An alternative role for acetylenes: Activation of fluorobenzenes toward nucleophilic aromatic substitution

Article abstract of DOI:10.1021/jo400668v

Acetylenes are increasingly versatile functional groups for a range of complexity-building organic transformations and for the construction of desirable molecular architectures. Herein we disclose a previously underappreciated aspect of arylacetylene reac

Full text of DOI:10.1021/jo400668v

Article
pubs.acs.org/joc
An Alternative Role for Acetylenes: Activation of Fluorobenzenes
toward Nucleophilic Aromatic Substitution
Nicholas P. Bizier, Jay Wm. Wackerly, Eric D. Braunstein, Mengfei Zhang, Stephen T. Nodder,
Stephen M. Carlin, and Jeffrey L. Katz*
Department of Chemistry, Colby College, 5754 Mayflower Hill Drive, Waterville, Maine 04901, United States
S
* Supporting Information
ABSTRACT: Acetylenes are increasingly versatile functional
groups for a range of complexity-building organic trans-
formations and for the construction of desirable molecular
architectures. Herein we disclose a previously underappre-
ciated aspect of arylacetylene reactivity by utilizing alkynes as
electron-withdrawing groups (EWG) for promoting nucleo-
philic aromatic substitution (SNAr) reactions. Reaction rates
for the substitution of 4-(fluoroethynyl)benzenes by p-cresol
1
were determined by H NMR spectroscopy, and these rate data were used to determine substituent (Hammett) constants for
terminal and substituted ethynyl groups. The synthetic scope of acetylene-activated SNAr reactions is broad; fluoroarenes bearing
one or two ethynyl groups undergo high-yielding substitution with a variety of oxygen and arylamine nucleophiles.
analyzed the inductive and resonance contributions to the
INTRODUCTION
■
+
Hammett constants through a comparison of σm, σm , σp, and
Acetylenes have emerged as increasingly important and
powerful functional groups in synthetic design and small
molecule and materials applications.1 The prevalence of
acetylenes in modern research efforts is evident from the
number of recent comprehensive treatises on the subject of
their use.2 Access to complex acetylene-containing systems has
been enabled by recent synthetic advances, most notably the
palladium-catalyzed cross coupling of terminal alkynes and aryl
halides as described by Sonogashira, Tohda, and Hagihara in
1975.3 The generality and efficiency of this Sonogashira
coupling method, and more modern variants,4 for the synthesis
of arylacetylenes has spawned the rapid development of
chemical, materials, and biological applications. Along with
methods for their synthesis, the accessibility of acetylenic
precursors has facilitated a parallel resurgence in reaction
development using alkynyl groups.5−7
σp+ values. These experiments confirmed that the ethynyl group
is overall electron-withdrawing, but Landgrebe also reported
that the group manifested an opposing electron-donating
resonance contribution in the stabilization of positive charge
(σp − σm = −0.16).13
+
+
The electronic complexity of acetylenes is also evident from
more modern spectroscopic, computational, and experimental
investigations.16 For example, a recent computational study by
Frontera and Deya17 focused on the ability of the ethynyl group
to perturb the ion−π interactions of an appended arene. As
expected, electron-withdrawing ethynyl substitution was found
to enhance anion−π interactions on pendant benzenes.
However, the authors also discovered that cation−π binding
was strengthened for certain cations and attributed this
enhanced binding to the ethynyl group’s ability to increase
arene polarizability.
The considerable research efforts devoted to the synthesis
and applications of acetylenes mask that a fundamental aspect
of acetylene chemistry remains underexplored. While both
experiment and theory predict that sp-hybridized carbon atoms
are significantly more electronegative than higher-valence
carbon bonding motifs,8 questions remain regarding the
electronic nature of the acetylene moiety. An electron-
withdrawing polarization for acetylenes was reported nearly a
century ago by Baker, Cooper, and Ingold after analyzing the
product mixtures from nitration reactions of phenylpropiolic
acids and esters.9 The substituent constants for the ethynyl and
phenylethynyl groups were first measured by Brown10 and by
Kochi and Hammond,11 with continued refinement by
Charton,12 Landgrebe,13 Taft,14 and others15 for those and
related acetylenic groups. The electronic complexity of the
ethynyl group was discussed by Landgrebe, who measured and
Our research group has a longstanding interest in the use of
nucleophilic aromatic substitution (SNAr) reactions for the
formation of heteracalixarene macrocycles.18 In surveying the
literature, we were struck by the lack of definitive studies on the
activating effect of ethynyl groups on nucleophilic halobenzene
substitution. Further, while electron-withdrawing character has
long been attributed to alkynes (vide supra), the compatibility
of ethynyl groups with SNAr reactions remained uncertain, as
there are very few reported examples of halobenzene SNAr
reactions with solely ethynyl activating groups.19
−
Several σp values for ethynyl groups, expected to be most
predictive of their effect on SNAr reaction rates, have been
Received: March 29, 2013
© XXXX American Chemical Society
A
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previously reported. Eaborn measured the substituent constant
for the ethynyl group at σp− = 0.53 via the alkaline solvolysis of
benzylstannanes and silanes.20 Exner21 and Litvinenko22
independently determined the value for the phenylethynyl
Table 1. Kinetics of 4-Fluorobenzenes 1 Reacted with p-
Cresol
−
group at σp = 0.39 and 0.30, respectively. However, we
questioned the utility of these values for predicting the effect of
ethynyl groups on SNAr reaction rates; it is unintuitive that a
phenylethynyl group is significantly weaker in electron-
withdrawing capacity than an ethynyl group, and the reactions
used to measure the substituent constants did not involve
intermediates that resemble the Meisenheimer complex of an
SNAr process.
With the goal of more completely describing the electronic
behavior of such an important functional group, we investigated
the electron-withdrawing polarization of ethynyl groups in the
context of SNAr reactions. We now report that ethynyl groups
are sufficiently electron-withdrawing to activate fluorobenzenes
for nucleophilic substitution by oxygen and arylamine
nucleophiles. Below we detail our quantitative rate measure-
ments and describe the scope of “acetylene-activated” SNAr
reactions with respect to both nucleophile and electrophile.
a
−
entry
electrophile
product
rate (k)
σp
b
b
1
2
3
4
5
6
7
1a (R = CCH)
1b (R = CCPh)
1c (R = CC-tBu)
1d (R = CC-nBu)
1e (R = COMe)
1f (R = CF3)
2a
2b
2e
2d
2e
2f
28.8
55.9
0.53,20 0.42
0.30,22 0.46
b
3.18
0.24
7150
636
3.70
0.8423
0.6524
0.2525
1g (R = Br)
2g
a
b
In units of 106 L mol−1 s−1. This work.
1a,b (Table 1, entries 1 and 2) exhibit remarkably strong
electron-withdrawing capacities for all-carbon functional
groups, with the measured substitution rate for phenyl-
ethynyl-substituted 1b only about 11 times slower than that
for the p-CF3-substituted system 1f.
RESULTS AND DISCUSSION
■
The inductive and resonance contributions to the electron-
withdrawing polarization of the ethynyl and phenylethynyl
groups were also investigated by reacting 3-(fluoroethynyl)-
benzene and 1-fluoro-3-(phenylethynyl)benzene26 with p-
cresol. Using 3-(fluoroethynyl)benzene (p-cresol, KOtBu,
DMSO, 100 °C, 18 h), preferential alkyne addition was
observed. For 1-fluoro-3-(phenylethynyl)benzene (p-cresol,
KOtBu, DMSO, 100 °C, 18 h), only recovered starting
material was obtained. Reaction of p-cresol and 1-fluoro-3-
(phenylethynyl)benzene under forcing conditions (KOtBu,
DMSO, 130 °C, 48 h) and analysis of the reaction mixture by
GC/MS revealed a mixture of unreacted starting material,
alkyne addition products (mixture of olefin isomers), and the
aromatic substitution product. These data indicate that the
inductive electron-withdrawing effect of the ethynyl and
phenylethynyl groups alone is insufficient to promote selective
aromatic substitution and establishes that an electron-with-
drawing resonance effect is critical for reactivity in SNAr
reactions.
To the best of our knowledge, nucleophilic fluorine displace-
ment of (4-fluorophenyl)acetylene (1a) has never been
reported, which suggests either that the ethynyl functional
group is unable to sufficiently stabilize the intermediate
Meisenheimer complex or that anionic alkyne addition is
chemoselectively favored over aromatic substitution. However,
under conditions well established to promote SNAr reactions,
we found that (4-fluorophenyl)acetylene (1a) underwent
substitution by p-cresol (KOtBu, DMSO, 100 °C, 12 h;
Scheme 1) to afford diaryl ether 2a in a remarkable 75%
Scheme 1. Substitution of (4-Fluorophenyl)acetylene (1a)
by p-Cresol
A large reduction in reaction rate is observed when moving
from the ethynyl-substituted fluorobenzene 1a to the tert-
butylethynyl-substituted system 1c (Table 1, entry 3). This is
likely a reflection of increased electron density of the internal
carbon of the tert-butyl group, adding electron density to the
alkyne,16,17 and a manifestation of hyperconjugative donation
into the alkyne by the tert-butyl substituent. Only traces of
substitution products were observed for the reaction of p-cresol
with the n-butylethynyl-substituted fluorobenzene 1d (entry 4),
preventing the calculation of a substituent constant for this
functional group. This reaction instead furnished a complex
mixture of products, which included products derived from
alkyne addition of p-cresol or tert-butoxide, as well as higher
molecular weight oligomeric species. We speculate that the
divergent reactivity observed for 1d (as compared to isomeric
1c) results from both the reduced steric suppression of alkyne
addition relative to 1c and the sensitivity of the propargylic
protons under the anionic reaction conditions.
isolated yield. Furthermore, only traces of products resulting
from addition of the phenoxide nucleophile to the terminal
ethynyl group were observed.
