Triphosgene-amine base promoted chlorination of unactivated aliphatic alcohols

Article abstract of DOI:10.1021/jo400341n

Unactivated α-branched primary and secondary aliphatic alcohols have been successfully transformed into their corresponding alkyl chlorides in high yields upon treatment with a mixture of triphosgene and pyridine in dichloromethane at reflux. These mild chlorination conditions are high yielding, stereospecific, and well tolerated by numerous sensitive functionalities. Furthermore, no nuisance waste products are generated in the course of the reactions.

Full text of DOI:10.1021/jo400341n

Article
pubs.acs.org/joc
Triphosgene−Amine Base Promoted Chlorination of Unactivated
Aliphatic Alcohols
Andres Villalpando, Caitlan E. Ayala, Christopher B. Watson,† and Rendy Kartika*
́
Department of Chemistry, Louisiana State University, 232 Choppin Hall, Baton Rouge, Louisiana 70803, United States
S
* Supporting Information
ABSTRACT: Unactivated α-branched primary and secondary
aliphatic alcohols have been successfully transformed into their
corresponding alkyl chlorides in high yields upon treatment
with a mixture of triphosgene and pyridine in dichloromethane
at reflux. These mild chlorination conditions are high yielding,
stereospecific, and well tolerated by numerous sensitive functionalities. Furthermore, no nuisance waste products are generated in
the course of the reactions.
and triethylamine in dichloromethane.9 As shown in Scheme 1,
these conditions were effective in producing primary alkyl
INTRODUCTION
The preparation of alkyl chlorides continues to be an area of
significant interest in organic synthesis. While several new
methods have been developed in recent years, many of these
have limited variability of substrate tolerance and efficiency.1−6
Our involvement in the development of new chlorination meth-
odology originated from our synthetic interests in chlorine-
containing natural products, such as the chlorosulfolipids
(Figure 1). The chlorosulfolipid class of natural products is
■
Scheme 1. Previous Work on Triphosgene−Triethylamine-
Promoted Chlorination
Figure 1. Examples of chlorosulfolipid natural products.
essentially highlighted by multiple chlorine and sulfate sub-
stitutions along the long hydrocarbon backbone. These note-
worthy features are accompanied by multiple stereogenic centers
of chlorine atoms, which present significant challenges for
structure elucidation and total synthesis.7,8
Intrigued by the unusual structural features of this class of
natural products, we initiated research to develop a mild method
for chemoselective chlorination of aliphatic alcohols, particularly
in the presence of nearby sensitive functionalities. In fact, we
recently reported a new method for the chemoselective chlorina-
tion of primary aliphatic alcohols using a mixture of triphosgene
chlorides in high yields while being compatible with various
acid- and base-sensitive functionalities that would be problematic
Received: February 14, 2013
© XXXX American Chemical Society
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under classical conditions. Furthermore, these conditions were
operationally simple, due to the fact that triphosgene exists as a
stable nonhygroscopic crystalline material at room temperature,
and this permits easy and safe handling.10−12
the two competing products were produced in a nearly 1:1 ratio
regardless of the quantity of triethylamine. Interestingly, entries
6−10 indicated the resistance of chloroformate 4 to further
transformation to either products 5 or 6 when an identical
series of optimization reactions were executed in toluene.
As a result of these initial studies, we concluded that tri-
ethylamine alone, as a base/activator, would not be effective for
our intended chlorination. Optimization studies then shifted
to the exploration of a mixture of amine bases, such as
pyridine and triethylamine. On the basis of the proposed
N-acylammonium ion intermediate 7,9 our chlorination reac-
tion could employ a stoichiometric amount of pyridine,
which would serve as a base in the chloroformylation step,16
while maintaining a substoichiometric amount of triethylamine
to promote chlorination. We realized that formation of
triethylammonium ion species would be favored in the proton
transfer equilibrium between protonated pyridine and triethyl-
amine upon chloroformylation of the alcohol starting material,
due to the difference in the pKa values of their conjugate acids.17
However, a low concentration of unprotonated triethylamine
is expected to remain in the equilibrium and should promote
nucleophilic substitution by chloride ions by forming
acylammonium ion intermediate 7.
During the course of substrate studies, we observed that
sterically hindered alcohols were not suitable for our method-
ology. For example, activation of 2,2-diphenyl-1-ethanol (1)
with a triphosgene−triethylamine mixture yielded only
diethylcarbamate adduct 2 in 85% yield, while the chlorination
product was not detected. Furthermore, exposure of secondary
alcohol 3 under identical conditions produced a mixture of alkyl
chloride 5 and diethylcarbamate 6 in 45% and 27% yields,
respectively. It appeared that the selectivity between formation
of alkyl chloride and diethylcarbamate was driven by sterics
via an intermediacy of acylammonium ion species 7, where the
ensuing nucleophilic attack by chloride ions could compet-
itively occur at two possible electrophilic carbon centers.13−15
Our mechanistic investigation also concluded that alcohols remain
unreactive toward triphosgene in the absence of triethylamine,
which serves as a base and nucleophilic catalyst to promote
chlorination.9 The broader applicability of our method to sterically
congested substrates is clearly limited by these selectivity
problems, and therefore, it is imperative that we address these
crucial issues.
As shown in Table 2, entries 1−8, activation of secondary
alcohol 3 with triphosgene in the presence of 1.2 equiv of
RESULTS AND DISCUSSION
As shown in Table 1, we proceeded with a comprehensive
optimization study by initially varying the amount of
■
Table 2. Optimization Study with Mixed Amine Base Systems
Table 1. Optimization Study Varying the Amount of
Triethylamine
b
yield, %
amt of Py,
equiv
amt of
Et3N, equiv
a
entry
conditions
3
4
5
6
1
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.2
1.7
2.2
1.0
1.2
1.7
2.2
0.25
0.50
0.75
1.00
0.25
0.50
0.75
1.00
0
0 °C → room temp
0 °C → room temp
0 °C → room temp
0 °C → room temp
0 °C → reflux
0
98
75
60
50
34
9
1
1
0
0
0
0
1
0
9
0
0
0
0
0
0
0
0
a
yield, %
2
0
0
25
39
50
66
90
100
90
7
3
entry
amt of Et3N, equiv
solvent
3
4
5
6
4
0
1
2
3
4
5
6
7
8
9
10
1.00
1.25
1.50
1.75
2.00
1.00
1.25
1.50
1.75
2.00
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
toluene
6
73
75
45
16
3
14
13
27
44
51
3
7
5
0
3
2
9
27
39
46
0
6
0 °C → reflux
0 °C → reflux
0
7
0
0
1
8
0 °C → reflux
0
1
0
9
0 °C → room temp
0 °C → room temp
0 °C → room temp
0 °C → room temp
0 °C → reflux
0 °C → reflux
0 °C → reflux
0 °C → reflux
93
75
35
28
69
0
0
11
3
86
87
87
54
65
10
11
12
13
14
15
16
0
0
25
65
72
31
56
98
100
5
5
0
0
2
6
5
0
0
1
18
21
27
13
0
0
2
0
44
0
a
Yields were determined by GC-MS analysis of the crude mixtures,
assuming that these compounds elicited identical GC responses.
