Access to "friedel-Crafts-Restricted" tert -alkyl aromatics by activation/methylation of tertiary benzylic alcohols

Article abstract of DOI:10.1021/jo202371c

Herein we describe a two-step protocol to prepare m-tert-alkylbenzenes. The appropriate tertiary benzylic alcohols are activated with SOCl₂ or concentrated HCl and then treated with trimethylaluminum, affording the desired products in 68-97% yields (22 examples). This reaction sequence is successful in the presence of a variety of functional groups, including acid-sensitive and Lewis-basic groups. In addition to t-Bu groups, 1,1-dimethylpropyl and 1-ethyl-1-methylpropyl groups can also be installed using this method.

Full text of DOI:10.1021/jo202371c

Article
pubs.acs.org/joc
Access to “Friedel−Crafts-Restricted” tert-Alkyl Aromatics by
Activation/Methylation of Tertiary Benzylic Alcohols
Joshua A. Hartsel, Derek T. Craft, Qiao-Hong Chen, Ming Ma, and Paul R. Carlier*
Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061, United States
S
* Supporting Information
ABSTRACT: Herein we describe a two-step protocol to prepare m-tert-
alkylbenzenes. The appropriate tertiary benzylic alcohols are activated with
SOCl2 or concentrated HCl and then treated with trimethylaluminum, affording
the desired products in 68−97% yields (22 examples). This reaction sequence is
successful in the presence of a variety of functional groups, including acid-
sensitive and Lewis-basic groups. In addition to t-Bu groups, 1,1-dimethylpropyl
and 1-ethyl-1-methylpropyl groups can also be installed using this method.
which incorporated two different alkyl groups to give a 1,1-
dimethylpropyl substituent. These remarkable transformations
are worthy of wider application. We envisioned a related strat-
egy starting from tertiary benzylic alcohols: in situ activation of
the alcohol followed by treatment with the appropriate methyl
organometallic (M-Me) would afford aromatics featuring
various tert-alkyl groups (Scheme 2).
INTRODUCTION
■
Because of intrinsic substituent directing effects, compounds
bearing tert-alkyl groups on benzene rings meta- to ortho-, para-
directing substituents are challenging to prepare. In the course
of our efforts to develop malaria mosquito-selective acetylcho-
linesterase inhibitors,1 we required such compounds, which we
term “Friedel−Crafts-restricted” tert-alkylbenzenes. Traditional
strategies to prepare these compounds use “temporary” o- or p-
hydroxy or amino groups to direct Friedel−Crafts2 or other
electrophilic aromatic substitution reactions;3,4 subsequent
removal of the temporary directing group then unveils the
desired meta-substitution pattern. We sought a more direct
route that would benefit from the large number of
commercially available meta-substituted benzoic acids and
acetophenones. One approach that appeared especially
promising was Reetz’s conversion of aryl ketone 1a to the
corresponding tert-alkyl benzene 2a by treatment with
Me2TiCl2 (Scheme 1).5
Scheme 2. Planned Transformation of Tertiary Benzylic
Alcohols (6−8) to tert-Alkylbenzenes (2, 4, 5) and Precedent
from Makriyannis (9)7
Scheme 1. Published Reetz Strategies5,6 To Convert
Aromatic Ketones to tert-Alkyl-Substituted Aromatics
Although ZnMe2 is known to react with tertiary alkyl and
benzylic chlorides,8 AlMe3 is 20-fold cheaper on a molar basis.
Successful use of this reagent (40−51% yield) was demon-
strated by Makriyannis in two examples, one of which (9)7 is
shown in Scheme 2. Shishido also applied this method to the
preparation of CF3-containing t-Bu isosteres from the
corresponding tertiary benzylic chlorides.9 These literature
precedents encouraged us to investigate the substrate scope of
Two years earlier, Reetz disclosed a potentially more general
strategy:6 addition of EtLi to 1b, isolation of the lithium
alkoxide 3b, and final treatment with ZnMe2/TiCl4 afforded 4b,
Received: November 18, 2011
Published: March 6, 2012
© 2012 American Chemical Society
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Table 1. Transformation of Tertiary Benzylic Alcohols to tert-Alkylbenzenes
entry
compd
X
Y
R1
R2
product
activation method
yield (%)
88
1
2
6b
6c
6d
6e
6f
OMe
OMe
OH
Me
Me
Ph
OMe
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
2b
2c
2d
2e
2f
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
A
B
A
A
A
A
A
B
93
83
85
85
70
93
81
93
97
89
68
94
70
94
3
H
4
Me
H
5
6
6g
6h
6i
H
2g
2h
2i
7
Cl
H
8
Br
H
9
6j
OTBS
NHC(O)Ph
NHC(O)Me
OMe
H
2j
b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
6k
6l
H
2k
2l
H
7b
7c
7d
7f
OMe
H
4b
4c
4d
4f
OMe
Et
OH
H
Et
Me
H
Et
a
7h
Cl
H
Et
4h
4h
4i
78 (87:13)
95
a
7i
Br
H
Et
Me
72 (85:15)
4i
95
97
92
80
71
8c
8d
8f
OMe
OH
Me
Ph
H
H
H
H
H
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
5c
5d
5f
8g
8h
5g
5h
5h
a
Cl
90 (56:44)
a
95 (96:4)
a
Weight recovery of a mixture of the intended methylated and unwanted elimination product (12h, 12i, and 13h, respectively) following
b
chromatography; the mole ratio (1H NMR) is given in parentheses. Methylation was slow at room temperature; reaction was carried out in 1,2-
dichloroethane at 60 °C.
this transformation and determine if much milder conditions
could be employed.
functionalities (OH, OMe, OTBS, NHC(O)R) are compatible
with this protocol. With regard to reaction temperature, most
reactions of the activated alcohols with AlMe3 were found to
proceed at or below room temperature, in contrast to the
high-temperature conditions reported for conversion of 9
(Scheme 2, 115 °C).7 Only in one case was it necessary to
perform the reaction at elevated temperature (60 °C, amido-
functionalized substrate 6k). On the basis of our reactions with
similar substrates 6b and 7b, it seems likely that the conversion
of 9 would also proceed well at room temperature.
