for the 6-exo cyclization of radical 4b. The rate constant
for cyclization of this radical at room temperature is 4 ¥ 105 s-1.
The important comparisons are for the 6-exo cyclizations of the
7,7-diphenyl-6-heptenyl radical (k = 5 ¥105 s-1),19 the 1-methyl-7,7-
diphenyl-6-heptenyl radical (k = 2 ¥ 105 s-1),19 the 1-methoxy-7,7-
diphenyl-6-heptenyl radical (k = 1.4 ¥ 105 s-1),14 and the 1-methyl-
1-methoxy-7,7-diphenyl-6-heptenyl radical (k = 1 ¥ 105 s-1).25 The
a-hydroxy-substituted radical 4b cyclizes somewhat faster than
most of its analogs.
Conclusions
The PTOC ester method was shown in this work to be viable for
the production of tertiary a-hydroxy radicals, and this method
might have synthetic utility. Rate constants for 5-exo and 6-exo
cyclizations of the a-hydroxy radicals 4a and 4b were measured
by laser flash photolysis methods. At room temperature, these
reactions have rate constants of k = 9 ¥ 107 s-1 and k = 4 ¥
105 s-1, respectively, which are somewhat faster than cyclizations
of analogous alkyl radicals. Reactions of these radicals with
thiophenol and t-butylthiol are efficient, and the rate constants
for H-atom trapping from the thiols are somewhat larger than
those for H-atom trapping of alkyl radicals.
We did not study cyclizations of a-hydroxy radicals with
unsubstituted alkene moieties at the terminus, but it is noteworthy
that the 5-exo cyclization of the 1-methoxy-5-hexenyl radical
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was warmed to -20 ◦C, stirred for 6 h, and allowed to warm
to room temperature over 2 h. The reaction was quenched with
aqueous HCl (10%) and diluted with 100 mL of Et2O. The layers
were partitioned, and the aqueous layer was extracted three times
with 50 mL of Et2O. The organic phases were combined, and the
mixture was washed sequentially with aqueous Na2S2O3 (10%)
and brine and dried over MgSO4. Rotary evaporation followed by
chromatography over silica gel (5–15% ethyl acetate in hexanes)
gave 1.44 g (44%) of the desired compound as a colorless oil. 1H
NMR: d 1.42 (m, 2H), 1.46 (s, 3H), 1.57, (s, 3H), 1.58 (s, 3H),
1.71 (m, 2H), 2.15 (m, 2H), 6.05 (t, J = 7.0 Hz, 1H), 7.15–7.34
(overlapping signals, 10H). 13C NMR: d 24.3, 25.0, 28.1, 28.8,
29.5, 38.4, 80.3, 109.38, 126.96, 126.98, 127.2, 128.1, 128.2, 128.9,
129.9, 140.1, 142.3, 142.6, 175.4.
Experimental
General
Nuclear magnetic resonance (NMR) spectra were recorded in
deuterated solvents on 300 or 500 MHz instruments. Chemical
shifts in 1H NMR spectra are reported in parts per million
(ppm) relative to tetramethylsilane (TMS) (d = 0 ppm). Chemical
shifts of 13C NMR spectra are reported in ppm using TMS
(d = 0 ppm) or the central peak of CDCl3 (d = 77.23 ppm)
for calibration. High resolution mass spectra were acquired by
the Mass Spectrometry Laboratory (MSL) of the University of
Illinois at Urbana/Champaign. All reagents were purchased from
Sigma–Aldrich Co. or Thermo–Fisher Scientific Inc. and were
used as received unless noted. THF, Et2O, and CH2Cl2 were puri-
fied and dried in a commercial solvent system. Air- or moisture-
sensitive reactions were performed under nitrogen or argon.
Reaction products were purified by column chromatography on
silica gel unless noted.