0
2
0
0
0
a
Reagents were added at 0 °C, and then the reaction mixture was
b
warmed to room temperature or reflux. Yields were determined by
GC-MS analysis of the crude mixtures, assuming that these
compounds elicited identical GC responses.
triethylamine while maintaining 0.5 equiv of triphosgene.
Secondary alcohol 3 was used as a model substrate for these
studies. We hypothesized that perhaps reducing the amount
of triethylamine would inhibit formation of the undesired
diethylcarbamate functionality. As shown in entry 1, the use of
1.0 equiv of triethylamine predominantly produced chlorofor-
mate 4 along with minimal alkyl chloride 5 and diethylcarba-
mate 6.16 According to our expectation, an incremental increase
of triethylamine from 1.0 to 2.0 equiv resulted in the dis-
appearance of 4. In these cases, however, formation of 5 and 6
was found to be equally facile. As indicated in entries 2−5,
pyridine with varying substoichiometric amounts of triethyl-
amine successfully suppressed the formation of diethylcarbamate
6. These reactions primarily afforded chloroformate 4 at room
temperature (entries 1−4), but heating the reaction mixtures to
reflux (entries 5−8) led to an increased production of alkyl
chloride 5. In fact, entry 7 details the GC-MS analysis of the
crude materials, revealing that the use of 1.2 equiv of pyridine
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and 0.75 equiv of triethylamine in dichloromethane at reflux
quantitatively converted secondary alcohol 3 to alkyl chloride 5.
Much to our surprise, an attempt to further investigate the
role of pyridine in this reaction yielded unanticipated results,
as studies in entries 9−12 indicated that the use of pyridine
by itself readily generated the target alkyl chloride. In fact,
secondary alcohol 3 was completely consumed and converted to
alkyl chloride 5 when the reaction was performed using excess
pyridine in refluxing dichloromethane (entries 13−16). These
conditions completely eliminated the problematic formation
of diethylcarbamate byproduct. Interestingly, while the use of
1.0 equiv of pyridine led to a mixture of 2:1 mixture of starting
material 3 and alkyl chloride 5 (entry 13), increasing the
amount of pyridine to 1.2 equiv fully consumed alcohol 3 and
yielded a 1:1 mixture of chloroformate 4 and alkyl chloride 5
(entry 14). These observations again strongly suggested an
intermediacy of the chloroformate species in our chlorination
reaction.
Table 3. Chlorination of Secondary Alcohols Containing
Various Functionalities and Protecting Groups
These results were intriguing, as there are precedents which
demonstrate that a triphosgene−pyridine mixture readily
chlorinates activated alcohols, such as those in benzylic, allylic,
or propargylic systems.18 There are also reports that demon-
strate the use of this mixture to convert aliphatic alcohols
to their corresponding chloroformates.19−22 However, to the
best of our knowledge, chlorination of unreactive aliphatic
secondary alcohols using this mixture has remained unexplored.
With these preliminary results in hand, we then examined the
generality of these chlorination conditions by screening a series
of secondary alcohols containing various common functional
and protecting groups. A typical reaction protocol involved addi-
tion of 0.5 equiv of triphosgene and 2.0 equiv of pyridine to a
solution of 1.0 equiv of secondary alcohol in dichloromethane
at 0 °C. The reaction mixture was then warmed to gentle reflux
overnight, followed by aqueous workup with a dilute HCl
solution and flash chromatography. It is crucial to note that
unlike the classical chlorination methods using SOCl2 or PPh3−
NCS activation, our reaction does not produce any nuisance
waste products. The typical crude reaction mixture upon workup
cleanly contains the desired alkyl chloride, although in most
cases, a minor elimination product (<10%) was detected by
a
b
Alcohols 8d−j are racemic. Yield based on product isolated by flash
c
chromatography. In most cases, a minor (<10%) elimination product
was detected in the crude mixture by either GC-MS or H NMR.
1
Our previous report also revealed the incompatibility of
α-branched primary alcohols with our triphosgene−triethylamine
chlorination conditions. Such substrates were readily transformed
to the diethylcarbamate functionality.9 This problem was readily
rectified with the new triphosgene−pyridine conditions. For
example, as shown in Table 4, α-phenyl and α-methyl phenethyl
alcohols 10a,b readily underwent chlorination to provide the
primary alkyl chlorides 11a,b in 81% and 86% yields,
1
crude GC-MS or H NMR analyses.
As shown in Table 3 entries 1−3, simple secondary alcohols
in both acyclic and cyclic forms 8a−c were readily converted to
their corresponding secondary alkyl chlorides 9a−c in excellent
yields. The use of enantiomerically pure alcohol 8a produced
optically active 9a in high yield. The absolute configuration
of this secondary chloride and its enantiomeric purity were
determined by comparing its optical rotation to the literature
value.23 These results confirmed that our chlorination reac-
tion is stereospecific and proceeds via an inversion of stereo-
chemistry. Our chlorination conditions proved to be mild, as
β-hydroxy ester 8d readily afforded β-chloro ester 9d in 82%
yield without suffering from any substantial elimination. Olefins
were also found to be a suitable functionality. Secondary
alcohols 8e,f, containing internal and terminal olefins, provided
their corresponding chlorides 9e,f in good yields. Common
protecting groups were also compatible under the reaction
conditions. Entries 7−10 show that tert-butyldimethylsilyl
ether, benzyl ether, p-methoxybenzyl ether, and p-toluoyl
containing starting materials 8g−j proceeded to chlorination
without complications to give the secondary chlorides 9g−j in
excellent yields.
Table 4. Chlorination of α-Branched Primary Alcohols
a
b
Alcohol 10b is racemic. Yield based on product isolated by flash
chromatography.
C
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respectively. N-Boc prolinol 10c also produced the correspond-
ing chloride 11c in 65% yield.
As an extension to the scope of substrate study, we continued
our exploration to demonstrate the feasibility of our method to
simultaneously introduce two carbon−chlorine bonds via global
chlorination of multiple hydroxy centers. Scheme 2 details our
We discovered that activation of unactivated aliphatic
secondary alcohols with triphosgene and pyridine in dichloro-
methane at reflux cleanly produced the desired alkyl chlorides
while eliminating the diethylcarbamoylation byproducts. These
new reaction conditions are very useful and will strongly compli-
ment the already existing chlorination methods. Our method is
operationally simple, high yielding, stereospecific, mild, and well
tolerated by a wide array of common functional and protecting
groups. More importantly, our chlorination reaction does not
produce any reactive or nuisance waste products, and the typical
crude materials cleanly contain the target alkyl chloride. An
extension of this work to other halogenation reactions and their
applications toward stereoselective syntheses of chlorine-containing
complex natural products are ongoing in our laboratories. Results
from these efforts will be reported in due course.