RESULTS AND DISCUSSION
■
Standard synthetic methods were employed to prepare a range
of tertiary benzylic alcohols from commercially available ace-
tophenones and carboxylic acids. These compounds (6b−l,
7b−d,f,h,i, and 8c,d,f−h) varied in the identity of the meta-
substituents (X and Y) and carbinol alkyl groups (R1 and R2,
Table 1).
Reactions of dimethylarylcarbinols 6 were explored first.
Each tertiary alcohol was activated by treatment with neat
SOCl2 (2.5 equiv, 0 °C, activation method A);10 after 2 h, the
residual SOCl2 was removed in vacuo at 0 °C. The residue
(whose chemical identity is discussed below) was dissolved in
CH2Cl2 and cooled to −78 °C, at which point AlMe3 (2 equiv)
was added. After being warmed to room temperature overnight,
the reaction was cooled to 0 °C and quenched with 1 M HCl.
Aqueous workup and chromatographic purification yielded tert-
butylbenzenes 2b−l in 68−97% yield (Table 1, entries 1−11).
Thus, the reaction sequence tolerates a variety of meta-sub-
stituents (OMe, OH, Me, Ph, Cl, and Br), including acid-sensi-
tive groups (TBS-protected phenol, 6j) and amides (6k, 6l).
The acid sensitivity of the TBS ether in 2j was confirmed by its
quantitative conversion to 2d following exposure (1 h) to 1 M
HCl in MeOH. Note that moderately strong Lewis base
Reaction of ethylmethylarylcarbinols 7 was nearly as suc-
cessful as that of dimethylarylcarbinols 6. As seen in Table 1,
entries 12−15, moderate to excellent yields of the desired
1,1-dimethylpropyl derivatives 4 were obtained. Unfortunately,
in the case of m-Cl and m-Br carbinols 7h and 7i, the desired
products 4h and 4i were contaminated with 13−15 mol %
of the chromatographically inseparable elimination products
(12h and 12i, entries 16 and 18, respectively).
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To assess whether this product mixture arose in part from
some difficulty in the alcohol activation step, tertiary benzylic
chlorides 14h and 14i were prepared by treating the
corresponding carbinols with concentrated HCl, followed by
extractive workup (activation method B). Reaction of 14h and
14i with AlMe3 at room temperature afforded the desired
products 4h and 4i in 95% yield with no trace of the elimina-
tion products 12h and 12i (Table 1, entries 17 and 19). Finally,
reactions of diethylaryl carbinols 8 (Table 1, entries 20−23)
gave moderate to excellent yields of 1-ethyl-1-methylpropyl-
benzenes 5. Elimination was again seen as a competing side
reaction in the m-Cl substrate 8h, giving 44 mol % of 13h
(Table 1, entry 24). Suspecting that some deficiency in the
alcohol activation was again responsible, the tertiary benzylic
chloride 15h was prepared. As we had seen for reaction of 14h
and 14i, reaction of 15h with AlMe3 gave an excellent yield
(93% overall) with only a trace (4%) of the elimination product
13h (Table 1, entry 25). Our analysis of the chloride inter-
mediate 15h suggests that the small amount of elimination
observed occurred prior to addition of AlMe3.
Scheme 4. Course of the Reaction of 8h with SOCl2; NMR
Chemical Shifts Were Measured in CD2Cl2
Given the divergent methylation results seen for 7h, 7i, and
8h using activation method A (treatment with SOCl2) and
activation method B (treatment with concd HCl), we
investigated the chemical identity of the SOCl2 activation
products of two substrates. Treatment of 6b with SOCl2 at 0 °C
for 2 h, followed by rapid concentration in vacuo at 0 °C gave a
product that was identical by 1H and 13C NMR spectroscopy to
tertiary benzylic chloride 16b formed by treatment of 6b with
concentrated HCl. Presumably 6b quickly reacts with SOCl2 to
form the chlorosulfite intermediate 17b, which then ionizes to a
tertiary benzylic carbocation/chlorosulfite ion pair 18b, ejects
SO2, and recombines to form chloride 16b (Scheme 3).11,12
reaction were taken at 1, 2, 5, and 24 h. After 1 h at room
temperature, some conversion of 19h to the chloride 15h and
elimination product 13h was evident. After 5 h at room
temperature, only 17% of the chlorosulfite 19h remained,
giving predominantly chloride 15h (52%) and elimination
product 13h (31%). At 24 h, all of the chlorosulfite 19h had
been converted to chloride 15h and elimination product 13h.
Olah has previously noted the tendency of tertiary
chlorosulfites to eliminate.13
Why would the chlorosulfite 19h be slower than 17b in its
conversion to the chloride? We note that based on σm values,
the m-Cl substituent (σm = 0.37) is more electron-withdrawing
than the m-OMe substitutent (σm = 0.10).14 If one m-Cl
substituent is more electron-withdrawing than two m-OMe
groups, the ionization of the chlorosulfite 19h would be slower
than ionization of 17b. Thus, it seems likely that the SOCl2
activation of m-Cl and m-Br ethylmethylaryl carbinols 7h and 7i
(Br σm = 0.37)14 also progressed only to the chlorosulfite stage
after 2 h at 0 °C. The inferior results for these substrates
(and 8h) using the SOCl2 activation method A could be
rationalized if tertiary benzylic chlorosulfites are more prone to
elimination on treatment with AlMe3 than are the corresponding
tertiary benzylic chlorides. As a final control experiment, alcohol
7h (without any prior activation) was treated with AlMe3 under
the standard conditions. As expected, 7h was recovered and no
methylated product 4h or elimination product 12h was formed.
To further assess the scope of this methylation protocol we
examined two substrate classes expected to be problematic.
First, if benzylic carbocation intermediates are formed during
both the chlorination and methylation steps, then pyridyldial-
kylcarbinols might prove challenging substrates, due to the
strongly electron-withdrawing nature of the pyridine ring.