Measurement of substituent constants for ethynyl groups
required the establishment of a linear free energy relationship
(LFER). Reaction rates were first measured using functional
groups with known σp values23−25 in the 4-position of
−
fluorobenzene (1e−g). The LFER was generated by plotting
the obtained rates versus the reported substituent constants for
the 4-position functional groups in 1e−g (see the Supporting
Information). Upon establishing the LFER, the reaction rates
measured for acetylenes 1a−c allowed calculation of σp− values
for the ethynyl, phenylethynyl, and tert-butylethynyl groups
(Table 1). Our measured substituent constants for the ethynyl
−
and phenylethynyl groups (σp = 0.42 and 0.46, respectively)
−
vary in order and magnitude from the previously published σp
values, with the phenylethynyl group promoting a faster
Vinyl groups have been previously measured as significantly
weaker electron-withdrawing groups than their ethynyl counter-
parts. To quantify this comparative activation in the context of
nucleophilic aromatic substitution, we subjected trans-4-
substitution rate relative to ethynyl.20−22 The σp value for
−
−
the tert-butylethynyl group (σp = 0.24) had not previously
been determined. The ethynyl and phenylethynyl groups in
B
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fluorostilbene (3) to substitution by p-cresol.27 As expected on
the basis of the published substituent constant of the trans-β-
(entry 3). Increased steric bulk on the phenoxy nucleophile was
also accommodated. o-Cresol was successfully condensed with
1a,b, giving 63% and 80% yields of diaryl ethers 2h,i,
respectively (entries 5 and 6).
styryl group (σp = 0.1310), nucleophilic substitution of 3
−
proceeded much more slowly than for the analogous
phenylethynyl system 1b, but extended reaction times did
lead to high-yielding aryl ether formation (Scheme 2). We
Substitution reactions of alternative nucleophiles with
phenylethynyl-substituted fluorobenzene 1b were next eval-
uated. Sodium ethoxide induced efficient fluorine substitution
of 1b, furnishing the corresponding aryl ethyl ether 5a in 90%
yield (ethanol, NaH, DMSO, 100 °C, 18 h, entry 7). NaH was
found to be the optimal base for alkoxide nucleophiles, but
DMSO remained the optimal solvent. Use of DMF or NMP
required longer reaction times and resulted in reduced yields of
substitution products. Increased steric bulk on the alkoxide
nucleophile was also accommodated. The product yield
remained high for the reaction of sodium isopropoxide with
1b, affording substitution product 5b in 76% yield (entry 8).
Substitution became very sluggish, however, using potassium
tert-butoxide as the nucleophile, furnishing only a 38% yield of
aryl ether product 5c (entry 9). Sodium allyloxide was also an
effective nucleophile when it was condensed with 1b, furnishing
the corresponding allyl aryl ether 5d in 80% yield (entry 10).
Electrophiles 1a,b were each reacted with sodium benzyl-
oxide,28 resulting in 54% (5e) and 76% yields (5f) of the
corresponding aryl ethers (entries 11 and 12). It should be
noted that alkyne addition of benzyloxide to 1a was the major
side product leading to the diminished yield of 5e and that use
of DMF or NMP as solvent did not significantly alter the
observed ratio of aromatic substitution to alkyne addition.
Arylamines were also found to be viable nucleophiles for the
substitution of 1b. Condensation of 1b with p-toluidine
furnished a high yield of the corresponding diaryl amine
substitution product 6a (84%, entry 13), as did reaction of 1b
with the more sterically encumbered o-toluidine (6b, 70%,
entry 14). However, attempts to substitute electrophile 1b
using aliphatic amines have not yet provided synthetically useful
yields of substitution products.
Scheme 2. Reaction of trans-4-Fluorostilbene (3)
measured a substituent constant for the trans-β-styryl group of
σp− = 0.24 under our reaction conditions, which is significantly
lower than that of the phenylethynyl group but nearly identical
with that of the more weakly activating tert-butylethynyl group
(see Table 1).
Having quantified the electron-withdrawing capacity of the
alkynes in 1a−c and established the viability of acetylene-
activated SNAr reactions, we next sought to examine the
synthetic scope. DMSO solvent was optimal; analogous
reactions conducted using DMF or NMP proceeded to lower
conversion and produced inferior yields of aromatic sub-
stitution products even at extended reaction times. Potassium
tert-butoxide was found to be the optimal base with respect to
operational simplicity and yield, but substitution of 1a,b was
also observed using p-cresol with NaH base. On a preparative
scale, phenylethynyl-activated electrophile 1b underwent
efficient substitution by p-cresol, producing aryl ether 2b in
88% yield (Table 2, entry 2). Although it was significantly less
activated toward substitution, tert-butylethynyl fluorobenzene
1c also underwent high-yielding aryl ether formation with p-
cresol at 130 °C over 72 h, furnishing product 2c in 86% yield
Chemoselectivity shifted almost completely for sulfur-based
nucleophiles, which were found to strongly favor alkyne
addition.29 The reaction between alkyne 1b and 4-methyl-
benzenethiol (KOtBu, DMSO, 4 h, 85 °C, entry 15) produced
only trace amounts of substitution product. The same
propensity for alkyne addition was also observed using
ethanethiol (KOtBu, DMSO, 18 h, 80 °C, entry 16).
Alternative bases and solvents were screened for each thiol
nucleophile but did not alter ratios of alkyne addition versus
substitution.
The reaction scope was investigated beyond simple (4-
fluorophenyl)acetylenes 1a−c, leading to further insights into
the factors that influence fluorine substitution versus alkyne
addition. When (2-fluorophenyl)acetylene 7a (R = H; see
Table 3) was subjected to reaction with p-cresol (KOtBu,
DMSO, 100 °C), only 5% of diaryl ether 8a was obtained. The
balance of the reaction mixture consisted of products resulting
from addition of p-cresol across the alkyne (mixture of olefin
isomers) and higher molecular weight materials. A similar
product mixture strongly favoring alkyne addition was also
obtained for the reaction of 7a with sodium benzyloxide. When
the more sterically shielded 1-fluoro-2-(phenylethynyl)benzene
7b was subjected to reaction with p-cresol (KOtBu, DMSO,
100 °C), fluorine substitution again became the dominant
reaction pathway. Using p-cresol or ethanol nucleophiles
produced the corresponding aryl ether products 8b,c in only
slightly lower yields as compared to reactions with the 4-fluoro
Table 2. Nucleophile Scope for SNAr Reactions of (4-
Fluorophenyl)acetylenes 1
entry
electrophile
nucleophile
p-cresol
base
product (yield, %)
1
1a (R = H)
1b (R = Ph)
1c (R = tBu)
1d (R = nBu)
1b (R = H)
1b (R = Ph)
1b (R = Ph)
1b (R = Ph)
1b (R = Ph)
1b (R = Ph)
1a (R = H)
1b (R = Ph)
1b (R = Ph)
1b (R = Ph)
1b (R = Ph)
1b (R = Ph)
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
NaH
2a (75)
2b (88)
2
p-cresol
a
3
p-cresol
2c (86)
b
4
p-cresol
2d (<5)
5
o-cresol
2h (63)
2i (80)
5a (90)
5b (76)
5c (38)
5d (80)
5e (54)
5f (76)
6a (84)
6b (70)
6
o-cresol
7
ethanol
8
isopropyl alcohol
KOtBu
NaH
9
none
10
11
12
13
14
15
16
allyl alcohol
benzyl alcohol
benzyl alcohol
p-toluidine
o-toluidine
4-CH3PhSH
ethanethiol
NaH
NaH
NaH
KOtBu
KOtBu
KOtBu
KOtBu
c
2j (<5)
c
2k (<5)
a
b
Conducted at 130 °C. A complex mixture of products resulted from
c
alkyne addition and isomerization. Alkyne addition was the
predominant reaction pathway.
C
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electron-withdrawing m-fluoro31 or m-phenoxy32 substituents
present on substrate 10 and subsequent substitution products
increase aromatic substitution rates as compared to those for
7a. Second, the presence of a weakly electron-donating p-
fluoro31 or p-phenoxy32 substituent, present on 10 but not 7a,
is expected to increase the electron density of the alkynyl
moiety in 10 and reduce the rate of alkyne addition relative to
7a.33
Table 3. Reactions of 2-Fluorophenylacetylenes 7
Following the successful substitution of both fluorine atoms
from 10, we turned to evaluating electrophiles bearing multiple
acetylene groups. As shown in Table 4, addition of a second
entry
electrophile
nucleophile
base
product (yield, %)
a
Table 4. Reaction of Diethynyldifluorobenzenes 12
1
2
3
4
5
6
7b (R = Ph)
7b (R = Ph)
7b (R = Ph)
7c (R = tBu)
7c (R = tBu)
7c (R = tBu)
p-cresol
ethanol
KOtBu
NaH
8b (74)
a
8c (86)
a
p-toluidine
p-cresol
ethanol
KOtBu
KOtBu
NaH
9a (71)
b
8d (67)
b
8e (56)
b
p-toluidine
KOtBu
9b (55)
a
b
Conditions: 100 °C, 18 h. Conditions: 150 °C, 72 h.
analogue 1b (74% and 86% yields, respectively; Table 3, entries
1 and 2). When p-toluidine was examined as a nucleophile in
the reaction with 1b, not only was substitution at the fluorine
atom observed but also the substrate underwent subsequent 5-
endo-dig anionic cyclization to produce 2-arylindole 9a (entry
3).30
Under more vigorous reaction conditions (72 h, 150 °C), 1-
fluoro-2-(tert-butylethynyl)benzene (7c) also underwent pref-
erential aromatic substitution. p-Cresol and ethanol reacted
with 7c to produce the corresponding ethers 8d (67% yield,
entry 4) and 8e (56% yield, entry 5). Furthermore, use of p-
toluidine once again led to the corresponding 2-tert-butylindole
(9b, 55% yield, entry 6) via tandem substitution−cyclization.