Scheme 2. Reactivity of 1,3- and 1,6-Diols
EXPERIMENTAL SECTION
■
All materials, unless otherwise stated, were purchased from commercial
sources and utilized without further purification. Anhydrous reactions
were conducted in oven-dried glassware, which was then cooled under
vacuum and purged with nitrogen gas. Anhydrous solvents (dichloro-
methane, toluene, acetonitrile, diethyl ether, and tetrahydrofuran)
were filtered through activated 3 Å molecular sieves under nitrogen
in a solvent purification system. Reactions were monitored either by
analytical thin-layer chromatography (TLC silica gel 60 F254, glass
plates) and analyzed using 254 nm UV light and anisaldehyde−sulfuric
acid or potassium permanganate stains or via gas chromatography−
mass spectrometry (GC-MS). The column for the GC-MS system was
5% phenyl methyl siloxane, measuring 30 m in length with an internal
diameter of 250 μm and film thickness of 0.25 μm. Low and high mass
readings were set to 40 to 800 m/z, respectively. Oven, inlet, and
detector temperatures were set to 250 °C, and helium was used as
the inert carrier gas. Column chromatography was completed using
initial attempts at this strategy using starting materials such
as 1,3-diol 12 and 1,6-diol 14. Treatment of these compounds
by doubling the amount of triphosgene and pyridine cleanly
afforded alkyl dichlorides 13 and 15 in 55% and 73% yields,
respectively. The lower isolated yields were most likely attributed
to the high volatility of the resulting alkyl chlorides. These results
suggested that, in the presence of excess triphosgene and pyridine,
global chloroformylation of the two hydroxy groups preceded the
potentially competitive intramolecular six-membered carbonate
cyclization resulting from monochloroformylation.24,25 This
hypothesis was clearly supported by the fact that exposure of
1,3-diol 12 to the typical 0.5 equiv of triphosgene and 2.0 equiv
of pyridine resulted in a mixture of chlorination at the primary
position, i.e. chloro alcohol 16, in 14% yield and cyclic carbonate
17 in 66% yield. These observations were consistent with our
previous report.9
1
silica gel. Unless otherwise noted, all H and 13C NMR spectra were
recorded in CDCl3 using a spectrometer operating at 400 MHz for 1H
1
and 100 MHz for 13C or at 250 MHz for H and 62.5 MHz for 13C.
Chemical shifts (δ) are reported in ppm relative to residual CHCl3 as
an internal reference (1H, 7.26 ppm; 13C, 77.00 ppm). Coupling
constants (J) are reported in hertz (Hz). Peak multiplicity is indicated
as follows: s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), x
(septet), h (heptet), b (broad), and m (multiplet). FT-IR spectra were
recorded using thin films, and absorption frequencies are reported
in reciprocal centimeters (cm−1). High-resolution mass spectrometry
(HRMS) analyses were performed using electron spray ionization−
time of flight (ESI-TOF) methods.
The mechanism of this chlorination reaction is proposed as
follows (Scheme 3). It is well precedented that activation of
Scheme 3. Proposed Reaction Mechanism
General Chlorination Procedure. Unless otherwise noted, the
alcohol (2.0 mmol) was placed in an oven-dried round-bottomed flask
and dissolved in anhydrous dichloromethane (15 mL). The solution
was then cooled to 0 °C. Pyridine (0.32 mL, 4.0 mmol) was then
added via syringe, followed by triphosgene (297 mg, 1.0 mmol) in one
portion. The solution was stirred for 5 min and then warmed to gentle
reflux overnight. The reaction mixture was then poured into a
separatory funnel containing 1 M HCl aqueous solution (30 mL), and
the biphasic mixture was shaken vigorously. Upon separation of layers,
the aqueous layer was re-extracted with dichloromethane (2 × 30 mL).
Organic extracts were collected, dried over MgSO4, filtered, and
concentrated under vacuum. The resulting crude material was purified
using flash column chromatography with silica gel as the stationary
phase and a hexanes/ethyl acetate, pentane/diethyl ether, or pentane/
dichloromethane mixture as the mobile phase.
(+)-(S)-(2-Chloropropyl)benzene (9a). Alcohol 8a (272 mg,
2.00 mmol) was utilized along with pyridine (0.32 mL, 4.00 mmol)
and triphosgene (297 mg, 1.00 mmol) to produce 9a in 89% yield as a
colorless oil (273 mg, 1.77 mmol). The purified product was eluted
with 100% hexanes. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.37−7.21
(5H, m), 4.24 (1H, x, J = 6.8 Hz), 3.11 (1H, dd, J = 13.8, 7.0 Hz), 2.98
(1H, dd, J = 13.9, 7.0 Hz), 1.53 (3H, d, J = 6.5 Hz). 13C NMR (62.5
MHz, CDCl3): δ (ppm) 137.9, 129.2, 128.3, 126.7, 58.4, 46.6, 24.6.
alcohol with a triphosgene−pyridine mixture leads to forma-
tion of the chloroformate functionality: viz., 18.16,19−22 It is
reasonable to presume that excess pyridine then readily adds to
the chloroformate to generate the putative N-acylpyridinium
ion intermediate 19.26−28 This carbonyl activation increases the
reactivity at the electrophilic secondary carbon center, which
allows for SN2 nucleophilic substitution by chloride ions. This
process releases CO2 and pyridine, while generating the alkyl
chloride with an inversion of stereochemistry.
CONCLUSION
■
In summary, we have successfully addressed the previously
unresolved issues concerning chlorination of aliphatic alcohols.
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GC-MS: M+ 154.6 calculated for C9H11Cl, experimental 154.0.
0.05 (6H, d, J = 7.1 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm)
137.9, 129.4, 128.4, 126.7, 60.3, 59.8, 45.1, 40.6, 25.9, 18.3, −5.4.
IR (cm−1): ν 3030, 2954, 2930, 2857, 1472, 1256, 1110, 910, 837,
778. HRMS-ESI: (M + H)+ 299.1592 calculated for C16H28ClOSi,
experimental 299.1599.