Hammett σ values for 2-, 3-, and 4-pyridyl rings are reported as
0.71, 0.55, and 0.94, respectively,15 and we chose to explore
reactions of 2-pyridyl tertiary carbinol 20a and 3-pyridyl tertiary
carbinol 20b. As expected, methylation of these substrates was
difficult and required elevated temperatures. Activation of 3-
pyridyl substrate 20b using method A, followed by treatment
with AlMe3 at 80 °C in 1,2-dichloroethane, gave the desired
methylated product 21b, but contaminated with 21 mol % of
chromatographically inseparable elimination product 22b.
Scheme 3. Rapid Conversion of 6b to 16b on Treatment
with SOCl2 at 0 °C and Possible Mechanism
However, treatment of 8h under the same conditions did not
lead to chloride 15h but rather to an intermediate we
tentatively identified as the chlorosulfite 19h. This compound
1
was nearly identical by H NMR spectroscopy (CDCl3) to
starting alcohol 8h, but was much less polar on TLC, with an
Rf very similar to that of tertiary benzylic chloride 15h. To
confirm our conclusion we carried out an NMR study of the
reaction of 8h with SOCl2 (5 equiv) in CD2Cl2 (Scheme 4).
After 2 h at 0 °C, the NMR sample tube was allowed to
1
reach room temperature, and H and 13C NMR spectra of the
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aliphatic and benzylic halides.16 We thus investigated other
ethyl organometallics. Interestingly, reaction with ClAlEt2 gave
a 9:91 mixture in favor of the hydride addition product 24c
(Table 2, entry 2). Reaction with BEt3 did not proceed: neither
23c or 24c was detected, and the tertiary benzylic chloride
derived from 8c was recovered. Finally, use of ZnEt2 in the
protocol gave a nearly 1:1 mixture of 23c and 24c. Thus an
effective protocol to install the 1,1-diethylpropyl group by
ethylation of a diethylaryl carbinol remains elusive.
To conclude our study, we explored reaction of tertiary
alcohol 25, bearing a tethered benzene ring, that was designed
to probe the mechanism of the reaction of tertiary chlorides
with AlMe3 (Scheme 5).
Scheme 5. Methylation of Tertiary Aliphatic Alcohol 25
Application of this protocol to 20a was less successful, giving
21a and the chromatographically inseparable elimination
product 22a in a 9:91 ratio. Activation of 20a and 20b by
conversion to the corresponding mesylates9 was also explored
but did not provide improved outcomes. Thus, neither pyridin-
2-yl- nor pyridin-3-yldialkylcarbinols (e.g., 20a, b) qualify as
good substrates for this reaction. Second, very strong electron-
releasing substitutents might be problematic, because they
could facilitate self-reaction of the benzylic chloride inter-
mediate. Since hydroxy, alkoxy, silyloxy, and amido substituents
were well-tolerated (Table 1, entries 1−3, 9−14, 20, and 21),
we explored dimethylamino-substituted aryldimethyl carbinol
6m. Regardless of the alcohol activation method employed and
conditions used for reaction with AlMe3, weight recoveries were
very low (<20% of theoretical yield of 2m). 1H NMR spectros-
copy of the reaction mixture suggested that oligomerization of
the activated alcohol had occurred.
The protocol described above allows installation of tert-alkyl
groups containing at least one methyl group. Installation of a
1,1-diethylpropyl (i.e., triethylcarbinyl) substituent would
necessitate use of an ethyl organometallic. To attempt such a
transformation, diethylarylcarbinol 8c was activated with SOCl2
and treated with various ethyl organometallics. Carbinol 8c was
chosen for the high yield observed in its SOCl2-activation/
methylation to 5c (Table 1, entry 17). Use of AlEt3 in the standard
protocol did give the intended product 23c but contaminated with
the chromatographically inseparable 24c (Table 2, entry 1).
In Miller’s studies of the reaction of AlEt3 with primary,
secondary, tertiary, and benzylic chlorides, it was proposed that
the observed product mixtures and relative rates were
consistent with the formation of ion-pair intermediates.16 In
this paradigm, the tertiary chloride derived from 25 would react
with AlMe3 to form ion-pair intermediate 27, which could
undergo two fates: methyl transfer to 26 or intramolecular
Friedel−Crafts alkylation leading to 28. In the event, 26 was
isolated in 74% yield, and Friedel−Crafts product 28 was not
detected. Thus, ion pair 27 appears to have a very short
lifetime.
CONCLUSION
■
In closing, based on the work of Reetz,5,6 Makriyannis,7 and
Shishido,9 we developed a mild two-step method to place tert-
alkyl groups on aromatic rings meta- to ortho, para-directing
groups. Tertiary benzylic alcohols are activated by treatment
with SOCl2 (method A) or concentrated HCl (method B) and
in most cases were found to react quickly with AlMe3 at or
below room temperature. In addition to t-butyl, the 1,1-dimethyl-
propyl(ethyldimethylcarbinyl) and 1-ethyl-1-methylpropyl(diethyl-
methylcarbinyl) substitutents were successfully installed. Eleven
different aromatic substitution patterns were examined, giving a
total of 22 examples in 68−97% yields (Table 1). For substrates
bearing moderate electron-withdrawing groups (e.g., m-Cl or
m-Br), activation method B was found to give the best results.
However, elimination remained a persistent problem for strongly
electron deficient substrates (e.g., pyridin-2-yl and pyridin-3-yl
substrates 20a,b). Substrates bearing very strong electron donors
(e.g., NMe2, 6m) also proved problematic.
Table 2. Attempted Synthesis of 1,1-Diethylpropyl-
Substituted Benzene 23c
a
b
entry
MEt
23c/24c
wt recovery (%)
1
2
3
4
AlEt3
77:23
9:91
94
72
ClAlEt2
BEt3
c
no reaction
NA
ZnEt2
46:54
96
a
b
1
Measured by H NMR spectroscopy. Based on the stoichiometry
c
indicated by 1H NMR spectroscopy. Recovered tertiary benzylic
EXPERIMENTAL SECTION
General Methods. High-resolution mass spectra (ESI and APCI)
were recorded on a time-of-flight LC/MS instrument. Because of their
demonstrated lability, characterization of tertiary benzylic chlorides or
■
chloride derived from 8c.