Ethyl 2-hydroxy-2-methyl-8,8-diphenyloct-7-enoate (11)
was prepared by a method similar to that reported for alkylation
of ethyl lactate.22 A 500 mL round-bottomed flask was equipped
with a stir bar and placed under N2 gas. Diisopropylamine (7.8 mL,
55.0 mmol) in 100 mL of THF was added. The mixture was cooled
5-Bromo-1,1-diphenylpent-1-ene (8a) and
6-bromo-1,1-diphenylhex-1-ene (8b)
◦
to -78 C, and n-BuLi (32.8 mL, 1.6 M in hexanes, 52.5 mmol)
were prepared as previously reported and had 1H and 13C NMR
that matched those previously reported.18–20
was added dropwise. The reaction mixture was stirred for 45 min,
and ethyl lactate (2.95 g, 25.0 mmol) in 10 mL of THF was added.
The flask was placed in a 0 ◦C bath, stirred for 45 min, and cooled
5-Iodo-1,1-diphenylpent-1-ene (9a)
◦
to -78 C. Iodide 9b (22.6 g, 62.4 mmol) in 50 mL of THF was
added dropwise. The flask was warmed to -10 ◦C, stirred for 4h,
and allowed to warm to room temperature over 1 h. Aqueous HCl
(100 mL, 10%) was added, followed by 100 mL of Et2O. The layers
were partitioned, and the aqueous layer was extracted three times
with 50 mL of Et2O. The organic layers were combined, washed
sequentially with aqueous Na2S2O3 (10%) and brine, and dried
over MgSO4. Rotary evaporation followed by chromatography
over silica gel (5–15% ethyl acetate in hexanes) gave 4.8 g (55%)
was prepared from bromide 8a by reaction with NaI in acetone
(similar to the reaction described below) and had NMR spectra
that matched those previously reported.21
6-Iodo-1,1-diphenylhex-1-ene (9b)
Bromide 8b (20.74 g, 65.8 mmol) was dissolved in 250 mL of
acetone, and NaI (30 g, 195 mmol) was added. The reaction was
stirred at room temperature overnight and diluted with 200 mL
of Et2O and 200 mL of water. The aqueous layer was extracted
three times with 100 mL of Et2O. The organic layers were combined
and washed sequentially with an aqueous 10% sodium bisulfate
solution and brine. The ethereal solution was dried over MgSO4,
and the solvent was removed via a rotary evaporator. Column
chromatography on silica gel (5% ethyl acetate in hexanes) gave
1
of the desired compound as a colorless oil. H NMR: d 1.25 (t,
J = 7 Hz, 3H), 1.37 (s, 3H), 1.42 (m, 4H), 1.59 (m, 1H), 1.69 (m,
1H), 2.10 (q, J = 7.5 Hz, 2H), 3.19 (s, 1H), 4.19, (q, J = 7 Hz,
2H), 6.05 (t, J = 7.5 Hz), 7.15–7.36 (overlapping signals, 10H).
13C NMR: d 14.3, 23.4, 26.1, 29.6, 30.1, 40.0, 61.8, 74.4, 126.8,
126.9, 127.2, 128.1, 128.2, 129.8, 130.0, 140.3, 141.8, 142.8, 177.3.
HRMS (EI+): Calcd for C23H28O3 352.2038; found, 352.2031.
1
22.6 g, (95%) of the title compound as a colorless oil. H NMR:
d 1.97 (m, 2H), 2.21 (m, 2H), 3.14 (t, J = 7.5 Hz, 2H), 6.02 (t,
J = 7.5 Hz, 1H), 7.15-7.36 (overlapping signals, 10H). 13C NMR:
d 6.2, 30.9, 34.1, 127.3, 127.4, 127.5, 127.7, 128.3, 128.5, 130.0,
140.0, 142.6, 143.2.