( )-4-Benzyloxy-2-chloro-1-phenylbutane (9h). Alcohol 8h
(256 mg, 2.00 mmol) was utilized along with pyridine (0.32 mL,
4.00 mmol) and triphosgene (297 mg, 1.00 mmol) to produce 9h in
84% yield as a colorless oil (462 mg, 1.69 mmol). The purified product
was eluted with 98/2 hexanes/EtOAc. 1H NMR (400 MHz, CDCl3): δ
(ppm) 7.34−7.21 (10H, m), 4.54−4.45 (2H, m), 3.88 (1H, m), 3.69−
3.60 (2H, m), 2.97 (1H, dd, J = 13.5, 6.0 Hz), 2.80 (1H, dd, J = 13.6,
6.4 Hz), 1.96−1.90 (2H, m). 13C NMR (100, CDCl3): δ (ppm) 138.3,
138.1, 129.5, 128.4, 128.0, 127.8, 126.4, 77.1, 72.1, 41.7, 40.6, 37.4. IR
(cm−1): ν 3063, 3023, 2925, 2866, 1496, 1456, 1350, 1289, 1073,
1029, 910, 737, 699, 651. HRMS-ESI: (M + Na)+ 297.1017 calculated
for C17H19ClNaO, experimental 297.1019.
( )-2-Chloro-4-((4-methoxybenzyl)oxy)-1-phenylbutane (9i). Al-
cohol 8i (572 mg, 2.00 mmol) was utilized along with pyridine
(0.32 mL, 4.00 mmol), and triphosgene (297 mg, 1.00 mmol) to
produce 9i in 82% yield as a colorless oil (498 mg, 1.64 mmol). The
purified product was eluted with 90/10 hexanes/EtOAc. 1H NMR
(400 MHz, CDCl3): δ (ppm) 7.33−7.19 (7H, m), 6.87 (2H, d, J = 8.6
Hz), 4.42 (2H, q, J = 10.9 Hz), 3.86 (1H, m), 3.81 (3H, s), 3.67−3.57
(2H, m), 2.95 (1H, dd, J = 13.6, 6.1 Hz), 2.78 (1H, dd, J = 13.7, 6.4
Hz), 1.96−1.86 (2H, m). 13C NMR (100 MHz, CDCl3): δ (ppm)
159.3, 138.2, 130.4, 129.5, 128.4, 126.4, 113.9, 76.8, 71.8, 55.3, 41.7,
40.7, 37.4. IR (cm−1): ν 3063, 3030, 2936, 2870, 1612, 1513, 1248,
1076, 1034, 822, 740, 701. HRMS-ESI: (M + Na)+ 327.1122 cal-
culated for C18H21ClNaO2, experimental 327.1133.
[α]25 = +23.12° (c = 2.2 in CHCl3). Compound 9a is known:23
D
literature [α]25D = +23.19° (c = 5 in CHCl3) for enantiomerically pure
(S)-(2-chloropropyl)benzene.
(2-Chloropropane-1,3-diyl)dibenzene (9b). Alcohol 8b (420 mg,
2.00 mmol) was utilized along with pyridine (0.32 mL, 4.00 mmol)
and triphosgene (297 mg, 1.00 mmol) to produce 9b in 87% yield as a
colorless oil (397 mg, 1.73 mmol). The purified product was eluted
with 100/0 → 90/10 hexanes/EtOAc. 1H NMR (250 MHz, CDCl3): δ
(ppm) 7.38−7.23 (10H, m), 4.34 (1H, dddd, J = 8.0, 8.0, 5.6, 5.2 Hz),
3.16 (2H, dd, J = 14.1, 5.6 Hz), 3.04 (2H, dd, J = 14.2, 8.0 Hz). 13C
NMR (62.5 MHz, CDCl3): δ (ppm) 137.8, 129.3, 128.3, 126.7, 63.9,
44.2. IR (cm−1): ν 3088, 3064, 3029, 1603, 1498, 1455, 911, 741, 700,
670. GC-MS: (M − H)+ 229.7 calculated for C15H14Cl, experimental
229.9. Compound 9b is known.29
N-Boc-4-chloropiperidine (9c). Alcohol 8c (403 mg, 2.00 mmol)
was utilized along with pyridine (0.32 mL, 4.00 mmol) and
triphosgene (297 mg, 1.00 mmol) to produce 9c in 88% yield as a
pale yellow oil (387 mg, 1.76 mmol). The purified product was eluted
1
with 90/10 → 80/20 pentane/diethyl ether. H NMR (400 MHz,
CDCl3): δ (ppm) 4.20 (1H, m), 3.73−3.68 (2H, m), 3.32−3.26
(2H, m) 2.06−1.99 (2H, m), 1.86−1.76 (2H, m), 1.46 (9H, s). 13C
NMR (100 MHz, CDCl3): δ (ppm) 154.5, 79.6, 56.8, 41.3 (b), 34.9,
28.3. IR (cm−1): ν 2977, 2870, 2839, 1692, 1478, 1419, 1366, 1264,
1218, 1165, 1110, 1001, 895, 767, 719. HRMS-ESI: (M + Na)+
242.0918 calculated for C10H18ClNNaO2, experimental 242.0918.
Ethyl ( )-3-Chloro-4-phenylbutyrate (9d). Alcohol 8d30 (417 mg,
2.00 mmol) was utilized along with pyridine (0.32 mL, 4.00 mmol)
and triphosgene (297 mg, 1.00 mmol) to produce 9d in 82% yield as a
pale yellow oil (372 mg, 1.64 mmol). The purified product was eluted
with 100% pentane. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.34−7.22
(5H, m), 4.51 (1H, dt, J = 13.4, 7.3 Hz), 4.16 ppm (2H, q, J = 6.8 Hz),
3.09 (2H, dd, J = 6.7, 4.6 Hz), 2.75−2.71 (2H, m), 1.27 (3H, t, J =
7.1 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 170.1, 137.0, 129.5,
128.6, 127.1, 60.9, 57.7, 44.3, 42.6, 14.2. IR (cm−1): ν 3065, 3030,
2983, 2905, 1737, 1654, 1304, 1150, 1096, 910, 747, 650. HRMS-
ESI: (M + H)+ 227.0833 calculated for C12H16ClO2, experimental
227.0835.
( )-3-Chloro-4-phenylbutyl 4-Methylbenzoate (9j). Alcohol 8j
(568 mg, 2.00 mmol) was utilized along with pyridine (0.32 mL,
4.00 mmol) and triphosgene (297 mg, 1.00 mmol) to produce 9j in
85% yield as a colorless oil (514 mg, 1.70 mmol). The purified product
was eluted with 90/10 hexanes/EtOAc. 1H NMR (400 MHz, CDCl3):
δ (ppm) 7.91 (2H, d, J = 8.2 Hz), 7.35−7.24 (5H, m), 4.55 (1H, ddd,
J = 11.2, 6.2, 4.7 Hz), 4.47 (1H, m), 4.32 (1H, m), 3.13 (2H, d, J = 6.8
Hz), 2.42 (3H, s), 2.31 (1H, m), 2.09 (1H, m). 13C NMR (100 MHz,
CDCl3): δ (ppm) 166.5, 143.8, 137.4, 129.6, 129.4, 129.1, 128.5,
127.4, 127.0, 61.8, 59.9, 45.0, 36.7, 21.7. IR (cm−1): ν 3087, 3062,
2964, 2861, 1715, 1270, 1177, 1109, 1021, 752, 700. HRMS-ESI:
(M + H)+ 303.1152 calculated for C18H20ClO2, experimental 303.1145.