Although 7b,c proved viable electrophiles for preferential
aromatic substitution, we remained concerned that the alkyne
addition observed with (2-fluorophenyl)acetylene 7a (vide
supra) indicated that unsubstituted ethynyl groups were
incompatible with o-fluorine atoms for SNAr activation. We
subsequently subjected (2,4-difluorophenyl)acetylene (10) to
reactions with p-cresol in varying stoichiometric ratios (Scheme
3). In dramatic contrast to 7a, difluorophenylacetylene 10
temp,
product
entry
electrophile
nucleophile
base
°C
(yield, %)
1
2
3
4
5
6
12a (R = H)
p-cresol
KOtBu
KOtBu
KOtBu
KOtBu
NaH
60
60
13a (93)
13b (89)
13c (87)
13d (45)
13e (82)
14 (38)
12b (R = Ph) p-cresol
12c (R = tBu) p-cresol
12d (R = nBu) p-cresol
12b (R = Ph) ethanol
80
60
60
12b (R = Ph) p-toluidine KOtBu
100
ethynyl group to the fluorobenzene lowers the required
reaction temperatures and increases yields of substitution
products. Diethynyl- and diphenylethynyl-substituted electro-
philes 12a,b undergo high-yielding substitution of both fluorine
atoms by p-cresol, furnishing the aryl ether products in 93%
(13a) and 89% yields (13b), respectively (Table 4, entries 1
and 2). The di-tert-butylethynyl-substituted electrophile 12c
reacts smoothly but more slowly with p-cresol than 12a,b,
furnishing the disubstitution product 13c in 87% yield (entry
3). Furthermore, unlike n-butylethynyl-substituted substrate 1d,
di-n-butylethynyl-substituted compound 12d does furnish
appreciable amounts of substitution product 13d on reaction
with p-cresol (45% yield, entry 4). Sodium ethoxide was also
found to cleanly displace both fluorine atoms on 12b (82%,
entry 5). Use of p-toluidine as a nucleophile (entry 6) leads to a
double substitution−anionic cyclization cascade, producing
benzodipyrrole 14 in 38% yield in which six new σ bonds are
formed. Benzodipyrrole 14 is only sparingly soluble in lower-
polarity organic solvents, and the lower isolated yield in part
reflects the difficulty of purification of this compound. Analysis
of this reaction at reduced temperature reveals the order of
bond-forming events (Scheme 4). Following the initial fluorine
displacement, the reaction proceeds first to exclusively form
intermediate indole 15, which displays reduced aromatic
electrophilicity relative to 12b. Slow substitution of the second
fluorine atom, followed by rapid anionic cyclization, then leads
to benzodipyrrole 14.
Scheme 3. Substitution of 2,4-Difluorophenylacetylene (10)
underwent preferential and high-yielding aromatic substitution.
Using 1 equiv of nucleophile led to modest selectivity for
substitution of the p- over the o-fluorine atom (3:5 ortho:para,
11a:11b, entry 1), while use of 2.1 equiv of p-cresol at longer
reaction times formed the disubstitution product 11c in 91%
isolated yield. The divergent outcomes observed with electro-
philes 7a and 10 suggest that multiple electronic factors play a
role in chemoselectivity for these processes. First, the weakly
CONCLUSION
■
For the first time, the electron-withdrawing capabilities of
ethynyl, phenylethynyl, and tert-butylethynyl groups have been
D
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Article
constants at 85 °C. Reactions were run in duplicate or triplicate, and
the averages of these data were used.
Scheme 4. Bond-Formation Sequence Yielding
Benzodipyrrole 14
1-Fluoro-4-(phenylethynyl)benzene (1b). In a sealed tube were
added PdCl2(PPh3)2 (94.9 mg, 0.135 mmol) and CuI (188 mg, 0.986
mmol). The mixture was purged with Ar for 5 min, and then degassed
4-fluoro-1-iodobenzene (1.00 mL, 8.75 mmol), degassed phenyl-
acetylene (0.980 mL, 8.92 mmol), and triethylamine (12 mL) were
added in that order. The mixture was stirred at room temperature for 2
h and then was diluted with CH2Cl2 and aqueous NH4Cl. The layers
were separated, and the aqueous phase was extracted with CH2Cl2 (3
× 80 mL). The combined organic layers were washed with H2O (80
mL) and dried over Na2SO4. The solvent was removed in vacuo to
give a brown powder. Purification by silica gel flash chromatography
(hexanes) gave 1.54 g (7.84 mmol, 90%) of 1b as an off-white solid.
1H NMR (500 MHz, CDCl3): δ 7.56−7.54 (m, 2H), 7.53−7.51 (m,
2H), 7.40−7.37 (m, 1H), 7.36−7.35 (m, 2H), 7.05 (dd, J = 8.8, 8.8
Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 162.5 (d, J = 249.4 Hz),
133.5 (d, J = 8.4 Hz), 131.5, 128.4, 128.3, 123.1, 119.4 (d, J = 3.3 Hz),
115.6 (d, J = 22.3 Hz), 89.0, 88.3. TLC: Rf = 0.38 (hexanes). IR (KBr
pellet): 3268 (m), 2922 (w), 2111 (w), 1881 (w), 1654 (w), 1508 (s),
1594 (s), 1486 (s), 1442 (m), 1388 (m), 1217 (s) cm−1. HRMS
(DART):: calcd for [C14H9F]+ 196.0688, found 196.0688.
quantified, and substituent constants determined, in the context
of SNAr reactions. Furthermore, we have explored the scope of
these acetylene-activated SNAr reactions and shown that high-
yielding substitution of (4-fluoroethynyl)benzenes 1a−c, (2-
fluoroethynyl)benzenes 7, and (difluoroethynyl)benzenes 12
can be achieved with a variety of oxygen and arylamine
nucleophiles. Arylamine nucleophiles were found to react with
(2-fluoroethynyl)benzenes 7 and (difluoroethynyl)benzenes 12
via tandem substitution−cyclization to furnish 2-substituted N-
aryl indoles 9 and benzodipyrroles 14, respectively.
1-Fluoro-4-(tert-butylethynyl)benzene (1c). In a sealed tube
were added PdCl2(PPh3)2 (261 mg, 0.372 mmol) and CuI (150 mg,
0.785 mmol). The mixture was purged with Ar for 5 min, and then
degassed 4-fluoro-1-iodobenzene (2.00 mL, 17.3 mmol), degassed tert-
butylacetylene (4.25 mL, 34.5 mmol), and triethylamine (24.0 mL)
were added in that order. The mixture was stirred at room temperature
for 2 h then was diluted with CH2Cl2 and aqueous NH4Cl. The layers
were separated, and the aqueous phase was extracted with CH2Cl2 (3
× 80 mL). The combined organic layers were washed with H2O (80
mL) and dried over Na2SO4. The solvent was removed in vacuo to
give a brown oil. Purification by silica gel plug (hexanes) gave 2.80 g
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all starting
materials were obtained from commercial suppliers and were used
without further purification. Triethylamine and (trimethylsilyl)-
acetylene were distilled onto activated 3 Å molecular sieves under
an atmosphere of Ar. p-Toluidine was purified via sublimation prior to
use. Synthesized compounds 1b,34 1d,35 3,36 7b,37 9a,38 and 12a39
have been previously reported, and in each case our obtained
characterization data match the literature values. Analytical thin-layer
chromatography was performed with 0.25 mm silica gel 60-F TLC
plates. Flash column chromatography was carried out with silica gel
(230−400 mesh). NMR spectra were recorded on a 500 MHz
spectrometer. Chemical shifts are expressed in parts per million (δ)
using residual solvent peaks as internal standards. All potentially
ambiguous signals were further characterized and assigned on the basis
of COSY, HMQC, HMBC, and/or NOESY spectroscopy. Mass
spectra were obtained using an accurate mass TOF spectrometer with
a DART interface.
1
(15.9 mmol, 92%) of 1c as a clear, colorless liquid. H NMR (500
MHz, CDCl3): δ 7.35 (dd, J = 8.9, 5.4 Hz, 2H), 6.96 (dd, J = 8.8, 8.8
Hz, 2H), 1.31 (s, 9H). 13C NMR (126 MHz, CDCl3): δ 162.0 (d, J =
248.0 Hz), 133.3 (d, J = 8.2 Hz), 120.1 (d, J = 3.4 Hz), 115.3 (d, J =
21.8 Hz), 98.1 (d, J = 1.6 Hz), 77.9, 31.0, 27.9. TLC: Rf = 0.60
(hexanes). IR (thin film): 2970 (s), 2901 (s), 2195 (w), 1890 (w),
1602 (m), 1507 (s), 1475 (m), 1292 (m), 1231 (s), 1155 (m) cm−1.
HRMS (DART): calcd for [C12H14FH]+ 177.1074, found 177.1076.
1-Fluoro-4-(n-butylethynyl)benzene (1d). In a sealed tube were
added PdCl2(PPh3)2 (85.2 mg, 0.121 mmol) and CuI (47.8 mg 0.251
mmol). The mixture was purged with Ar for 5 min, and then degassed
4-fluoro-1-iodobenzene (1.00 mL, 8.75 mmol), degassed n-butylace-
tylene (1.03 mL, 8.93 mmol), and triethylamine (12 mL) were added
in that order. The mixture was stirred at room temperature for 2 h and
then was diluted with CH2Cl2 and aqueous NH4Cl. The layers were
separated, and the aqueous phase was extracted with CH2Cl2 (3 × 80
mL). The combined organic layers were washed with H2O (80 mL)
and dried over Na2SO4. The solvent was removed in vacuo to give a
brown oil. Purification by silica gel flash chromatography (hexanes)
Kinetics and Linear Free Energy Relationship. Following the
precedent established by Miller40 and Bevan,41 SNAr reaction rates
were measured for a series of fluorobenzenes (1a−g). The reactions
were carried out in DMSO with an excess of the nucleophile p-cresol.
Substitution was observed to occur with reasonable rates at 85 °C, and
this temperature was used for all rate measurements, which were
1
gave 1.33 g (7.52 mmol, 86%) of 1d as an off-white solid. H NMR
(500 MHz, CDCl3): δ 7.36 (dd, 2H, J = 8.9, 5.5 Hz), 6.97 (dd, J = 8.8,
8.8 Hz, 2H), 2.39 (t, J = 7.1 Hz, 2H), 1.85−1.84 (m, 2H), 1.53−1.45
(m, 2H), 0.95 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ
162.0 (d, J = 248.4 Hz), 133.3 (d, J = 8.4 Hz), 120.1 (d, J = 3.7 Hz),
115.3 (d, J = 21.9 Hz), 90.0 (d, J = 1.4 Hz), 79.5, 30.8, 22.0, 19.0, 13.6.