It seemed likely that 24c arose from β-hydride delivery, as
Miller suggested in his studies of the reaction of AlEt3 with
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1
chlorosulfites by HRMS or elemental analysis was not attempted. H
NMR spectra of known tert-alkylbenzenes (i.e., those not listed below)
synthesized in this work are provided in the Supporting Information to
document purity. Known dimethylarylcarbinols 6b−i,l,m and 20a,b
were prepared in 89−97% yield by the addition of lithium trime-
thylmagnesate to the corresponding acetophenones in THF.17 Known
ethylmethylaryl carbinols 7c, 7d, 7f, 7h, and 7i were prepared in 87−
98% yields by Zn2+-catalyzed addition of EtMgCl to the corresponding
acetophenones;18 ethylmethylaryl carbinol 7b19 was prepared in 75%
yield by addition of EtMgCl to 3,5-dimethoxyacetophenone. Known
diethylarylcarbinols 8c, 8d, 8f, and 8h and diethylcarbinol 25 were
prepared in 86−94% overall yield by conversion of the corresponding
benzoic acids to the methyl ester, followed by reaction with EtMgBr
(2.5 equiv) in THF.20 In all cases, analytical data of synthesized known
compounds matched that of the literature.
7.44 (dt, J = 7.7, 1.8 Hz, 1H), 7.26−7.32 (overlapped, 2H),
2.13−2.24 (m, 2H), 1.95 (s, 3H), 0.94 (t, J = 7.3 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 147.1, 134.1, 129.4, 127.5, 126.5,
124.3, 73.7, 39.4, 31.2, 9.7. To a solution of the chloride,
prepared from the above step, in dichloromethane (7 mL)
at −78 °C was added trimethylaluminum in hexanes (2.0 M in
hexanes, 1.4 mL, 2.8 mmol), and the reaction mixture was
stirred at −78 °C for 3 h, and allowed to warm to room
temperature overnight. The reaction was quenched cautiously
at 0 °C with HCl (1 M) and extracted with dichloromethane
(20 mL × 3). The combined extracts were washed with brine,
dried over anhydrous Na2SO4, and concentrated to provide
methylated product 4h as a colorless oil (185 mg, 93% for two
1
steps; contains 2 mol % elimination product 12h): H NMR
(500 MHz, CDCl3) δ 7.31 (t, J = 2.0 Hz, 1H), 7.27−7.22
(overlapped, 2H), 7.16 (dt, J = 7.1, 2.0 Hz, 1H), 1.65 (q, J = 7.4
Hz, 2H), 1.29 (s, 6H), 0.70 (t, J = 7.4 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 151.7, 134.0, 129.2, 126.4, 125.5, 124.2, 38.1,
36.8, 28.3, 9.1; HRMS (EI) calcd for C11H15Cl 182.0862, found
182.0860 (−0.2 mmu, −1.3 ppm).
General Procedure for SOCl2 Activation (Method A)/
Methylation of Tertiary Benzylic Carbinols. 1-tert-Butyl-3-
methoxybenzene (2c).21 A dry Schlenk flask (50 mL) equipped
with a rubber septum and a magnetic stirbar was charged with
2-(3-methoxyphenyl)propan-2-ol (6c, 400 mg, 2.41 mmol),
placed in an ice bath, and purged with nitrogen. Thionyl
chloride (438 mg, 6.02 mmol) was added via syringe, and the
reaction was allowed to stir at 0 °C for 2 h; in some cases up to
1 mL of CH2Cl2 was added to improve mixing. Volatiles were
then removed at 0 °C under reduced pressure. The residue was
diluted with dichloromethane (8 mL) and cooled to −78 °C in
a dry ice/acetone bath. Trimethylaluminum (2.0 M in hexanes,
2.4 mL, 4.8 mmol) was injected into the flask, allowed to stir
for 3 h at −78 °C, and then stirred overnight at room tem-
perature. The reaction was then cooled to 0 °C and cautiously
quenched by the addition of HCl (1 M, 10 mL). Following
extraction with dichloromethane (3 × 25 mL), the organic
layers were combined, washed with brine, dried with anhydrous
Na2SO4, filtered, and evaporated under reduced pressure. The
residue was purified on silica gel (5: 1 hexane/ethyl acetate) to
Bromo-3-tert-pentylbenzene (4i). This compound (129 mg, oil)
was prepared in 95% yield from alcohol 7i (145 mg, 0.63 mmol) by
the method B procedure described above for 4h. Spectral data for
1
chloride 14i (containing 2 mol % elimination 12i): H NMR (500
MHz, CDCl3) δ 7.70 (t, J = 2.0 Hz, 1H), 7.48 (ddd, J = 8.0, 2.0, 1.0
Hz, 1H), 7.43 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H),
2.12−2.23 (m, 2H), 1.94 (s, 3H), 0.94 (t, J = 7.3 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 147.3, 130.4, 129.7, 129.3, 124.8, 122.4, 73.6,
1
39.4, 31.2, 9.7. Spectral data for 4i: H NMR (500 MHz, CDCl3) δ
7.47 (t, J = 1.9 Hz, 1H), 7.32 (ddd, J = 7.8, 1.9, 1.0 Hz, 1H), 7.26 (ddd,
J = 7.8, 1.9, 1.0 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 1.64 (q, J = 7.5 Hz,
2H), 1.28 (s, 6H), 0.70 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 152.1, 129.5, 129.3, 128.4, 124.7, 122.4, 38.1, 36.8, 28.3, 9.1.
Anal. Calcd for C11H15Br: C, 58.17; H, 6.66. Found: C, 58.41; H, 6.87.
1-Methoxy-3-(3-methylpentan-3-yl)benzene (5c). This compound
was prepared from 8c (260 mg, 1.34 mmol) using the method A
procedure for 2c, providing 5c (249 mg, 95% yield) as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 7.23 (t, J = 8.0 Hz, 1H), 6.91 − 6.86
(m, 1H), 6.84 (t, J = 2.2 Hz, 1H), 6.71 (dd, J = 8.0, 2.2 Hz, 1H), 3.81
(s, 3H), 1.72 (dq, J = 14.9, 7.5 Hz, 2H), 1.54 (dq, J = 14.9, 7.5 Hz,
2H), 1.22 (s, 3H), 0.67 (t, J = 7.5 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 159.5, 149.7, 128.8, 119.4, 113.6, 109.7, 55.2, 41.5, 35.4,
22.9, 8.9; HRMS (APCI) 193.1587 calcd for C13H21O [M + H]+,
found 193.1581 (−3.23 ppm).