2-Chloro-1,1-diphenylethane (11a). Alcohol 10a (397 mg,
2.00 mmol) was utilized along with pyridine (0.32 mL, 4.00 mmol)
and triphosgene (297 mg, 1.00 mmol) to produce 11a in 81% yield
as a light yellow oil (350 mg, 1.62 mmol). The purified product was
( )-4-Chloro-5-phenylpent-1-ene (9e). Alcohol 8e31 (324 mg,
2.00 mmol) was utilized along with pyridine (0.32 mL, 4.00 mmol)
and triphosgene (297 mg, 1.00 mmol) to produce 9e in 94% yield as a
colorless oil (340 mg, 1.88 mmol). The purified product was eluted
1
with 100% pentane. H NMR (400, MHz, CDCl3): δ (ppm) 7.36−
7.24 (5H, m), 5.93 (1H, m), 5.20−5.15 (2H, m), 4.17 (1H, m), 3.10
(1H, dd, J = 14.1, 6.2 Hz), 3.04 (1H, dd, J = 14.1, 6.4 Hz), 2.59 (1H,
m), 2.48 (1H, m). 13C NMR (100 MHz, CDCl3): δ (ppm) 137.8,
134.0, 129.4, 128.5, 126.8, 118.3, 62.5, 44.2, 41.8. IR (cm−1): ν 3080,
3030, 2981, 2952, 1643, 1604, 1543, 1433, 1284, 1031, 993, 920, 700,
618. GC-MS: M+ 180.1 calculated for C11H13Cl, experimental 180.0.
Compound 9e is known.6
1
eluted with 100% hexanes. H NMR (250 MHz, CDCl3): δ (ppm)
7.35−7.21 (10H, m), 4.34 (1H, t, J = 7.8 Hz), 4.07 (2H, d, J = 7.8 Hz).
13C NMR (62.5 MHz, CDCl3): δ (ppm) 141.2, 128.5, 127.9, 126.9,
53.5, 47.1. IR (cm−1): ν 3062, 3029, 1494, 1452, 910, 737, 699. GC-MS:
M+ 216.1 calculated for C14H13Cl, experimental 216.0. Compound 11a is
known.32
( )-1-Chloro-2-phenylpropane (11b). Alcohol 10b (0.28 mL,
2.00 mmol) was utilized along with pyridine (0.32 mL, 4.00 mmol)
and triphosgene (297 mg, 1.00 mmol) to produce 11b in 86% yield as
a colorless oil (266 mg, 1.73 mmol). The purified product was eluted
with 100% hexanes. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.39−7.19
(5H, m), 3.72 (1H, dd, J = 10.7, 6.2 Hz), 3.61 (1H, dd, J = 10.7,
7.8 Hz), 3.12 (1H, x, J = 7.0 Hz), 1.42 (3H, d, J = 7.0 Hz). 13C NMR
(62.5 MHz, CDCl3): δ (ppm) 143.2, 128.5, 127.1, 126.8, 50.7, 42.2,
18.9. IR (cm−1): ν 3030, 2970, 2875, 1494, 1454, 1015, 910, 762, 720,
699. GC-MS: (M)+ 154.1 calculated for C9H11Cl, experimental 154.0.
Compound 11b is available commercially.
( )-(E)-4-Chloro-1-phenylhepta-1,6-diene (9f). Alcohol 8f (377
mg, 2.00 mmol) was utilized along with pyridine (0.32 mL, 4.00
mmol) and triphosgene (297 mg, 1.00 mmol) to produce 9f in 82%
yield as a yellow oil (339 mg, 1.64 mmol). The purified product was
1
eluted with 100% pentane. H NMR (400 MHz, CDCl3): δ (ppm)
7.38−7.17 (5H, m), 6.48 (1H, d, J = 15.8 Hz), 6.25 (1H, m), 5.94−
5.83 (1H, m), 5.18−5.10 (2H, m), 4.03 (1H, m), 2.72−2.61 (2H, m),
2.59−2.50 (2H, m). 13C NMR (100 MHz, CDCl3): δ (ppm) 137.1,
134.0, 133.2, 128.6, 127.4, 126.2, 125.5, 118.2, 61.5, 42.0, 41.2. IR
(cm−1): ν 3081, 3061, 3028, 2980, 2946, 1644, 1495, 1449, 1289, 967,
918, 744, 694. HRMS-ESI: (M + H)+ 207.0935 calculated for
C13H16Cl, experimental 207.0936.
( )-4-((tert-Butyldimethylsilyl)oxy)-2-chloro-1-phenylbutane
(9g). Alcohol 8g (560 mg, 2.00 mmol) was utilized along with pyridine
(0.32 mL, 4.00 mmol) and triphosgene (297 mg, 1.00 mmol) to
produce 9g in 90% yield as a colorless oil (536 mg, 1.80 mmol). The
purified product was eluted with 100/0 → 90/10 hexanes/EtOAc.
1H NMR (400 MHz, CDCl3): δ (ppm) 7.36−7.22 (5H, m), 4.33 (1H,
ddt, J = 10.1, 9.8, 3.4 Hz), 3.85−3.73 (2H, m), 3.08 (2H, d, J = 6.8
Hz), 2.03 (1H, m), 1.81 (1H, ddt, J = 14.3, 9.8, 4.4 Hz), 0.89 (9H, s),
(S)-N-Boc-2-(chloromethyl)pyrrolidine (11c). Alcohol 10c (345 mg,
2.00 mmol) was utilized along with pyridine (0.32 mL, 4.00 mmol) and
triphosgene (297 mg, 1.00 mmol) to produce 11c in 65% yield as a
colorless oil (244 mg, 1.11 mmol). The purified product was eluted
1
with 90/10 hexanes/EtOAc. H NMR (400 MHz, CDCl3): δ (ppm)
4.04 (0.5H, b), 3.95 (0.5H, b), 3.75 (0.5H, b, d, J = 9.9 Hz),
3.66 (0.5H, b, d, J = 9.9 Hz), 3.54 (0.5H, t, J = 9.0 Hz), 3.46−3.33
E
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The Journal of Organic Chemistry
Article
(2.5H, m), 2.00 (2H, t, J = 6.4 Hz), 1.88−1.78 (2H, m), 1.46 (9H, s).