2-Hydroxy-2-methyl-7,7-diphenylhept-6-enoic acid (12a)
Dioxolanone 10 (0.655 g, 1.87 mmol) was dissolved in THF (6
mL), 6 mL of 1.0 M LiOH in H2O was added, and the mixture
was heated at reflux. The mixture was stirred vigorously until the
reaction appeared to be complete by TLC (ca. 6 h). The mixture
was cooled in an ice water bath, and 1 M NaHSO4 solution was
added dropwise to bring the pH to 4. The reaction mixture was
poured into a separatory funnel and extracted three times with
15 mL of ethyl acetate. The organic phases were combined, washed
with brine, and dried over MgSO4. Rotary evaporation followed
by high vacuum left 511 mg (88%) of the title compound as a
white foam. 1H NMR: d 1.40 (m, 1H), 1.46, (s, 3H), 1.68, (m, 2H),
1.79 (m, 1H), 2.15, (q, J = 7.5 Hz, 2H), 6.06 (t, J = 7.5 Hz, 1H),
7.15–7.38 (overlapping signals, 10H). 13C NMR: d 24.0, 26.0, 29.6,
39.5, 74.6, 126.9, 127.0, 127.2, 128.1, 128.2, 129.1, 129.9, 140.12,
5-(5,5-Diphenylpent-4-enyl)-2,2,5-trimethyl-1,3-dioxolan-4-one
(10)
A 500 mL round-bottomed flask was equipped with a stir bar and
placed under nitrogen. Diisopropylamine (1.47 mL, 10.4 mmol)
in 100 mL of THF was added. The flask was cooled to -78 ◦C
and n-BuLi (6.50 mL, 1.6 M in hexanes, 10.4 mmol) was added
dropwise. The mixture was stirred for 45 min, and 2,2,5-trimethyl-
1,3-dioxolan-4-one31 (1.35 g, 10.4 mmol) in 25 mL of THF was
◦
added dropwise. The mixture was placed in a 0 C bath, stirred
◦
for 45 min, and cooled to -78 C. Iodide 9a (3.28 g, 9.43 mmol)
dissolved in 15 mL of THF was added dropwise. The mixture
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142.2, 142.6, 181.9. HRMS (EI+): Calcd for C20H22O3 310.1569;
found, 310.1582.
7,7-Diphenylhept-6-en-2-ol (13)
1H NMR: d 1.24 (d, J = 7 Hz, 3H), 1.46 (m, 2H), 1.55 (m, 2H),
2.15 (m, 2H), 3.75 (m, 1H), 6.08 (t, J = 7.5 Hz, 1H), 7.16–7.35
(overlapping signals, 10H). 13C NMR: d 23.5, 26.1, 29.6, 38.8, 68.0,
126.0, 126.8, 127.0, 128.1, 128.2, 129.6, 129.9, 140.1, 141.9, 143.0.
HRMS (EI+): Calcd for C19H23O 266.1671, found, 266.1661.
2-Hydroxy-2-methyl-8,8-diphenyloct-7-enoic acid (12b)
was prepared as above from ester 11 (4.43 g, 12.56 mmol). The title
compound was isolated as a white foam (3.71 g, 91%). 1H NMR:
d 1.23 (m, 2H), 1.41 (s, 3H), 1.45 (m, 2H), 1.60 (m, 1H), 1.72 (m,
1H), 2.10 (q, J = 7.5 Hz, 2H), 6.04 (t, J = 7.5 Hz, 1H), 7.15–7.36
(overlapping signals, 10H). 13C NMR: d 23.3, 25.9, 29.6, 29.8, 30.0,
39.8, 74.7, 126.8, 126.9, 127.2, 128.1, 128.2, 129.6, 130.0, 140.2,
141.9, 142.8, 181.9. HRMS (EI+): Calcd for C21H24O3, 324.1725;
found, 324.1712.
(1R, 2R)- and (1S, 2S)-2-Benzhydryl-1-methylcyclopentanol (14a,
major isomer)
1H NMR: d 0.82 (s, 3H), 1.46 (m, 2H), 1.57 (bs, 1H), 1.70 (m, 4H),
2.61 (m, 1H), 4.03 (d, J = 11.5 Hz, 1H), 7.14 (m, 2H), 7.26 (m, 4H),
7.35 (m, 2H), 7.41 (m, 2H). 13C NMR: d 19.8, 22.3, 24.9, 43.8, 55.4,
57.1, 82.1, 126.1, 126.3, 128.4, 128.5, 129.3, 129.5, 143.0, 143.1.