TLC: Rf = 0.46 (hexanes). IR (thin film): 2962 (s), 2934 (s), 2203
(m), 1712 (m), 1673 (m), 1601 (m), 1507 (s), 1234 (s), 1155 (s)
cm−1. HRMS (DART): calcd for [C12H13F]+ 176.1001, found
176.1026.
1-Ethynyl-4-(p-tolyloxy)benzene (2a). In a reaction flask under
Ar, 1a (125 mg, 1.04 mmol), p-cresol (127 mg, 1.17 mmol), and
DMSO (3 mL) were added. The reaction was started with the addition
of KOtBu (129 mg, 1.15 mmol). The reaction mixture was stirred in
an oil bath at 100 °C for 12 h. The reaction was quenched by dilution
with CH2Cl2 and 1 M HCl. The layers were separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 80 mL). The
combined organic layers were washed with H2O (80 mL) and dried
1
quantified by H NMR. Anionic alkyne addition side reactions were
minimal for 1a−c and did not interfere with the rate measurements.
General Procedure for Rate Measurements. A dry reaction
tube was charged with p-cresol (1.6 mmol) and KOtBu (1.6 mmol).
After the atmosphere was purged with Ar, dry DMSO (2.7 mL)
containing 280 mM 1,3-dimethyl-2-imidazolidone as an internal
standard was added. The solution was heated to 85 °C in an oil
bath, and once the temperature had stabilized, the electrophile 1 (1.0
mmol) was added to initiate the reaction. Reactions were run on time
scales ranging from 30 min to 200 h. Between 8 and 10 aliquots (0.07
mL each) were taken for each reaction. For analysis, each aliquot was
removed via syringe, quenched with 1 M HCl (1.5 mL), and extracted
1
into CDCl3 (1 mL). Aliquots were analyzed by H NMR with the
concentrations of unreacted nucleophile and electrophile calculated by
integration in comparison to the internal standard. Nonlinear least-
squares curve fitting was used to obtain the second-order rate
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The Journal of Organic Chemistry
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over Na2SO4. The solvent was carefully removed in vacuo to give a
brown oil (the product is somewhat volatile). Purification by silica gel
flash chromatography (hexanes → CH2Cl2/hexanes, 1/5) gave 163 mg
(0.782 mmol, 75%) of 2a as a clear, colorless, viscous liquid. 1H NMR
(500 MHz, CDCl3): δ 7.43 (d, J = 8.9 Hz, 2H), 7.16 (d, J = 8.1 Hz,
2H), 6.93 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 3.02 (s, 1H),
2.35 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 158.6, 153.7, 133.7,
133.7, 130.4, 119.7, 117.7, 116.1, 83.3, 76.3, 20.7. TLC: Rf = 0.26
(CH2Cl2/hexanes, 1/10). IR (CH2Cl2) 3287 (m), 3038 (w), 2923
(w), 2108 (w), 1895 (w), 1773 (w), 1598 (m), 1508 (m), 1493 (s),
1413 (w), 1380 (w), 1279 (m), 1235 (s), 1208 (m), 1166 (m), 1103
(m), 1043 (w), 1016 (m) cm−1. HRMS (DART): calcd for
[C15H12OH]+ 209.0961, found 209.0966.
1-(Phenylethynyl)-4-(p-tolyloxy)benzene (2b). In a reaction
flask under Ar, 1b (194 mg, 0.988 mmol), p-cresol (118 mg, 1.09
mmol), and DMSO (3 mL) were added. The reaction was started with
the addition of KOtBu (120 mg, 1.08 mmol). The reaction mixture
was stirred in an oil bath at 100 °C for 18 h. The reaction was
quenched by dilution with CH2Cl2 and 1 M HCl. The layers were
separated and the aqueous phase was extracted with CH2Cl2 (3 × 80
mL). The combined organic layers were washed with H2O (80 mL)
and dried over Na2SO4. The solvent was removed in vacuo to give a
brown oil. Purification by silica gel flash chromatography (CH2Cl2/
hexanes, 1/4) gave 247 mg (0.867 mmol, 88%) of 2b as a white solid.
1H NMR (500 MHz, CDCl3): δ 7.55−7.53 (m, 2H), 7.48 (d, J = 8.9
Hz, 2H), 7.36−7.33 (m, 3H), 7.17 (d, J = 8.1 Hz, 2H), 6.95 (d, J = 8.5
Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 2.36 (s, 3H). 13C NMR (126 MHz,
CDCl3): δ 158.1, 153.9, 133.6, 133.1, 131.5, 130.4, 128.3, 128.1, 123.4,
119.6, 117.9, 117.4, 89.0, 88.6, 20.7. TLC: Rf = 0.60 (CH2Cl2/hexanes,
1/9). IR (KBr pellet): 3284 (m), 2925 (s), 2107 (w), 1729 (s), 1573
(s), 1495 (s), 1370 (s), 1279 (m), 1215 (s), 1149 (s) cm−1. HRMS
(DART): calcd for [C21H16O]+ 284.1201, found 284.1221.
1-(tert-Butylethynyl)-4-(p-tolyloxy)benzene (2c). In a reaction
flask under Ar, 1c (174 mg, 0.985 mmol), p-cresol (117 mg, 1.08
mmol), and DMSO (3 mL) were added. The reaction was started with
the addition of KOtBu (120 mg, 1.07 mmol). The reaction mixture
was stirred in an oil bath at 130 °C for 26 h. The reaction was
quenched by dilution with CH2Cl2 and 1 M HCl. The layers were
separated, and the aqueous phase was extracted with CH2Cl2 (3 × 80
mL). The combined organic layers were washed with H2O (80 mL)
and dried over Na2SO4. The solvent was carefully removed in vacuo to
give a brown oil. Purification by silica gel flash chromatography
(hexanes → CH2Cl2/hexanes, 1/10) gave 225 mg (0.850 mmol, 86%)
of 2c as a clear, colorless, viscous liquid. 1H NMR (500 MHz, DMSO-
d6): δ 7.32 (d, J = 8.9 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.94 (d, J =
8.5 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 2.30 (s, 3H), 1.27 (s, 9H). 13C
NMR (126 MHz, DMSO-d6): δ 157.0, 153.3, 133.3, 132.9, 130.5,
119.4, 117.6, 117.4, 97.6, 78.3, 30.8, 27.5, 20.3. TLC: Rf = 0.33 (thin
film/hexanes, 1/10). IR (CH2Cl2): 3039 (w), 2968 (m), 2900 (w),
2925 (w), 2867 (w), 2400 (w), 1888 (w), 1600 (m), 1496 (s), 1456
(w), 1411 (w), 1362 (w), 1273 (m), 1235 (s), 1208 (m), 1166 (m),
1102 (m), 1041 (w), 1016 (m) cm−1. HRMS (DART): calcd for
[C19H20O]+ 264.1514, found 264.1519.
3033 (w), 2107 (w), 1601 (m), 1583 (m), 1499 (s), 1487 (s), 1234
(s), 1180 (s), 1110 (m) cm−1. HRMS (DART): calcd for
[C15H12OH]+ 209.0960, found 209.0961.
1-(Phenylethynyl)-4-(o-tolyloxy)benzene (2i). In a reaction
flask under Ar, 1b (49.1 mg, 0.250 mmol), o-cresol (29.7 mg, 0.275
mmol), and DMSO (1.0 mL) were added. The reaction was started
with the addition of KOtBu (30.8 mg, 0.257 mmol). The reaction
mixture was stirred in an oil bath at 100 °C for 18 h. The reaction was
quenched by dilution with CH2Cl2 and 1 M HCl. The layers were
separated, and the aqueous phase was extracted with CH2Cl2 (3 × 20
mL). The combined organic layers were washed with H2O (20 mL)
and dried over Na2SO4. The solvent was removed in vacuo to give a
brown oil. Purification by silica gel flash chromatography (CH2Cl2/
hexanes, 1/9) gave 56.8 mg (0.200 mmol, 80% yield) of 2i as a white
solid. 1H NMR (500 MHz, CDCl3): δ 7.55−7.51 (m, 2H), 7.50−7.46
(m, 2H), 7.39−7.32 (m, 3H), 7.31−7.26 (m, 1H), 7.24−7.19 (m, 1H),
7.13 (td, J = 7.5, 1.3 Hz, 1H), 6.98 (dd, J = 8.0, 1.3 Hz, 1H), 6.90−6.85
(m, 2H), 2.24 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 158.2, 153.7,
133.2, 131.6, 131.5, 130.3, 128.3, 128.1, 127.3, 124.6, 123.5, 120.4,
117.0, 116.9, 89.1, 88.5, 16.1. TLC: Rf = 0.50 (CH2Cl2/hexanes, 1/9).
IR (ATR): 3056 (w), 2923 (w), 2852 (w), 2216 (w), 1893 (w), 1595
(m), 1583 (m), 1505 (s), 1488 (s), 1237 (s) cm−1. HRMS (DART):
calcd for [C21H16O]+ 284.1201, found 284.1220.