1
yield a colorless oil (368 mg, 93% yield). H and 13C NMR
spectral data matched those reported in the literature.
N-(3-tert-Butylphenyl)benzamide (2k). This compound was
prepared from N-(3-(2-hydroxypropan-2-yl)phenyl)benzamide
(6k, 17.4 mg, 0.068 mmol) using the procedure described above for
2c, with a minor modification: following activation via method A, the
reaction with AlMe3 was conducted at 60 °C using 1,2-dichloroethane
as solvent. Following aqueous workup, the residue was purified on
silica gel (5: 1 hexane/ethyl acetate) to yield 2k as a white solid (16.7
1
3-(3-Methylpentan-3-yl)phenol (5d). This compound was pre-
pared from 8d (102 mg, 0.566 mmol) using the method A procedure
mg, 97% yield): H NMR (400 MHz, CDCl3) δ 7.90−7.87 (m, 3H),
7.63 (s, 1H), 7.54−7.45 (m, 4H), 7.32−7.25 (m, 1H), 7.28−7.18 (m,
1H), 1.34 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 165.73, 152.30,
137.65, 135.11, 131.75, 128.75, 126.99, 121.67, 117.51, 117.37, 34.69,
31.29; HRMS (APCI) 254.1539 calcd for C17H19NO [M + H]+, found
254.1535 (−1.56 ppm).
1
for 2c, providing 5d (93 mg, 92%) as a colorless oil: H NMR (500
MHz, CDCl3) δ 7.16 (t, J = 8.0 Hz, 1H), 6.86 (ddd, J = 8.0, 1.7, 0.9
Hz, 1H), 6.81 − 6.72 (m, 1H), 6.64 (ddd, J = 8.0, 1.7, 0.9 Hz, 1H),
4.64 (s, 1H), 1.74−1.66 (m, 2H), 1.58 − 1.48 (m, 2H), 1.21 (s, 3H),
0.67 (t, J = 7.4 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 155.3, 150.2,
129.1, 119.5, 114.0, 112.2, 41.4, 35.4, 22.8, 8.8; HRMS (APCI)
177.1285 calcd for C12H17O [M − H]−, found 177.1278 (−4.03 ppm).
1-Methyl-3-(3-methylpentan-3-yl)benzene (5f). This compound
was prepared from 8f (333 mg, 1.87 mmol) using the method A
1-Methoxy-3-tert-pentylbenzene (4c). This compound was pre-
pared from 7c (199 mg, 1.10 mmol) using the method A procedure for
1
2c, providing 185 mg of 4c (94% yield) as a colorless oil: H NMR
(500 MHz, CDCl3) δ 7.23 (t, J = 8.0 Hz, 1H), 6.96 − 6.91 (m, 1H),
6.89 (t, J = 2.0 Hz, 1H), 6.72 (dd, J = 8.0, 2.0 Hz, 1H), 3.81 (s, 3H),
1.63 (q, J = 7.4 Hz, 2H), 1.27 (s, 6H), 0.68 (t, J = 7.4 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 159.5, 151.5, 129.0, 118.71, 118.70, 112.9,
109.9, 55.3, 38.1, 37.0, 28.6, 9.3; HRMS (APCI) 179.1430 calcd for
C12H19O [M + H]+, found 179.1429 (−0.79 ppm).
1
procedure for 2c, providing 5f (263 mg, 80%) as a colorless oil: H
NMR (400 MHz, CDCl3) δ 7.22 − 7.15 (m, 1H), 7.11 − 7.05 (m,
2H), 6.98 (d, J = 7.3 Hz, 1H), 2.35 (s, 3H), 1.73 (dq, J = 14.8, 7.5 Hz,
2H), 1.55 (dq, J = 14.8, 7.5 Hz, 2H), 1.23 (s, 3H), 0.67 (t, J = 7.4 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 147.8, 137.3, 127.8, 127.5,
126.0, 123.8, 41.24, 35.3, 23.0, 21.9, 8.9; HRMS (APCI) 370.3468
calcd for C26H44N [2M + NH4]+, found 370.3496 (7.35 ppm).
3-(3-Methylpentan-3-yl)-1,1′-biphenyl (5g). This compound was
prepared from 8g (253 mg, 1.05 mmol) using the method A procedure
General Procedure for HCl Activation (Method B)/Methyl-
ation of Tertiary Benzylic Carbinols. Chloro-3-tert-pentylben-
zene (4h). A flask was charged with 2-(3-chlorophenyl)butan-
2-ol (7h, 202 mg, 1.09 mmol), to which was added con-
centrated hydrochloric acid (1.5 mL). The mixture was stirred
at room temperature for 3 h prior to being extracted with
CH2Cl2 (3 × 3 mL). The combined extracts were washed with
brine, dried over anhydrous Na2SO4, and concentrated under
reduced pressure to give the corresponding chloride 14h
(containing 2 mol % elimination product 12 h) as a colorless
1
for 2c, providing 5g (170 mg, 71%) as a colorless oil: H NMR (500
MHz, CDCl3) δ 7.67−7.69 (m, 2H), 7.59 (t, 1H, J = 1.7 Hz), 7.36−
7.52 (m, 5H), 7.34−7.36 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
148.3, 142.1, 140.9, 128.8, 128.4, 127.4, 127.2, 125.83, 125.80, 124.3,
41.5, 35.4, 23.1; HRMS (APCI) calcd for C18H22 [M]+ 238.1722,
found 238.1716 (−2.52 ppm).
1
oil: H NMR (500 MHz, CDCl3) δ 7.56 (t, J = 2.0 Hz, 1H),
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Article
3-(1-Chloro-3-(3-methylpentan-3-yl)benzene (5h). This com-
pound (28 mg, oil) was prepared in 93% yield from alcohol 8h
(30 mg, 0.15 mmol) via the corresponding chloride using the method
B procedure as described for 4h. Spectral data for chloride 15h
(contains 3 mol % elimination product 13h) is given below in the
section describing NMR analysis of the reaction of 8h with SOCl2.