13C NMR (100, MHz, CDCl3): δ (ppm) 154.5, 154.2, 79.8, 79.5, 58.1,
58.0, 47.3, 46.8, 45.5, 45.3, 29.2, 28.4, 23.6, 22.8. IR (cm−1): ν 2977,
dried over MgSO4, concentrated under vacuum, and taken to the next
step without further purification. This crude material was then dis-
solved in THF (50 mL), and MeONHMe·HCl (1.85 g, 18.99 mmol)
was added. A catalytic amount of sodium hydride (∼5 mg) was then
added to the solution, and the reaction mixture was stirred for 3 h. The
reaction was quenched with a half-saturated NH4Cl solution (50 mL).
Upon separation of layers, the organic layer was washed with a
saturated NaHCO3 solution (50 mL), which was then back-extracted
with EtOAc (3 × 50 mL). The organic layers were combined, dried
over MgSO4, filtered, and concentrated in vacuo. The resulting crude
material was purified with 80/20 hexanes/EtOAc to yield the Weinreb
amide 21 in 57% yield (2.39 g, 11.66 mmol) as a yellow oil. 1H NMR
(400 MHz, CDCl3): δ (ppm) 7.38−7.20 (5H, m), 6.51 (1H, d, J =
15.9 Hz), 6.37 (1H, ddd, J = 15.8, 6.9, 6.8 Hz), 3.72 (3H, s), 3.39 (2H,
d, J = 6.4 Hz), 3.21 (3H, s). 13C NMR (100 MHz, CDCl3): δ (ppm)
137.1, 133.1, 128.5, 127.4, 126.3, 122.8, 61.2, 36.5, 32.3 (b), 29.7.
FT-IR (cm−1): ν 2936, 1749, 1722, 1448, 1419, 1177, 999, 968, 910,
735. HRMS-ESI: (M + H)+ 206.1176 calculated for C12H16NO2,
experimental 206.1170.
The Weinreb amide 21 (1.16g, 5.65 mmol) was dissolved in dry
THF (50 mL), and the solution was cooled to 0 °C. Allylmagnesium
bromide (11.3 mL, 11.3 mmol, 1.0 M in Et2O) was then added slowly
over 20 min. The reaction mixture was stirred for 1 h and then
quenched with a half-saturated NH4Cl (50 mL) solution. Upon
separation of layers, the aqueous layer was extracted with EtOAc (3 ×
50 mL). The organic layers were combined and dried over MgSO4.
The crude material was concentrated in vacuo and purified with 90/10
hexanes/EtOAc to afford ketone 22 in 82% yield (855 mg, 4.59 mmol)
as a yellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.38−7.22 (5H,
m), 6.48 (1H, d, J = 15.9 Hz), 6.31 (1H, ddd, J = 16.0, 7.1, 6.9 Hz),
6.00−5.89 (1H, m), 5.23−5.15 (2H, m), 3.36 (2H, d, J = 7.0 Hz), 3.27
(2H, d, J = 6.9 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 206.4,
136.8, 133.9, 130.3, 128.6, 127.6, 126.3, 121.7, 119.2, 47.3, 46.4. FT-IR
(cm−1): ν 3082, 3061, 3027, 2981, 1717, 1639, 1578, 1449, 1424,
1323, 1071, 993, 967, 912, 741, 695, 650. HRMS-ESI: (M + H)+
187.1117 calculated for C13H15O, experimental 187.1117.
D
2879, 1695, 1392, 1171, 1118, 910, 733. [α]25 = −7.29° (c = 1.6 in
CHCl3). HRMS-ESI: (M + Na)+ 242.0924 calculated for
C10H18ClNNaO2, experimental 242.0917.
( )-(2,4-Dichlorobutyl)benzene (13). Alcohol 1233 (332 mg,
2.00 mmol) was utilized along with pyridine (0.65 mL, 8.00 mmol)
and triphosgene (593 mg, 2.00 mmol) in 30 mL of CH2Cl2 to produce
13 in 55% yield as a colorless oil (223 mg, 1.10 mmol). The purified
1
product was eluted with 100/0 → 90/10 hexanes/EtOAc. H NMR
(400 MHz, CDCl3): δ (ppm) 7.36−7.22 (5H, m), 4.35 (1H, m),
3.78−3.69 (2H, m), 3.13 (1H, dd, J = 14.1, 7.3 Hz), 3.06 (1H, dd, J =
14.0, 6.6 Hz), 2.20 (1H, m), 2.08 (1H, m). 13C NMR (100 MHz,
CDCl3): δ (ppm) 137.1, 129.4, 128.5, 127.0, 60.0, 44.8, 41.7, 40.1. IR
(cm−1): ν 3031, 2965, 1496, 1454, 1318, 1285, 910, 735, 701. GC-MS:
M+ 202.0 calculated for C10H12Cl2, experimental 202.0. HRMS-ESI:
(M − H − 2Cl)+ 131.0855 calculated for C10H11, experimental
131.0857.
( )-4,8-Dichlorooct-1-ene (15). Alcohol 1434 (288 mg, 2.00 mmol)
was utilized along with pyridine (0.64 mL, 8.00 mmol) and
triphosgene (593 mg, 2.00 mmol) in 30 mL of CH2Cl2 to produce
15 in 73% yield as a colorless oil (264 mg, 1.47 mmol). The purified
1
product was eluted with 100/0 → 90/10 hexanes/EtOAc. H NMR
(400 MHz, CDCl3): δ (ppm) 5.85 (1H, m), 5.16−5.12 (2H, m), 3.93
(1H, m), 3.55 (2H, t, J = 6.4 Hz), 2.53−2.49 (2H, m), 1.87−1.66 (6H,
m). 13C NMR (100 MHz, CDCl3): δ (ppm) 134.0, 118.1, 62.2, 44.7,
42.7, 37.0, 32.1, 23.8. IR (cm−1): ν 3081, 2950, 2868, 1643, 995, 911,
735, 650. GC-MS: (M)+ 180.0 calculated for C8H14Cl2, experimental
179.9. HRMS-ESI: (M − 2H − 2Cl + Na)+ 131.0831 calculated for
C8H12Na, experimental 131.0838.
( )-4-Chloro-1-phenylbutan-2-ol (16) and ( )-4-Benzyl-1,3-dioxan-
2-one (17). Alcohol 1233 (332 mg, 2.00 mmol) was utilized along with
pyridine (0.32 mL, 4.00 mmol) and triphosgene (297 mg, 1.00 mmol)
to produce 17 in 66% yield as a colorless oil (254 mg, 1.32 mmol) and
16 in 14% yield as a colorless oil (50 mg, 0.27 mmol). The purified
products were eluted with 90/10 → 80/20 → 70/30 hexanes/EtOAc.