(E)-1-Fluoro-4-styrylbenzene (3). In a sealed tube were added
PdCl2(PPh3)2 (70.3 mg, 0.0100 mmol) and CsCO3 (1.70 g, 5.23
mmol). The mixture was purged with Ar for 5 min, and then trans-
vinylboronic acid (746 mg, 5.07 mmol), DMF/H2O (8 mL/2 mL,
respectively), and 4-fluoro-1-iodobenzene (0.576 mL, 5.07 mmol)
were added in that order. The mixture was heated to 100 °C for 10
min, then tetrabutylammonium bromide (322 mg, 0.999 mmol) was
added, and the mixture was heated for 2 h at 100 °C, followed by 18 h
at 65 °C. After this time period the reaction mixture was diluted with
CH2Cl2 and aqueous NH4Cl. The layers were separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 80 mL). The
combined organic layers were washed with H2O (80 mL) and dried
over Na2SO4. The solvent was removed in vacuo to give a brown
powder. Purification by silica gel flash chromatography (hexanes) gave
0.463 g (2.34 mmol, 45%) of 3 as a white solid. 1H NMR (500 MHz,
CDCl3): δ 7.47−7.45 (m, 4H), 7.38 (dd, J = 8.4, 6.9 Hz, 2H), 7.31−
7.26 (m, 1H), 7.12−7.01 (m, 4H). 13C NMR (126 MHz, CDCl3): δ
162.5 (d, J = 251 Hz), 133.5, 133.4, 128.4, 128.4, 128.3, 123.1, 119.4,
119.4, 115.6 (d, J = 25 Hz). TLC: Rf = 0.28 (hexanes). IR (KBr
pellet): 3022 (w), 1893 (m), 1831 (m), 1593 (s), 1508 (s), 1448 (s),
1236 (s), 1158 (s), 1097 (s) cm−1. HRMS (DART): calcd for
[C14H11F]+ 198.0845, found 198.0847.
(E)-1-Methyl-4-(4-styrylphenoxy)benzene (4). In a reaction
flask under Ar, 6 (196 mg, 1.00 mmol), p-cresol (116 mg, 1.07 mmol),
and DMSO (3.0 mL) were added. The reaction was started with the
addition of KOtBu (123 mg, 1.09 mmol). The reaction mixture was
stirred in an oil bath at 120 °C for 72 h. The reaction was quenched by
dilution with CH2Cl2 and 1 M HCl. The layers were separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 80 mL). The
combined organic layers were washed with H2O (80 mL) and dried
over Na2SO4. The solvent was removed in vacuo to give a brown oil.
Purification by silica gel flash chromatography (hexanes → CH2Cl2/
hexanes, 1/5) gave 208 mg (0.727 mmol, 73% yield) of 4 as a white
1-Ethynyl-4-(o-tolyloxy)benzene (2h). In a reaction flask under
Ar, 1a (63.0 mg, 0.525 mmol), o-cresol (62.3 mg, 0.577 mmol), and
DMSO (1.0 mL) were added. The reaction was started with the
addition of KOtBu (64.7 mg, 0.577 mmol). The reaction mixture was
stirred in an oil bath at 100 °C for 18 h. The reaction was quenched by
dilution with CH2Cl2 and 1 M HCl. The layers were separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were washed with H2O (20 mL) and dried
over Na2SO4. The solvent was carefully removed in vacuo to give a
brown oil (the product is somewhat volatile). Purification by silica gel
flash chromatography (CH2Cl2/hexanes, 1/9) gave 87.3 mg (0.330
1
solid. H NMR (500 MHz, CDCl3): δ 7.51 (d, J = 7.1 Hz, 2H), 7.47
(d, J = 8.8 Hz, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.26 (tt, J = 7.3, 1.2 Hz,
1H), 7.16 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 19.3 Hz, 2H) 6.99−6.98 (m,
2H), 6.97 (d, J = 13.9 Hz, 1H), 6.96 (d, J = 13.8 Hz, 1H), 2.35 (s, 3H).
13C NMR (126 MHz, CDCl3): δ 157.5, 154.5, 137.4, 133.1, 132.2,
130.3, 128.7, 128.0, 127.8, 127.6, 127.4, 126.4, 119.2, 118.5, 20.7.
TLC: Rf = 0.33 (EtOAc/hexanes, 1/20). IR (KBr pellet): 3058 (w),
3025 (m), 2341 (w), 1950 (w), 1888 (m), 1601 (s), 1593 (s), 1507
(s), 1448 (s), 1284 (s), 1260 (s), 1169 (s), 1104 (m) cm−1. HRMS
(DART): calcd for [C21H18O]+ 286.1357, found 286.1370.
1-Ethoxy-4-(phenylethynyl)benzene (5a). In a reaction flask
under Ar, 60% NaH in mineral oil (60.0 mg, 1.50 mmol) was added
followed by hexanes (2.0 mL), and the mixture was stirred at room
temperature for 20 min. The dispersion was allowed to settle, and the
1
mmol, 63%) of 2h as a clear, colorless, viscous liquid. H NMR (500
MHz, CDCl3): δ 7.48−7.39 (m, 1H), 7.32−7.23 (m, 1H), 7.12 (td, J =
7.5, 1.5 Hz, 1H), 6.95 (dd, J = 8.0, 1.5 Hz, 1H), 6.88−6.76 (m, 2H),
3.20 (s, 1H), 2.21 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 158.5,
153.5, 133.7, 131.6, 130.3, 127.3, 124.7, 120.5, 116.7, 115.7, 83.4, 76.2,
16.1. TLC: Rf = 0.33 (CH2Cl2/hexanes, 1/9). IR (ATR): 3287 (m),
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hexanes was removed. DMSO (1.0 mL) and ethanol (0.116 mL, 1.99
mmol) were added and stirred for 1 h at 50 °C (until the solution
became homogeneous). 1b (197 mg, 1.01 mmol) dissolved in DMSO
(2.0 mL) was added to start the reaction, and the mixture was then
stirred in an oil bath at 50 °C for 18 h. The reaction was quenched by
dilution with CH2Cl2 and 1 M HCl. The layers were separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 80 mL). The
combined organic layers were washed with H2O (80 mL) and dried
over Na2SO4. The solvent was removed in vacuo to give a brown oil.
Purification by silica gel flash chromatography (CH2Cl2/hexanes, 2/3)
gave 200 mg (0.901 mmol, 90%) of 5a as a white solid. 1H NMR (500
MHz, CDCl3): δ 7.51 (dd, J = 8.0, 1.6 Hz, 2H), 7.46 (d, J = 8.9 Hz,
2H), 7.37−7.30 (m, 3H), 6.87 (d, J = 8.9 Hz, 2H), 4.05 (q, J = 7.0 Hz,
2H), 1.43 (t, J = 7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 159.0,
133.0, 131.4, 128.3, 127.9, 123.6, 115.2, 114.5, 89.4, 88.0, 63.5, 14.8.
TLC: Rf = 0.60 (CH2Cl2/hexanes, 2/3). IR (ATR): 3048 (w), 3028
(w), 2916 (m), 2402 (w), 2219 (w), 1890 (w), 1781 (w), 1602 (m),
1589 (s), 1500 (s), 1400 (m), 1252 (s) cm−1. HRMS (DART): calcd
for [C16H14O]+ 222.1045, found 222.1045.
1-Isopropoxy-4-(phenylethynyl)benzene (5b). In a reaction
flask under Ar, 60% NaH in mineral oil (23.2 mg, 0.581 mmol) was
added followed by hexanes (2.0 mL), and the mixture was stirred at
room temperature for 20 min. The dispersion was allowed to settle,
and the hexanes was removed. DMSO (1.0 mL) and isopropyl alcohol
(0.045 mL, 0.58 1 mmol) were added and stirred for 1 h at 50 °C
(until the solution became homogeneous). 1b (103 mg, 0.525 mmol)
dissolved in DMSO (1.0 mL) was added to start the reaction, and the
mixture was then stirred in an oil bath at 100 °C for 18 h. The reaction
was quenched by dilution with CH2Cl2 and 1 M HCl. The layers were
separated, and the aqueous phase was extracted with CH2Cl2 (3 × 20
mL). The combined organic layers were washed with H2O (20 mL)
and dried over Na2SO4. The solvent was removed in vacuo to give a
brown oil. Purification by silica gel flash chromatography (CH2Cl2/
hexanes, 1/9) gave 94.1 mg (0.399 mmol, 76%) of 5b as a white solid.
1H NMR (500 MHz, CDCl3): δ 7.57−7.41 (m, 4H), 7.40−7.24 (m,
3H), 6.92−6.82 (m, 2H), 4.59 (sep, J = 6.0 Hz, 1H), 1.36 (d, J = 6.0
Hz, 6H). 13C NMR (126 MHz, CDCl3): δ 158.0, 133.1, 131.4, 128.3,
127.9, 123.7, 115.7, 115.0, 89.5, 87.9, 69.9, 22.0. TLC: Rf = 0.25
(CH2Cl2/hexanes, 1/9). IR (ATR): 3033 (m), 2926 (m), 2219 (w),
1972 (w), 1900 (w), 1678 (w), 1595 (s), 1508 (s), S1454 (m), 1378
(m), 1281 (m), 1241 (s), 1175 (m) cm−1. HRMS (DART): calcd for
[C17H16OH]+ 237.1274, found 237.1277.
separated, and the aqueous phase was extracted with CH2Cl2 (3 × 20
mL). The combined organic layers were washed with H2O (20 mL)
and dried over Na2SO4. The solvent was removed in vacuo to give a
brown oil. Purification by silica gel flash chromatography (CH2Cl2/
hexanes, 1/9) gave 80.2 mg (0.342 mmol, 80%) of 5d as a white solid.
1H NMR (500 MHz, CDCl3): δ 7.52−7.51 (m, 2H), 7.48 (dt, J = 9.0,
3.0 Hz, 2H), 7.37−7.32 (m, 3H), 6.91 (dt, J = 9.0, 2.0 Hz, 2H), 6.07
(ddt, J = 17.0, 10.5, 5.0 Hz, 1H), 5.44 (dq, J = 17.0, 1.5 Hz, 1H), 5.32
(dq, J = 10.5, 1.5 Hz, 1H), 4.57 (dt, J = 5.0, 1.5 Hz, 1H). 13C NMR
(126 MHz, CDCl3): δ 158.6, 133.0, 132.9, 131.4, 128.3, 127.9, 123.6,
117.9, 115.5, 114.8, 89.3, 88.1, 68.8. TLC: Rf = 0.18 (CH2Cl2/hexanes,
1/9). IR (ATR): 3034 (s), 2917 (w), 2859 (w), 2217 (w), 1954 (w),
1669 (m), 1592 (m), 1505 (s), 1281 (m), 1231 (s) cm−1. HRMS
(DART): calcd for [C17H14OH]+ 235.1117, found 235.1117.