1-(2-Hydroxy-2-methyl-6,6-diphenylhex-5-enoyloxy)pyridine-
2(1H)-thione (1a)
(1S, 2R)- and (1R, 2S)-2-Benzhydryl-1-methylcyclopentanol (14a,
1-Hydroxy-1H-pyridine-2-thione (0.127 g, 1.0 mmol) and 1-ethyl-
3-(3-dimethylaminopropyl) carbodiimide (0.192 g, 1.0 mmol) were
dissolved in 2 mL of CH2Cl2 in a 25 mL round-bottomed flask.
The flask was shielded from light, and acid 12a (0.311 g, 1.0
mmol) dissolved in 3 mL of CH2Cl2 was added. The mixture was
stirred for 5 min and poured onto a silica gel (35 g) column. The
column was eluted with 60% ethyl acetate in hexanes. After rotary
evaporation and high vacuum (< 1 Torr), the desired product
remained as a yellow oil (0.212 g, 50%). 1H NMR: d 1.61 (m, 1H),
1.64 (s, 3H), 1.72 (m, 1H), 1.87 (m, 1H), 1.97 (m, 1H), 2.18 (q, J =
7.5 Hz, 2H), 3.62 (bs, 1H), 6.08 (t, J = 7.5 Hz, 1H), 6.70 (td, J =
7, 1.5 Hz, 1H), 7.17–7.26 (overlapping signals, 8H), 7.29, (d, J =
7.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 2H), 7.60, (d, J = 7 Hz, 1H), 7.68
(dd, J = 7.5, 1.5 Hz, 1H). 13C NMR: d 23.9, 26.0, 29.7, 39.6, 76.2,
114.4, 126.9, 127.0, 127.2, 128.1, 128.3, 129.1, 129.9, 132.4, 132.8,
136.8, 140.1, 142.3, 142.6, 167.1, 175.4.
minor isomer)
1H NMR: d 1.23 (s, 3H), 1.48 (m, 2H), 1.56 (bs, 1H), 1.71 (m, 4H),
2.93 (m, 1H), 3.72 (d, J = 11.5 Hz, 1H), 7.17 (m, 2H), 7.25, (m 4H),
7.30 (m, 2H), 7.43 (m, 2H). 13C NMR: d 20.1, 24.8, 27.8, 40.1, 43.6,
55.6, 82.4, 126.2, 126.3, 128.5, 128.7, 129.6, 129.9, 143.0, 143.2.
HRMS (ES+) of a mixture of 14a isomers: Calcd for C19H23O
266.1671; found, 266.1657.
t-Butylthiol trapping reaction
PTOC ester 1b (0.195 g, 0.45 mmol) and (CH3)3CSH (0.25 mL,
2.25 mmol) were dissolved in 45 mL of THF in a flask shielded
from light. Argon gas was bubbled through the solution with
a syringe needle for five minutes with stirring. The flask was
maintained under argon while being irradiated with a 250 W
tungsten filament lamp until TLC showed no trace of the PTOC
ester. The solvent was removed via rotary evaporator, and the
residue was chromatographed on silica gel to give the compounds
13b (47 mg, 38%), 8,8-diphenyloct-7-en-2-one (32 mg, 26%), and
both diastereomers of 14b (combined 18 mg, 15%).