7.71 (ddd, J = 8.1, 2.6, 1.5 Hz, 1H), 7.25 (dd, J = 5.9, 4.8 Hz, 1H), 1.35
(s, 9H); 13C NMR (125 MHz, CDCl3) δ 146.7, 146.2, 133.5, 123.2,
114.4, 31.0.
Analytical data for 3-(prop-1-en-2-yl)pyridine (22b): 1H NMR
(500 MHz, CDCl3) δ 8.73 (br.s, 1H), 8.51 (m, 1H), 7.74 (br.d, J = 8.1
Hz, 1H), 7.26 (dd, J = 8.1, 3.0 Hz, 1H), 5.42 (s, 1H), 5.19 (s, 1H),
2.17 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 148.6, 147.2, 146.8,
140.9, 137.4, 133.6, 123.8, 21.5.
1
Spectral data for 5h (contains 3 mol % elimination product 13h): H
NMR (500 MHz, CDCl3) δ 7.27 (dd, J = 7.8, 2.2 Hz, 1H), 7.23 (d, J =
7.8 Hz, 1H), 7.15−7.18 (overlapped, 2H), 1.69−1.76 (m, 2H), 1.53−
1.60 (m, 2H), 1.24 (s, 3H), 0.68 (t, J = 7.4 Hz, 6H); 13C NMR (125
MHz, CDCl3) δ 150.1, 134.0, 129.1, 127.0, 125.4, 124.9, 41.5, 35.2,
22.7, 8.7. Anal. Calcd for C12H17Cl: C, 73.27; H, 8.71. Found: C,
73.17; H, 8.69.
2-(3-((tert-Butyldimethylsilyl)oxy)phenyl)propan-2-ol (6j). This
compound (710 mg) was prepared as a colorless oil in 89% yield by
the addition of lithium trimethylmagnesate17 to 1-(3-((tert-
butyldimethylsilyl)oxy)phenyl) ethanone (750 mg, 3 mmol) in
THF, using the procedure outlined below for 6k: 1H NMR (500
MHz, CDCl3) δ 7.20 (t, J = 8.0 Hz, 1H), 7.07 (ddd, J = 8.0, 1.8, 1.0
Hz, 1H), 6.99 (t, J = 2.1 Hz, 1H), 6.73 (ddd, J = 8.0, 2.5, 1.0 Hz, 1H),
1.57 (s, 6H), 1.00 (s, 9H), 0.22 (s, 6H); 13C NMR (125 MHz, CDCl3)
δ 155.8, 151.2, 129.3, 118.4, 117.4, 116.7, 72.6, 31.9, 25.9, 18.9, −4.2;
HRMS (ESI) 249.1675 calcd for C15H25OSi [M − H2O + H]+ found
249.1655 (−5.52 ppm).
N-(3-(2-Hydroxypropan-2-yl)phenyl)benzamide (6k). Under ni-
trogen, a dry 50 mL Schlenk flask equipped with a magnetic stirbar
was charged with 15 mL of dry THF and then placed in an ice bath.
Methylmagnesium chloride (3 M in ether, 0.84 mL, 2.51 mmol) and
methyllithium (3 M in ether, 0.84 mL, 2.51 mmol) were added. After
the mixture was stirred at 0 °C for 30 min, a solution of N-(3-
acetylphenyl)benzamide (200 mg, 0.84 mmol) in 10 mL of dry THF
was added. After 1 h, the ice bath was removed, and the reaction was
allowed to stir at room temperature overnight. The reaction was
cooled to 0 °C, quenched with saturated NaHCO3 solution, and
extracted with ethyl acetate (3 × 15 mL). The organic layers were
combined, dried with anhydrous Na2SO4, and filtered, and the solvent
was evaporated under reduced pressure. The residue was purified on
silica gel (1:1 hexane/ethyl acetate) to yield 6k as a white solid (178
mg, 84% yield): 1H NMR (400 MHz, CD3OD) δ 7.93−7.91 (m, 2H),
7.79 (s, 1H), 7.59−7.48 (m, 4H), 7.31−7.29 (m, 2H), 1.55 (s, 6H);
13C NMR (100 MHz, CD3OD) δ 167.50, 150.36, 138.11, 134.91,
131.42, 128.19, 128.05, 127.18, 120.57, 119.06, 117.45, 71.52, 30.47;
HRMS (APCI) calcd for C16H17NO2Na 279.1184 [M + Na]+, found
279.1179 (−1.9 ppm).
(3-Ethyl-3-methylpentyl)benzene (26). This compound was pre-
pared from 25 (250 mg, 1.26 mmol) using the method A procedure
1
for 2c, providing 26 (178 mg, 74%) as a colorless oil: H NMR (500
MHz, CDCl3) δ 7.34−7.37 (m, 2H), 7.23−7.27 (m, 3H), 2.56−2.60
(m, 2H), 1.53−1.57 (m, 2H), 1.38 (q, 4H, J = 7.9 Hz), 0.90−0.94 (m,
9H); 13C NMR (125 MHz, CDCl3) δ 143.9, 128.4, 125.6, 41.0, 35.3,
31.1, 30.4, 24.1, 8.1. Anal. Calcd for C14H22: C, 88.35; H, 11.65.
Found: C, 88.50; H, 11.66.
Investigation of SOCl2 Activation of Tertiary Benzylic
Carbinols. 1-(2-Chloropropan-2-yl)-3,5-dimethoxybenzene
(16b).22 This compound was prepared in 98% yield from
alcohol 6b and concentrated HCl using the same procedure
described for the synthesis of chloride 14h en route to methy-
lated product 4h. Treatment of 6b with SOCl2 for 2 h at 0 °C
followed by concentration in vacuo gave the identical com-
1
pound: H NMR (500 MHz, CDCl3) δ 6.77 (d, J = 2.2 Hz,
2H), 6.42 (t, J = 2.2 Hz, 1H), 3.84 (s, 6H), 1.99 (s, 6H); 13C
NMR (125 MHz, CDCl3) δ 160.5, 148.7, 104.2, 99.0, 69.5,
55.4, 34.2.