1-(Benzyloxy)-4-ethynylbenzene (5e). In a reaction flask under
Ar, 60% NaH in mineral oil (43 mg, 0.11 mmol) was added followed
by hexanes (2.0 mL), and the mixture was stirred at room temperature
for 20 min. The dispersion was allowed to settle, and the hexanes was
removed. DMSO (2.0 mL) and benzyl alcohol (0.117 mL, 0.110
mmol) were added, and the mixture was stirred for 1 h at 50 °C (until
the solution became homogeneous). 1a (116 mg, 0.966 mmol)
dissolved in DMSO (1.0 mL) was added to start the reaction, and the
mixture was then stirred in an oil bath at 100 °C for 18 h. The reaction
was quenched by dilution with CH2Cl2 and 1 M HCl. The layers were
separated, and the aqueous phase was extracted with CH2Cl2 (3 × 20
mL). The combined organic layers were washed with H2O (20 mL)
and dried over Na2SO4. The solvent was removed in vacuo to give a
brown oil. Purification by silica gel flash chromatography (ether:-
hexanes, 1/9) gave 111 mg (0.534 mmol, 54%) of 5e as a white solid.
1H NMR (500 MHz, CDCl3): δ 7.47−7.36 (m, 6H), 7.35 (dt, J = 7.3,
1.5 Hz, 1H), 6.94 (dt, J = 8.5, 3.0 Hz, 2H), 5.09 (s, 2H), 3.02 (s, 1H);
13C NMR (126 MHz, CDCl3): δ 159.1, 136.5, 133.6, 128.6, 128.1,
127.5, 114.7, 114.5, 83.6, 75.9, 70.0. TLC: Rf = 0.11 (CH2Cl2/hexanes,
1/9). IR (ATR): 3271 (m), 2104 (w), 1897 (w), 1653 (m), 1637 (m),
1599 (m), 1540 (s), 1466 (m), 1455 (m), 1384 (m), 1224 (s), 1171
(m) cm−1. HRMS (DART): calcd for [C15H12OH]+ 209.0961, found
209.0967.
1-(Benzyloxy)-4-(phenylethynyl)benzene (5f). In a reaction
flask under Ar, 60% NaH in mineral oil (8.1 mg, 0.18 mmol) was
added followed by hexanes (2.0 mL), and the mixture was stirred at
room temperature for 20 min. The dispersion was allowed to settle,
and the hexanes was removed. DMSO (1.0 mL) and benzyl alcohol
(0.021 mL, 0.20 mmol) were added, and the mixture was stirred for 30
min at 50 °C (until the solution became homogeneous). 1b (35.3 mg,
0.198 mmol) dissolved in DMSO (1.0 mL) was added to start the
reaction, and the mixture was then stirred in an oil bath at 100 °C for
18 h. The reaction was quenched by dilution with CH2Cl2 and 1 M
HCl. The layers were separated, and the aqueous phase was extracted
with CH2Cl2 (3 × 20 mL). The combined organic layers were washed
with H2O (20 mL) and dried over Na2SO4. The solvent was removed
in vacuo to give a brown oil. Purification by silica gel flash
chromatography (CH2Cl2/hexanes, 1/9) gave 38.4 mg (0.135 mmol,
76%) of 5f as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.47−7.21
(m, 11 H), 7.18 (s, 1H), 6.91−6.85 (m, 2H), 5.01 (s, 2H). 13C NMR
(126 MHz, CDCl3): δ 158.8, 136.6, 133.1, 131.5, 128.6, 128.3, 128.1,
127.9, 127.5, 123.6, 115.0, 114.9, 89.3, 88.1, 70.0. TLC: Rf = 0.06
(CH2Cl2/hexanes, 1/9). IR (ATR): 3033 (w), 2921 (w), 2853 (w),
2220 (w), 1899 (w), 1596 (m), 1508 (m), 1454 (m), 1377 (m), 1280
(m), 1238 (m) cm−1. HRMS (DART): calcd for [C21H16OH]+
285.1274, found 285.1274.
1-tert-Butoxy-4-(phenylethynyl)benzene (5c). In a reaction
flask was added 1b (50.1 mg, 0.256 mmol), DMSO (1.0 mL), and
KOtBu (30.8 mg, 0.275 mmol), and the mixture was then stirred in an
oil bath at 100 °C for 18 h. The reaction was quenched by dilution
with CH2Cl2 and 1 M HCl. The layers were separated and the aqueous
phase was extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were washed with H2O (20 mL) and dried over Na2SO4. The
solvent was removed in vacuo to give a brown oil. Purification by silica
gel flash chromatography (CH2Cl2/hexanes, 1/9) gave 23.8 mg (0.095
1
mmol, 38%) of 5c as a white solid. H NMR (500 MHz, CDCl3): δ
7.55−7.49 (m, 2H), 7.48−7.42 (m, 2H), 7.37−7.31 (m, 2H), 7.27 (d, J
= 1.4 Hz, 1H), 7.01−6.95 (m, 2H), 1.38 (d, J = 1.2 Hz, 9H); 13C
NMR (126 MHz, CDCl3): δ 155.7, 132.4, 131.5, 128.3, 128.0, 123.8,
123.4, 117.9, 89.2, 88.7, 79.1, 28.9. TLC: Rf = 0.14 (CH2Cl2/hexanes,
1/9). IR (ATR): 2974 (m), 2927 (w), 2213 (w), 1908 (w), 1726 (w),
1593 (m), 1499 (s), 1441 (m), 1364 (s), 1234 (s), 1154 (s), 1096 (m)
cm−1. HRMS (DART): calcd for [C18 H18OH]+ 251.1430, found
251.1435.
1-(Allyloxy)-4-(phenylethynyl)benzene (5d). In a reaction flask
under Ar, 60% NaH in mineral oil (18 mg, 0.43 mmol) was added
followed by hexanes (2.0 mL), and the mixture was stirred at room
temperature for 20 min. The dispersion was allowed to settle, and the
hexanes was removed. DMSO (1.0 mL) and allyl alcohol (0.032 mL,
0.47 mmol) were added, and the mixture was stirred for 1 h at 50 °C
(until the solution became homogeneous). 1b (84.4 mg, 0.471 mmol)
dissolved in DMSO (1.0 mL) was added to start the reaction, and the
mixture was then stirred in an oil bath at 100 °C for 18 h. The reaction
was quenched by dilution with CH2Cl2 and 1 M HCl. The layers were
4-Methyl-N-(4-(phenylethynyl)phenyl)aniline (6a). In a reac-
tion flask under Ar, 1b (197 mg, 1.00 mmol), p-toluidine (214 mg,
1.99 mmol), and DMSO (3.0 mL) were added. The reaction was
started with the addition of KOtBu (231 mg, 2.06 mmol). The
reaction mixture was stirred in an oil bath at 100 °C for 18 h. The
reaction was quenched by dilution with CH2Cl2 and 1 M HCl. The
layers were separated, and the aqueous phase was extracted with
CH2Cl2 (3 × 80 mL). The combined organic layers were washed with
H2O (80 mL) and dried over Na2SO4. The solvent was removed in
vacuo to give a brown oil. Purification by silica gel flash
G
dx.doi.org/10.1021/jo400668v | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
chromatography (hexanes → EtOAc/hexanes, 1/10) gave 237 mg
(0.838 mmol, 84%) of 6a as a white solid. 1H NMR (500 MHz,
CDCl3): δ 7.52 (dd, J = 8.1, 1.5 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H),
7.36−7.30 (m, 3H), 7.14 (dd, J = 8.6, 0.6 Hz, 2H), 7.05 (d, J = 8.4 Hz,
2H), 6.95 (d, J = 8.8 Hz, 2H), 5.75 (s, 1H), 2.34 (s, 3H). 13C NMR
(126 MHz, CDCl3): δ 144.3, 139.0, 132.9, 132.0, 131.4, 129.9, 128.3,
127.7, 123.8, 120.1, 115.5, 113.9, 90.0, 87.8, 20.7. TLC: Rf = 0.38
(EtOAc/hexanes, 1/9). IR (KBr pellet): 3413 (s), 3052 (w), 2916
(w), 2214 (m), 1891 (w), 1609 (s), 1594 (s), 1524 (s), 1324 (s), 1177
(m) cm−1. HRMS (DART): calcd for [C21H17N]+ 283.1361, found
283.1368.
1453 (s), 1363 (s), 1302 (s), 1263 (s), 1103 (s) cm−1. HRMS
(DART): calcd for [C12H13FH]+ 177.1074, found 177.1064.
1-Ethynyl-2-(p-tolyloxy)benzene (8a). In a reaction flask under
Ar, 7a (130 mg, 1.08 mmol), p-cresol (130 mg, 1.20 mmol), and
DMSO (3.0 mL) were added. The reaction was started with the
addition of KOtBu (134 mg, 1.19 mmol). The reaction mixture was
stirred in an oil bath at 100 °C for 16 h. The reaction was quenched by
dilution with CH2Cl2 and 1 M HCl. The layers were separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 80 mL). The
combined organic layers were washed with H2O (80 mL) and dried
over Na2SO4. The solvent was carefully removed in vacuo to give a
brown oil (the product is somewhat volatile). Purification by silica gel
flash chromatography (hexanes → CH2Cl2/hexanes, 1/5) gave 14.3
2-Methyl-N-(4-(phenylethynyl)phenyl)aniline (6b). In a re-
action flask under Ar, 1b (49.3 mg, 0.251 mmol), o-toluidine (60.3 mg,
0.553 mmol), and DMSO (1.0 mL) were added. The reaction was
started with the addition of KOtBu (61.9 mg, 0.552 mmol). The
reaction mixture was stirred in an oil bath at 100 °C for 18 h. The
reaction was quenched by dilution with CH2Cl2 and 1 M HCl. The
layers were separated, and the aqueous phase was extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were washed with
H2O (20 mL) and dried over Na2SO4. The solvent was removed in
vacuo to give a brown oil. Purification by silica gel flash
chromatography (hexanes → EtOAc/hexanes, 1/10) gave 50.0 mg
(0.175 mmol, 70%) of 6b as a yellow oil. 1H NMR (500 MHz,
CDCl3): δ 7.54−7.52 (m, 2H), 7.45−7.39 (m, 2H), 7.38−7.15 (m,
6H), 7.03 (tt, J = 7.4, 1.2 Hz, 1H), 6.91−6.82 (m, 2H), 5.52 (s, 1H),
2.27 (s, 3H); 13C NMR (126 MHz, CDCl3): δ 144.6, 139.9, 132.9,
131.4, 131.1, 129.9, 128.2, 127.7, 126.8, 123.8, 123.3, 120.9, 115.8,
113.9, 90.0, 87.8, 17.9. TLC: Rf = 0.29 (EtOAc/hexanes, 1/9). IR
(ATR): 3393.7 (w), 3029.6 (w), 2924.5 (w), 2210.9 (m), 1610 (m),
1593 (m), 1513 (s), 1412 (m), 1319 (m), 1295 (m), 1181 (m) cm−1.