Ketone 22 (855 mg, 4.60 mmol) as a solution in Et2O (20 mL) was
added via cannula to a cooled (0 °C) suspension of lithium aluminum
hydride (209 mg, 5.50 mmol). The reaction mixture was then warmed
to room temperature and set to reflux for 30 min. After the reaction
mixture was cooled to 0 °C, deionized water (0.21 mL) was slowly
added, which was followed by 15% aqueous sodium hydroxide solution
(0.21 mL) and then deionized water (0.63 mL). This workup
sequence resulted in the formation of white precipitates. The solution
was then stirred for 1 h. The filtrate was collected using vacuum
filtration and concentrated in vacuo. The crude material was then
purified with 90/10 → 80/20 hexanes/EtOAc to give 8f with a yield of
1
Data for the less polar product (16) are as follows. H NMR (400
MHz, CDCl3): δ (ppm) 7.38−7.22 (5H, m), 4.08 (1H, ddd, J = 15.8,
7.9, 4.7 Hz), 3.80−3.65 (2H, m), 2.86 (1H, dd, J = 13.5, 4.2 Hz), 2.71
(1H, dd, J = 13.5, 8.6 Hz), 2.01−1.93 (2H, m), 1.66 (1H, d, J =
3.0 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 137.7, 129.3, 129.6,
126.6, 69.4, 43.9, 41.7, 39.1. IR (cm−1): ν 3425, 3378, 3063, 3029,
2943, 2920, 1946, 1454, 1081, 742, 701. HRMS-ESI: (M + Na)+
207.0553 calculated for C10H13ClNaO, experimental 207.0543. Data
1
for the more polar product (17) are as follows. H NMR (400 MHz,
CDCl3): δ (ppm) 7.37−7.22 (5H, m), 4.67 (1H, m), 4.45−4.27 (2H,
m), 3.15 (1H, dd, J = 13.8, 5.7 Hz), 2.92 (1H, dd, J = 13.8, 7.3 Hz),
2.03−1.83 (2H, m). 13C NMR (100 MHz, CDCl3): δ (ppm) 148.6,
135.0, 129.4, 128.7, 127.1, 79.5, 66.8, 41.3, 26.2. IR (cm−1): ν 3352,
3028, 2973, 2932, 2875, 1753, 1409, 1250, 1188, 1124, 911, 738, 703.
HRMS-ESI: (M − CO + 3H)+ 167.1072 calculated for C10H15O2,
experimental 167.1055.
1
94% (811 mg, 4.31 mmol) as a colorless oil. H NMR (400 MHz,
CDCl3): δ (ppm) 7.37−7.20 (5H, m), 6.49 (1H, d, J = 16.1 Hz), 6.25
(1H, ddd, J = 15.9, 7.1, 6.9 Hz), 5.87 (1H, m), 5.19−5.14 (2H, m),
3.78 (1H, m), 2.48−2.33 (3H, m), 2.24 (1H, m), 1.76 (1H, m). 13C
NMR (100 MHz, CDCl3): δ (ppm) 137.2, 134.6, 133.1, 128.5, 127.3,
126.1, 118.2, 70.2, 41.4, 40.5, 29.7. FT-IR (cm−1): ν 3416, 3079, 3027,
2930, 1641, 1599, 1495, 1449, 1073, 997, 967, 912, 742. HRMS-ESI:
(M + H)+ 189.1274 calculated for C13H17O, experimental 189.1275.
( )-4-((tert-Butyldimethylsilyl)oxy)-1-phenylbutan-2-ol (8g).
Preparation of Secondary Alcohols 8f−j.
( )-(E)-1-Phenylhepta-1,6-dien-4-ol (8f).
Diol 1233 (479 mg, 2.88 mmol) was dissolved in CH2Cl2 (75 mL).
Imidazole (432 mg, 6.34 mmol) was then added, and the reaction
mixture was cooled to −42 °C. TBSCl (478 mg, 3.17 mmol) was then
added in one portion. The reaction mixture was stirred overnight while
being slowly warmed to room temperature and then quenched with
a half-saturated NH4Cl solution (50 mL). Upon separation of layers,
the aqueous layer was extracted with CH2Cl2 (3 × 30 mL), washed
with brine, dried over MgSO4, filtered, and concentrated under
vacuum. The crude material was purified with 90/10 hexanes/EtOAc
to give 8g in 56% yield as a colorless oil (452 mg, 1.61 mmol).
trans-Styrylacetic acid (20; 3.30 g, 20.35 mmol) was dissolved in THF
(50 mL), and carbonyldiimidazole (4.30 g, 26.45 mmol) was then
added in one portion. The reaction mixture was then stirred overnight.
The crude reaction mixture was concentrated in vacuo, diluted with
Et2O (50 mL), and then washed with saturated brine solution (3 ×
50 mL). Collected aqueous layers were extracted with Et2O (3 × 50 mL)
and combined with the organic layer. The organic fractions were then
F
dx.doi.org/10.1021/jo400341n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H NMR (400 MHz, CDCl3): δ (ppm) 7.32−7.20 (5H, m), 4.08 (1H,
m), 3.90 (1H, p, J = 4.8 Hz), 3.79 (1H, ddd, J = 10.4, 6.5, 6.3 Hz), 3.35
(1H, d, J = 2.0 Hz), 2.85 (1H, dd, J = 13.5, 7.0 Hz), 2.74 (1H, dd, J =
13.5, 6.2 Hz), 1.71−1.66 (2H, m), 0.91 (9H, s), 0.08 (6H, s). 13C
NMR (100 MHz, CDCl3): δ (ppm) 138.8, 129.4, 128.4, 126.3, 73.0,
62.6, 44.0, 37.6, 25.9, 18.2, −5.5. IR (cm−1): ν 3455, 2954, 2930, 2857,
1472, 1255, 1085, 909, 836, 777, 740, 700. HRMS-ESI: (M + H)+
281.1931 calculated for C16H29O2Si, experimental 281.1922.
( )-4-Benzyloxy-1-phenylbutan-2-ol (8h).
2.00 mmol), and p-toluoyl chloride (0.63 mL, 4.80 mmol) were
sequentially added. After it was stirred for 3 h, the reaction mixture was
quenched with 2 M HCl solution (40 mL). Upon separation of layers,
the aqueous solution was extracted with CH2Cl2 (3 × 30 mL), dried
over MgSO4, filtered, and concentrated under vacuum. The resulting
crude material was then dissolved in THF (25 mL) and treated with
1.0 M TBAF solution in THF (8.0 mL, 8.00 mmol). After the mixture
was stirred overnight, EtOAc (100 mL) was added. This organic
solution was washed sequentially with deionized H2O and brine, and it
was then dried over MgSO4, filtered, and concentrated under vacuum.