NMR Study of Reaction of 8h with SOCl2 in CD2Cl2. Alcohol 8h
(30 mg, 0.15 mmol) was dissolved in 750 μL of CD2Cl2, transferred to
an NMR tube, and placed in an ice bath. After 5 min, SOCl2 (60 uL,
98 mg, 0.81 mmol) was added, and the tube was agitated to achieve
mixing. After 2 h, the tube was removed from the ice bath and allowed
1
to warm to room temperature. H and 13C NMR spectra were taken
after 1, 2, 5, and 25 h at room temperature. Mole ratios of chlorosulfite
19h, chloride 15h, and alkene 13h were determined by integration
(see Scheme 4).
3-(3-Chlorophenyl)pentan-3-ol (8h): 1H NMR (500 MHz,
CD2Cl2) δ 7.32 (t, J = 2.1 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 7.16
(dt, J = 7.8, 1.6 Hz, 1H), 7.12 (ddd, J = 7.4, 2.2, 1.6 Hz, 1H), 1.65−
1.78 (m, 4H), 0.65 (t, J = 7.4 Hz, 6H); 13C NMR (125 MHz, CD2Cl2)
δ 148.7, 134.3, 129.6, 126.6, 126.3, 124.3, 77.4, 35.5, 7.9.
(E)-1-Chloro-3-(pent-2-en-3-yl)benzene (13h). Resonances de-
duced from examination of a 73:27 mixture of 15h and 13h: 1H
NMR (500 MHz, CD2Cl2) δ 7.22−7.23 (m, 1H), 7.13−7.15 (m, 3H),
5.66 (q, J = 6.9 Hz, 1H), 2.41 (q, J = 7.6 Hz, 2H), 1.71 (d, J = 6.9 Hz,
3H), 0.88 (t, J = 7.6 Hz, 3H); 13C NMR (125 MHz, CD2Cl2) δ 145.6,
141.6, 134.3, 129.9, 126.70, 126.67, 124.8, 123.9, 22.8, 14.2, 13.4.
1-Chloro-3-(3-chloropentan-3-yl)benzene (15h, Contains 3 mol %
of Elimination Product 13h): 1H NMR (500 MHz, CD2Cl2) δ 7.42 (t,
J = 2.0 Hz, 1H), 7.28 (ddd, J = 7.8, 1.9, 1.3 Hz, 1H), 7.21 (dt, J = 7.8,
0.5 Hz, 1H), 7.17 (ddd, J = 7.9, 2.0, 1.3 Hz, 1H), 2.06 (q, J = 7.2 Hz,
4H), 0.78 (t, J = 7.2 Hz, 6H); 13C NMR (125 MHz, CD2Cl2) δ 145.6,
134.4, 129.7, 127.49, 127.47, 125.3, 80.3, 37.6, 9.3.
3-([1,1′-Biphenyl]-3-yl)pentan-3-ol (8g). A modification of Hart-
mann’s procedure20 was used: methyl 3-phenylbenzoate (499 mg, 2.35
mmol) was dissolved in 5 mL of THF and cooled to −78 °C. EtMgCl
(2 M in THF, 3.5 mL, 7.5 mmol) was added and the mixture stirred
for 5 h at this temperature, at which point TLC indicated completion.
The reaction was quenched by the addition of saturated aq NH4Cl and
warmed to room temperature. Following aqueous workup and column
chromatography (5% EtOAc in hexanes), 8g was obtained as a color-
1
less oil (560 mg, 94%): H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H),
3-(3-Chlorophenyl)pentan-3-yl sulfochloridite (chlorosulfite 19h):
7.72−7.74 (m, 2H), 7.40−7.56 (m, 6H), 2.14 (br s, 1H), 1.93−2.03
(m, 4H), 0.92 (t, 3H, J = 7.3 Hz); 13C NMR (125 MHz, CDCl3) δ
146.6, 141.7, 141.0, 128.9, 128.6, 127.5, 127.4, 125.3, 124.7, 124.6,
77.7, 35.2, 8.1; HRMS (APCI) calcd for C17H19 [M − OH]+ 223.1481
found 223.1498 (+7.62 ppm).
1H NMR (500 MHz, CD2Cl2) δ 7.32 (t, J = 2.1 Hz, 1H), 7.19 (t, J =
7.4 Hz, 1H), 7.16 (dt, J = 7.8, 1.6 Hz, 1H), 7.12 (ddd, J = 7.4, 2.1, 1.6
Hz, 1H), 1.66−1.78 (m, 4H), 0.65 (t, J = 7.4 Hz, 6H); 13C NMR (125
MHz, CD2Cl2) δ 148.7, 134.3, 129. 9, 126.7, 126.3, 124.3, 77.7, 35.5,
8.0. Note: although the pyramidal geometry at sulfur should render the
CH2 and CH3 carbons diastereotopic, we could only resolve a single
CH2 resonance and a single CH3 resonance in the 13C NMR spectrum
at 125 MHz.
Attempted Activation/Ethylation of Diethylarylcarbinol
8c. 1-(3-Ethylpentan-3-yl)-3-methoxybenzene (23c). The meth-
od A procedure for 2c described above was applied to diethy-
larylcarbinol 8c (255 mg, 1.31 mmol) using triethylaluminum
(1.0 M in hexanes, 2.6 mL, 2.6 mmol) in place of trime-
thylaluminum. This procedure afforded an inseparable 77:23
mixture of the desired compound 23c and the undesired hydri-
de addition product 21c as a light yellow oil (245 mg, 94%).
3-tert-Butylpyridine (21b) and 3-(Prop-1-en-2-yl)pyridine (22b).
The method A procedure for 2c described above was applied to
2-(pyridin-3-yl)propan-2-ol (20b, 137 mg, 1 mmol) using 1,2-
dichloroethane in place of dichloromethane as solvent and elevating
the reaction temperature to 85 °C. This reaction was quenched with
10% NaHCO3 solution, and the resulting mixture was extracted with
dichloromethane. The combined extracts were dried over anhydrous
Na2SO4 and concentrated to afford an inseparable 79:21 mixture
of the desired compound 21b and the undesired elimination product
22b as a light yellow oil (122 mg, 89% mass recovery).