HRMS (DART): calcd for [C21H17N]+ 283.1361, found 283.1368.
1-Fluoro-2-(phenylethynyl)benzene (7b). In a sealed tube were
added PdCl2(PPh3)2 (125 mg, 0.178 mmol) and CuI (188 mg 0.986
mmol). The mixture was purged with Ar for 5 min, and then degassed
2-fluoro-1-iodobenzene (1.00 mL, 8.75 mmol), degassed phenyl-
acetylene (0.980 mL, 8.92 mmol), and triethylamine (12 mL) were
added in that order. The mixture was stirred at room temperature for 2
h and then was diluted with CH2Cl2 and aqueous NH4Cl. The layers
were separated, and the aqueous phase was extracted with CH2Cl2 (3
× 80 mL). The combined organic layers were washed with H2O (80
mL) and dried over Na2SO4. The solvent was removed in vacuo to
give a brown powder. Purification by silica gel flash chromatography
(hexanes) gave 1.54 g (7.84 mmol, 90%) of 7b as an off-white solid.
1H NMR (500 MHz, CDCl3): δ 7.62−7.55 (m, 2H), 7.42−7.38 (m,
3H), 7.37−7.32 (m, 1H), 7.17−7.12 (m, 2H). 13C NMR (126 MHz,
CDCl3): δ 162.6 (d, J = 250.1 Hz), 133.4, 131.6, 129.9 (d, J = 7.7 Hz),
128.5, 128.3, 123.9 (d, J = 2.6 Hz), 122.9, 115.4 (d, J = 20.8 Hz), 111.9
(d, J = 15.3 Hz), 94.4, 82.7. TLC: Rf = 0.6 (hexanes). IR (ATR): 3060
(w), 2214 (w), 1949 (w), 1875 (w), 1670 (w), 1595 (m), 1570 (m),
1497 (s), 1450 (s), 1441 (s), 1262 (s), 1218 (s), 1158 (m), 1096 (m)
cm−1. HRMS (DART): calcd for [C14H9FH]+ 197.0761, found
197.0765.
1
mg (0.0687 mmol, 5.0%) of 8a as a light yellow, viscous liquid. H
NMR (500 MHz, CDCl3): δ 7.54 (dd, J = 7.7, 1.7 Hz, 1H), 7.27−7.25
(m, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.04 (dt, J = 7.5, 1.1 Hz, 1H), 6.94
(d, J = 8.5 Hz, 2H), 6.83 (dd, J = 8.3, 0.9 Hz, 1H), 3.25 (s, 1H), 2.34
(s, 3H). 13C NMR (126 MHz, CDCl3): δ 159.0, 154.4, 134.2, 133.2,
130.2, 130.1, 122.7, 119.1, 117.8, 113.8, 81.5, 79.5, 20.7. TLC: Rf =
0.17 (CH2Cl2/hexanes, 1/10). IR (thin film): 3296 (m), 2920 (s),
2850 (s), 2107 (w), 1719 (m), 1599 (m), 1495 (m), 1462 (m), 1377
(m), 1208 (m), 1165 (w) cm−1. HRMS (DART): calcd for
[C15H12OH]+ 209.0961, found 209.0976.
1-(Phenylethynyl)-2-(p-tolyloxy)benzene (8b). In a reaction
flask under Ar, 7b (64.9 mg, 0.331 mmol), p-cresol (39.0 mg, 0.361
mmol), and DMSO (1.0 mL) were added. The reaction was started
with the addition of KOtBu (40.7 mg, 0.363 mmol). The reaction
mixture was stirred in an oil bath at 100 °C for 18 h. The reaction was
quenched by dilution with CH2Cl2 and 1 M HCl. The layers were
separated, and the aqueous phase was extracted with CH2Cl2 (3 × 20
mL). The combined organic layers were washed with H2O (230 mL)
and dried over Na2SO4. The solvent was removed in vacuo to give a
brown oil. Purification by silica gel flash chromatography (CH2Cl2/
hexanes, 1/9) gave 69.3 mg (0.244 mmol, 74%) of 8b as a white solid.
1H NMR (500 MHz, CDCl3): δ 7.61 (d, J = 10 Hz, 1H), 7.43 (dd, J =
6.6, 2.9 Hz, 2H), 7.35−7.26 (m, 4H), 7.18 (d, J = 10 Hz, 2H), 7.12 (t,
J = 10 Hz, 1H), 6.99−6.96 (m, 2H), 2.37 (s, 3H). 13C NMR (126
MHz, CDCl3): δ 157.9, 155.1, 133.6, 132.7, 131.7, 130.2, 130.1, 129.6,
128.2, 123.3, 123.2, 118.9, 118.5, 115.6, 94.2, 85.3, 20.7. TLC: Rf =
0.31 (CH2Cl2/hexanes, 1/9). IR (thin film): 3062 (m), 2923 (m),
2855 (w), 2222 (w), 1950 (w), 1596 (m), 1572 (m), 1505 (s), 1482
(s), 1445 (s), 1223 (s). HRMS (DART): calcd for [C21H16OH]+
285.1274, found 285.1288.
1-Ethoxy-2-(phenylethynyl)benzene (8c). In a reaction flask
under Ar, 60% NaH in mineral oil (18.5 mg, 0.460 mmol) was added
followed by hexanes (2.0 mL), and the mixture was stirred at room
temperature for 20 min. The dispersion was allowed to settle, and the
hexanes was removed. DMSO (1.0 mL) and ethanol (0.116 mL, 0.460
mmol) were added, and the mixture was stirred for 1 h at 50 °C (until
the solution became homogeneous). 7b (82.0 mg, 0.418 mmol)
dissolved in DMSO (2.0 mL) was added to start the reaction, and the
mixture was then stirred in an oil bath at 100 °C for 18 h. The reaction
was quenched by dilution with CH2Cl2 and 1 M HCl. The layers were
separated, and the aqueous phase was extracted with CH2Cl2 (3 × 20
mL). The combined organic layers were washed with H2O (20 mL)
and dried over Na2SO4. The solvent was removed in vacuo to give a
brown oil. Purification by silica gel flash chromatography (CH2Cl2/
hexanes, 1/9) gave 88 mg (35.9 mmol, 86%) of 8c as a white solid. 1H
NMR (500 MHz, CDCl3): δ 7.56 (dt, J = 8.0, 1.5 Hz, 2H), 7.51 (dt, J
= 8.0, 1.5 Hz, 1H), 7.41−7.24 (m, 4H), 6.98−6.87 (m, 2H), 4.15 (q, J
= 7.0, 2H), 1.51 (t, J = 7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ
159.5, 133.4, 131.6, 129.6, 128.2, 128.0, 123.8, 120.4, 112.9, 112.2,
93.4, 85.9, 64.4, 14.8. TLC: Rf = 0.42 (CH2Cl2/hexanes, 1/9). IR (thin
film): 3062 (w), 2222 (w), 1950 (w), 1596 (m), 1571 (m), 1497 (s),
1482 (s), 1451 (m), 1443 (m), 1262 (m), 1220 (s), 1097 (m) cm−1.
HRMS (DART): calcd for [C16H14OH]+ 223.1117, found 223.1118.
1-(tert-Butylethynyl)-2-(p-tolyloxy)benzene (8d). In a reaction
flask under Ar, 7c (127 mg, 0.722 mmol), p-cresol (85.8 mg, 0.794
mmol), and DMSO (2.0 mL) were added. The reaction was started
with the addition of KOtBu (88.9 mg, 0.794 mmol). The reaction
1-Fluoro-2-(tert-butylethynyl)benzene (7c). In a sealed tube
were added PdCl2(PPh3)2 (261 mg, 0.372 mmol) and CuI (149 mg
0.785 mmol). The mixture was purged with Ar for 5 min, and then
degassed 4-fluoroiodobenzene (2.00 mL, 17.3 mmol), degassed tert-
butylacetylene (4.25 mL, 34.5 mmol), and triethylamine (24 mL) were
added in that order. The mixture was stirred at room temperature for 2
h and then was diluted with CH2Cl2 and aqueous NH4Cl. The layers
were separated, and the aqueous phase was extracted with CH2Cl2 (3
× 80 mL). The combined organic layers were washed with H2O (80
mL) and dried over Na2SO4. The solvent was removed in vacuo to
give a brown oil. Purification by silica gel plug (hexanes) gave 2.80 g
1
(15.9 mmol, 83%) of 7c as a clear, colorless liquid. H NMR (500
MHz, CDCl3): δ 7.42 (dt, J = 8.0, 2.0 Hz, 1H), 7.27−7.22 (m, 1H),
7.08−7.04 (m, 2H), 1.38 (s, 9H). 13C NMR (126 MHz, CDCl3): δ
162.7 (d, J = 248.8 Hz), 133.5, 129.0, 123.7, 115.3, 112.5, 103.9, 72.4,
30.9, 28.2. TLC: Rf = 0.55 (hexanes). IR (thin film): 2967 (s), 2854
(s), 2244 (m), 1719 (w), 1578 (m), 1572 (m), 1493 (s), 1475 (s),
H
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The Journal of Organic Chemistry
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mixture was stirred in an oil bath at 150 °C for 72 h. The reaction was
quenched by dilution with CH2Cl2 and 1 M HCl. The layers were
separated, and the aqueous phase was extracted with CH2Cl2 (3 × 20
mL). The combined organic layers were washed with H2O (2 × 30
mL) and dried over Na2SO4. The solvent was removed in vacuo to
give a brown oil. Purification by silica gel flash chromatography
(CH2Cl2/hexanes, 1/9) gave 128 mg (0.484 mmol, 67%) of 8d as a
7.27 (m, 4H), 7.16 (t, J = 10 Hz, 1H), 6.76 (d, J = 10 Hz, 1H), 6.55 (s,
1H), 2.55 (s, 3H), 1.24 (s, 9H). 13C NMR (126 MHz, CDCl3): δ
150.7, 140.9, 138.5, 137.6, 130.5, 129.7, 121.1, 119.8, 119.7, 99.2, 31.1,
30.9, 21.3. TLC: Rf = 0.40 (CH2Cl2/hexanes, 2/98). IR (ATR): 3028
(w), 2987 (w), 2967 (w), 1914 (w), 1523 (m), 1509 (s), 1455 (s),
1377 (m), 1358 (s), 1309 (m), 1253 (m), 1214 (m), 1107 (m) cm−1.