Purification of the resulting crude material with 80/20 hexanes/EtOAc
gave 8j in 65% yield as a colorless oil (744 mg, 2.62 mmol). 1H NMR
(400 MHz, CDCl3): δ (ppm) 8.01−7.89 (2H, m), 7.34−7.23 (7H, m),
4.59 (1H, ddd, J = 11.1, 8.6, 5.2 Hz), 4.43 (1H, p, J = 5.6 Hz), 4.01
(1H, ddt, J = 8.6, 8.6, 4.3 Hz), 2.88 (1H, dd, J = 13.6, 4.6 Hz), 2.78
(1H, dd, J = 13.6, 8.2 Hz), 2.44 (1H, s), 2.42 (3H, s), 2.03 (1H, m),
1.89 (1H, m). 13C NMR (400 MHz, CDCl3): δ (ppm) 167.0, 143.7,
138.1, 130.2, 129.7, 129.5, 129.1, 128.6, 127.4, 126.6, 69.6, 62.0, 44.0,
36.0, 21.7. IR (cm−1): ν 3482, 3029, 2957, 2919, 1712, 1612, 1455,
1274, 1178, 1111, 1021, 972, 842, 753, 701. HRMS-ESI: (M + H)+
285.1491 calculated for C18H21O3, experimental 285.1494.
Diol 1233 (2.78g, 16.8 mmol) in a solution of DMF (20 mL) was
slowly added via cannula to a cooled suspension (0 °C) of NaH
(0.426 g, 18.42 mmol) in DMF (20 mL). After the mixture was stirred
for 30 min, benzyl bromide (1.99 mL, 16.8 mmol) was added. The
reaction mixture was then warmed to room temperature and stirred
overnight. After the reaction was quenched with a half-saturated
NH4Cl solution, the mixture was then extracted with EtOAc (3 ×
30 mL), and the collected organic layers were washed with water and
dried over MgSO4. The crude material was purified with 90/10 →
80/20 → 70/30 hexanes/EtOAc, and alcohol 8h was isolated in 24%
yield (1.08 g, 3.95 mmol) as a yellow oil. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.36−7.19 (10H, m), 4.59 (1H, d, J = 11.4 Hz), 4.48
(1H, d, J = 11.4 Hz), 3.86 (1H, m), 3.81−3.70 (2H, m), 3.04 (1H, dd,
J = 13.4, 5.8 Hz), 2.79 (1H, dd, J = 13.6, 7.0 Hz), 2.22 (1H, t, J = 5.0
Hz), 1.67−1.81 (2H, m). 13C NMR (100 MHz, CDCl3): δ (ppm)
138.4, 138.1, 129.5, 128.5, 128.4, 128.0, 127.8, 126.3, 79.6, 71.6, 60.7,
40.5, 30.1. IR (cm−1): ν 3410, 3086, 3063, 3029, 2493, 2875, 1604,
1496, 1454, 1056, 1029, 910, 738, 699. HRMS-ESI: (M + H)+
257.1536 calculated for C17H21O2, experimental 257.1529.
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures giving GC-MS chromatograms for Tables 1 and 2 and
NMR (1H and 13C) spectra for characterized compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
( )-4-((4-Methoxybenzyl)oxy)-1-phenylbutan-2-ol (8i).
Corresponding Author
*E-mail for R.K.: rkartika@lsu.edu.
Notes
The authors declare no competing financial interest.
Alcohol 239 (2.88g, 10.3 mmol) was dissolved in THF (150 mL) and
cooled to 0 °C. NaH (1.12 g, 46.8 mmol) was then added slowly, and
the suspension was stirred for 30 min. PMBCl (2.31 g, 14.8 mmol)
was then added, and the reaction mixture was brought to room
temperature and stirred overnight. The reaction was then slowly
quenched with methanol (60 mL), followed by addition of a half-
saturated brine solution (50 mL). Upon separation of layers, the
aqueous solution was extracted with EtOAc (3 × 50 mL). The organic
layers were combined and washed with saturated NaCl, dried over
MgSO4, filtered, and concentrated under vacuum. The resulting crude
material was dissolved in THF (50 mL) and treated with 1.0 M TBAF
solution in THF (20.5 mL, 20.56 mmol). After this solution was
stirred overnight, EtOAc (100 mL) was added. This organic solution
was washed sequentially with deionized H2O and brine, and it was
then dried over MgSO4, filtered, and concentrated under vacuum.
Purification of the resulting crude material with 80/20 → 70/30 →
60/40 hexanes/EtOAc gave alcohol 8i in 23% yield as a colorless oil
†Undergraduate research participant.
ACKNOWLEDGMENTS
■
Generous financial support from Louisiana State University is
greatly appreciated. A.V. thanks the National Science Foundation
for the Bridge to the Doctorate Project (BDP) Fellowship
(NSF1141152). C.E.A. thanks the Louisiana Board of Regents
for the BOR Fellowship (LEQSF(2011-16)-GF-03). We thank
Professor George Stanley for kindly allowing us to use the
GC-MS instrument in his laboratories.
REFERENCES
■
(1) Cahiez, G.; Lefevre, N.; Poizat, M.; Moyeux, A. Synthesis 2013,
45, 231.
(2) Denton, R. M.; An, J.; Adeniran, B.; Blake, A. J.; Lewis, W.;
Poulton, A. M. J. Org. Chem. 2011, 76, 6749.
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(4) Shibuya, G. M.; Kanady, J. S.; Vanderwal, C. D. J. Am. Chem. Soc.
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1
(664 mg, 2.32 mmol). H NMR (400 MHz, CDCl3): δ (ppm) 7.32−
7.20 (7H, m), 6.91−6.83 (2H, m), 4.52 (1H, d, J = 11.1 Hz), 4.41
(1H, d, J = 11.0 Hz), 3.85 (1H, m), 3.81 (3H, t, J = 4.2 Hz), 3.78−3.66
(2H, m), 3.03 (1H, dd, J = 13.5, 5.8 Hz), 2.77 (1H, dd, J = 13.5, 5.8
Hz), 1.81−1.62 (2H, m). 13C NMR (100 MHz, CDCl3): δ (ppm)
159.3, 138.4, 130.2, 129.6, 128.7, 128.4, 126.3, 113.9, 79.4, 71.2, 60.7,
55.3, 40.5, 36.1. IR (cm−1): ν 3417, 2941, 1613, 1514, 1249, 1035, 822,
741, 703. HRMS-ESI: (M + Na)+ 309.1467 calculated for C18H22NaO3,
experimental 309.1465.
( )-3-Hydroxy-4-phenylbutyl 4-Methylbenzoate (8j).
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Alcohol 239 (1.12g, 4.00 mmol) was dissolved in CH2Cl2 (40 mL)
and cooled to 0 °C. DIPEA (3.56 mL, 20.0 mmol), DMAP (0.24 g,
G
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