Analytical data for 3-tert-butylpyridine (21b): 1H NMR (500
MHz, CDCl3) δ 8.67 (d, J = 2.6 Hz, 1H), 8.43 (br d, J = 4.8 Hz, 1H),
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Article
Analytical data for 23c: 1H NMR (500 MHz, CDCl3) δ 7.21 (t,
1H, J = 8 Hz), 6.94 (t, 1H, J = 8 Hz), 6.87 (s, 1H), 6.73 (t, 1H,
J = 8 Hz), 4.20 (s, 3H), 1.65 (q, 6H, J = 7.0 Hz), 0.65 (t, 9H,
J = 7.0 Hz); 13C NMR (125 MHz, CDCl3) δ 159.4, 149.4,
128.6, 119.6, 113.9, 109.5, 55.1, 43.9, 28.8, 8.1; HRMS
(APCI) calcd for C14H23O 207.1743 [M + H]+, found
207.1738 (−2.75 ppm).
(15) Blanch, J. H. J. Chem. Soc. B 1966, 937−939.
(16) Miller, D. B. J. Org. Chem. 1966, 31, 908−912.
(17) Hatano, M.; Matsumura, T.; Ishihara, K. Org. Lett. 2005, 7,
573−576.
(18) Hatano, M.; Ito, O.; Suzuki, S.; Ishihara, K. J. Org. Chem. 2010,
75, 5008−5016.
(19) Djura, P.; Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1978,
395−400.
(20) Hartmann, R. W.; Kranzfelder, G.; Von Angerer, E.;
Schoenenberger, H. J. Med. Chem. 1980, 23, 841−848.
(21) Jeffery, E.; Meisters, A.; Mole, T. Aust. J. Chem. 1974, 27, 2569−
2576.
(22) Shih, N.-Y.; Mangiaracina, P. Lipoxygenase Inhibitors. Int. Pat.
Appl. CP/US90/05824, Oct 17, 1990; Chem Abstr. 1991, 115,
114147.
1-Methoxy-3-(pentan-3-yl)benzene (24c). The method A proce-
dure for 2c described above was applied to diethylarylcarbinol 8c (246
mg, 1.26 mmol), using diethylaluminum chloride (1 M in hexanes,
3.16 mL, 3.16 mmol) in place of trimethylaluminum. This procedure
afforded a 9:91 ratio of 23c and 24c as a colorless oil (228 mg, 71%).
1
Analytical data for 21c: H NMR (500 MHz, CDCl3) δ 7.212 (t, 1H,
J = 7.7 Hz), 6.71−6.76 (m, 3H), 3.80 (s, 3H), 2.27−2.31 (m, 1H),
1.66−1.74 (m, 2H), 1.51−1.58 (m, 2H), 0.78 (t, 3H, J = 7.4 Hz); 13C
NMR (125 MHz, CDCl3) δ 159.6, 147.7, 129.0, 120.4, 113.8, 110.7,
55.1, 49.8, 29.3, 12.3; HRMS calcd for C12H19O 179.1430 [M + H]+,
found 179.1439 (+4.97 ppm).
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra (1H and 13C) of all new compounds and H
1
NMR spectra of known compounds described in Table 1. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: pcarlier@vt.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health for financial support
of this work (1R01AI082581-01) and Mr. Eugene Camerino
for help with analytical characterization.
REFERENCES
■
(1) Carlier, P. R.; Anderson, T. D.; Wong, D. M.; Hsu, D. C.; Hartsel,
J.; Ma, M.; Wong, E. A.; Choudhury, R.; Lam, P. C.-H.; Totrov, M. M.;
Bloomquist, J. R. Chem.-Biol. Interact. 2008, 175, 368−375.
(2) Faldt, A.; C. Krebs, F.; Thorup, N. J. Chem. Soc., Perkin Trans. 2
1997, 2219−2228.
(3) Carpenter, M. S.; Easter, W. M.; Wood, T. F. J. Org. Chem. 1951,
16, 586−617.
(4) Austin, M.; Egan, O. J.; Tully, R.; Pratt, A. C. Org. Biomol. Chem.
2007, 5, 3778−3786.
(5) Reetz, M. T.; Westermann, J.; Kyung, S.-H. Chem. Ber. 1985, 118,
1050−1057.
(6) Reetz, M. T.; Westerman, J. J. Org. Chem. 1983, 48, 254−255.
(7) Nikas, S. P.; Grzybowska, J.; Papahatjis, D. P.; Charalambous, A.;
Banijamali, A. R.; Chari, R.; Fan, P. S.; Kourouli, T.; Lin, S. Y.;
Nitowski, A. J.; Marciniak, G.; Guo, Y.; Li, X. Y.; Wang, C. L. J.;
Makriyannis, A. AAPS J. 2004, 6, 1−13.
(8) Reetz, M. T.; Wenderoth, B.; Peter, R.; Steinbach, R.;
Westermann, J. J. Chem. Soc., Chem. Commun. 1980, 1202−1204.
(9) Tanaka, H.; Shishido, Y. Bioorg. Med. Chem. Lett. 2007, 17,
6079−6085.
(10) Treatment of 3-hydroxy substrates 6d, 7d, and 8d with SOCl2
was performed at −20 °C.
(11) Lewis, E. S.; Boozer, C. E. J. Am. Chem. Soc. 1952, 74, 308−311.
(12) Schreiner, P. R.; Schleyer, P. v. R.; Hill, R. K. J. Org. Chem. 1993,
58, 2822−2829.
(13) Olah, G. A.; Wu, A. H.; Farooq, O. J. Org. Chem. 1989, 54,
1375−1378.
(14) Anslyn, E. V.; Dougherty, D. A. In Modern Physical Organic
Chemistry; University Science Books: Sausalito, CA, 2006; pp 421−88.
3133
dx.doi.org/10.1021/jo202371c | J. Org. Chem. 2012, 77, 3127−3133