1-(2-Hydroxy-2-methyl-8,8-diphenyloct-7-enoyloxy)pyridine-
2(1H)-thione (1b)
was prepared as above from acid 12b (1.55 g, 4.80 mmol). The title
compound was isolated as a yellow oil (0.914 g, 50%). 1H NMR:
d 1.40 (m, 1H), 1.50 (m, 2H), 1.57 (m, 1H), 1,83 (m, 1H), 1.92 (m,
1H), 2.15 (q, J = 7.5 Hz, 2H), 3.50 (bs, 1H), 6.08 (t, J = 7.5 Hz,
1H), 6.61 (td, J = 7, 1.5 Hz, 1H),7.15–7.26 (overlapping signals,
8H), 7.30 (d, J = 7.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 2H), 7.56 (d,
J = 6 Hz, 1H), 7.66 (dd, J = 6.5, 1.5 Hz, 1H). 13C NMR: d 23.4,
26.2, 29.7, 30.3, 40.0, 76.4, 114.3, 126.8, 126.9, 127.2, 128.1, 128.2,
129.6, 129.9, 132.9, 136.9, 137.9, 140.2, 141.9, 142.7, 168.3, 175.5
8,8-Diphenyloct-7-en-2-ol (13b)
1H NMR: d 1.17 (d, J = 7 Hz, 3H), 1.31–1.48 (overlapping signals,
6H), 1.61 (bs, 1H), 2.12 (q, J = 7.5 Hz, 2H), 3.75 (m, 1H), 6.08 (t,
J = 7.5 Hz, 1H), 7.16–7.38 (overlapping signals, 10H). 13C NMR: d
23.5, 25.4, 29.7, 30.0, 39.2, 68.1, 126.8, 126.9, 127.2, 128.1, 128.2,
129.8, 130.0, 140.2, 141.7, 142.8. HRMS (EI+): Calcd for C20H24O
280.1827; found, 280.1834
Thiophenol trapping reaction
8,8-Diphenyloct-7-en-2-one
PTOC ester 1a (0.105 g, 0.25 mmol) and thiophenol (77 mL,
0.75 mmol) were dissolved in 25 mL of THF in a flask shielded
from light. Argon gas was bubbled through the solution with a
syringe needle for 5 min. The flask was kept under argon pressure
and irradiated with a 250 W tungsten filament lamp until TLC
showed no trace of the PTOC ester. The solution was washed
with 1 M aqueous NaOH to remove the thiol and extracted
three times with 25 mL of Et2O. The combined organics were dried
over MgSO4, and the solvent was removed via rotary evaporator.
The remaining residue was chromatographed on silica gel to give
compound 13a (14 mg, 21%) and a mixture of diastereomers 14a
(combined 41 mg, 61%).
1H NMR: d 1.44 (qu, J = 7.5 Hz, 2H), 1.58 (m, 2H), 2.10 (s, 3H),
2.12 (m, 2H), 2.36 (t, J = 7.5 Hz, 2H), 6.07 (t, J = 7.5 Hz, 1H),
7.15–7.39 (overlapping signals, 10H). 13C NMR: d 23.3, 29.4, 29.9,
43.5, 126.8, 126.9, 127.2, 128.1, 128.2, 129.4, 129.9, 140.2, 142.0,
142.7, 209.0. HRMS (EI+): Calcd for C20H22O 278.1671; found,
278.1664.
2-Benzhydryl-1-methylcyclohexanol (14b)
was produced as a 3.3 : 1 mixture of diastereomers. In the proton
NMR spectrum, signals for the major isomer at d 4.34, 2.28,
and 1.04 did not overlap with the corresponding signals from the
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minor isomer at d = 3.79, 2.54 and 1.56; other signals for the
Notes and References
diastereomers overlapped. Except as noted, signals reported are
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1
for the mixture. H NMR: d 1.04 (s, 2.3H, major isomer), 1.2–
1.65 (overlapping m, 8H overlapped with s, 0.7H, minor isomer),
2.29 (m, 0.8 H, major isomer), 2.57 (dt, J = 3.4, 11.8 Hz, 0.25
H, minor isomer), 3.78 (d, J = 11.1 Hz, 0.2 H, minor isomer),
4.35 (d, J = 7.3 Hz, 0.7 H, major isomer), 7.13–7.40 (m, 10H).
13C NMR: (major isomer) d 21.9, 26.2, 26.9, 30.61, 41.6, 49.0,
50.6, 72.5, 125.9, 126.1, 128.2, 128.3, 128.5, 129.5144.0, 144.7,
146.1; (minor isomer) d 22.1, 23.8, 29.7, 29.9, 42.2, 55.6, 74.4,
126.1, 126.7, 128.0, 128.7, 129.0. HRMS (EI+): calc for C20H24O
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of ten independent kinetic measurements.
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This work was supported by a grant from the National Science
Foundation.
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