HRMS (DART): calcd for [C19H21NH]+ 264.1747, found 264.1754.
1-Ethynyl-2-fluoro-4-(p-tolyloxy)benzene (11a). In a reaction
flask were added 10 (272 mg, 1.97 mmol) and p-cresol (212 mg, 1.96
mmol). The flask was then purged with Ar for 5 min. To this flask was
added 0.40 M KOtBu in DMSO (5.0 mL), and the reaction mixture
was then heated to 100 °C. After 6 h the reaction was quenched with 1
M HCl. The mixture was then extracted with CH2Cl2 (3 × 80 mL).
Then the combined organic layers were washed with H2O (80 mL)
and dried over Na2SO4. Most of the CH2Cl2 in a small sample of the
organic solution was removed in vacuo; the residual brown liquid was
dissolved in CDCl3, and a 1H NMR spectrum was obtained to
determine the ratios of the species present. The NMR sample was
recombined with the organic solution, and the solvents were removed
in vacuo. Purification by silica gel flash chromatography (EtOAc/
hexanes, 2/98) gave 129 mg (0.568 mmol, 29%) of 11a as a clear,
1
clear oil. H NMR (500 MHz, CDCl3): δ 7.44 (d, J = 7.5 Hz, 1H),
7.27−7.22 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H),
6.97 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.0 Hz, 2H), 2.37 (s, 3H). 13C
NMR (126 MHz, CDCl3): δ 150.7, 140.9, 138.5, 137.5, 130.5, 129.6,
126.8, 121.1, 119.7, 119.6, 110.3, 99.0, 33.3, 31.0, 21.3. TLC: Rf = 0.18
(CH2Cl2/hexanes, 1/9). IR (thin film): 2968 (s), 2925 (s), 2242 (w),
1612 (m), 1599 (m), 1574 (m), 1505 (s), 1487 (s), 1446 (s), 1362
(m), 1263 (s), 1236 (s), 1206 (s) cm−1. HRMS (DART): calcd for
[C19H20OH]+ 265.1587, found 265.1573.
1-Ethoxy-2-(tert-butylethynyl)benzene (8e). In a reaction flask
under Ar, 60% NaH in mineral oil (19.0 mg, 0.475 mmol) was added
followed by hexanes (2.0 mL), and the mixture was stirred at room
temperature for 20 min. The dispersion was allowed to settle, and the
hexanes was removed. DMSO (1.0 mL) and ethanol (0.028 mL, 0.475
mmol) were added, and the mixture was stirred for 1 h at 50 °C (until
the solution became homogeneous). 7c (76.0 mg, 0.432 mmol)
dissolved in DMSO (2.0 mL) was added to start the reaction, and the
mixture was then stirred in an oil bath at 150 °C for 72 h. The reaction
was quenched by dilution with CH2Cl2 and 1 M HCl. The layers were
separated, and the aqueous phase was extracted with CH2Cl2 (3 × 20
mL). The combined organic layers were washed with H2O (20 mL)
and dried over Na2SO4. The solvent was removed in vacuo to give a
brown oil. Purification by silica gel flash chromatography (CH2Cl2/
hexanes, 2/3) gave 47.7 mg (0.236 mmol, 56%) of 8e as a clear oil. 1H
NMR (500 MHz, CDCl3): δ 7.27 (dd, J = 7.5, 2.0 Hz, 1H), 7.16−7.08
(m, 1H), 6.82−6.72 (m, 2H), 3.99 (q, J = 7.0 Hz, 2H), 1.38 (t, J = 7.0
Hz, 9H), 1.27 (s, 9H). 13C NMR (126 MHz, CDCl3): δ 159.5, 133.1,
128.7, 120.4, 113.8, 112.4, 102.7, 64.3, 31.1, 28.2, 14.8. TLC: Rf = 0.11
(CH2Cl2/hexanes, 1/9). IR (ATR): 2968 (m), 2240 (w), 1596 (m),
1575 (m), 1492 (s), 1474 (s), 1361 (m), 1292 (m), 1275 (s), 1260
(s), 1243 (s) cm−1. HRMS (DART): calcd for [C14H18O]+ 203.1430,
found 203.1437.
2-Phenyl-1-(p-tolyl)-1H-indole (9a). In a reaction flask under Ar,
7b (105 mg, 0.534 mmol), p-toluidine (239 mg, 1.07 mmol), and
DMSO (1.0 mL) were added. The reaction was started with the
addition of KOtBu (245 mg, 1.68 mmol). The reaction mixture was
stirred in an oil bath at 100 °C for 18 h. The reaction was quenched by
dilution with CH2Cl2 and 1 M HCl. The layers were separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were washed with H2O (20 mL) and dried
over Na2SO4. The solvent was removed in vacuo to give a brown oil.
Purification by silica gel flash chromatography (hexanes → EtOAc/
hexanes, 1/10) gave 108 mg (0.379 mmol, 71%) of 9a as a yellow oil.
1H NMR (500 MHz, CDCl3): δ 7.78−7.59 (m, 1H), 7.39−7.04 (m,
12H), 6.81 (s, 1H), 2.42 (s, 3H). 13C NMR (126 MHz, CDCl3): δ
140.8, 139.1, 137.0, 135.9, 132.7, 129.9, 128.9, 128.2, 128.1, 127.8,
127.2, 122.2, 120.5, 110.7, 103.4, 21.2. TLC: Rf = 0.80 (EtOAc/
hexanes, 2/8). IR (ATR): 3030 (w), 2922 (w), 1698 (w), 1675 (w),
1600 (m), 1512 (s), 1455 (s), 1351 (m), 1208 (m), 1109 (m), 1020
(m) cm−1. HRMS (DART): calcd for [C21H17N]+ 283.1361, found
283.1362.
1
yellowish liquid. H NMR (500 MHz, CDCl3): δ 7.39 (t, J = 8.3 Hz,
1H), 7.21−7.18 (m, 2H), 7.00−6.95 (m, 2H), 6.70 (ddd, J = 8.6, 2.4,
0.7 Hz, 1H), 6.66 (dd, J = 10.7, 2.4 Hz, 1H), 3.24 (d, J = 0.6 Hz, 1H),
2.36 (s, 3H). 19F NMR (470 MHz, CFCl3): δ −107.87 (dd, J = 10.6,
8.1 Hz). 13C NMR (126 MHz, CDCl3): δ 164.1 (d, J = 252.8 Hz),
160.2 (d, J = 10.4 Hz), 152.9, 134.6 (d, J = 3.0 Hz), 134.5, 130.5,
120.0, 113.1 (d, J = 3.2 Hz), 105.0 (d, J = 24.6 Hz), 104.3 (d, J = 16.1
Hz), 81.3 (d, J = 3.2 Hz), 76.9, 20.8. TLC: Rf = 0.17 (EtOAc/hexanes,
2:98). IR (thin film): 3299 (s), 3032 (m), 2924 (s), 2854 (s), 2113
(m), 1903 (w), 1736 (w), 1620 (s), 1604 (s), 1571 (s), 1495 (s), 1418
(s), 1275 (s), 1214 (s), 1167 (s), 1098 (s) cm−1. HRMS (DART):
calcd for [C15H12FOH]+ 227.0867, found 227.0868.
1-Ethynyl-4-fluoro-2-(p-tolyloxy)benzene (11b). Compound
11b was never isolated as a pure sample, but it could be isolated as the
major product of a mixture (contaminated with 11a and 11c). This
was obtained by silica gel flash chromatography (run twice, EtOAc/
1
hexanes, 2/98; CH2Cl2/hexanes, 1/9). H NMR (500 MHz, CDCl3):
δ 7.50 (dd, J = 8.6, 6.4 Hz, 1H), 7.27−7.20 (m, 2H), 6.97−6.94 (m,
2H), 6.73 (ddd, J = 8.6, 7.9, 2.5 Hz, 1H), 6.48 (dd, J = 10.2, 2.5 Hz,
1H), 3.24 (d, J = 0.6 Hz, 1H), 2.36 (s, 3H). 19F NMR (470 MHz,
CFCl3): δ −107.52 (ddd, J = 9.9, 7.3, 7.3 Hz). 13C NMR (126 MHz,
CDCl3): δ 163.3 (d, J = 250.8 Hz), 160.8 (d, J = 10.2 Hz), 153.3, 135.2
(d, J = 10.0 Hz), 134.3, 130.4, 119.4, 109.6 (d, J = 22.3 Hz), 109.2 (d, J
= 3.5 Hz), 104.7 (d, J = 25.9 Hz), 81.2 (d, J = 1.8 Hz), 78.7 (d, J = 1.2
Hz), 20.8. TLC: Rf = 0.10 (EtOAc/hexanes, 2/98). IR (thin film):
3284 (s), 3070 (w), 2924 (w), 2109 (m), 1903 (w), 1736 (w), 1626
(s), 1611 (s), 1573 (s), 1509 (s), 1496 (s), 1281 (s), 1219 (s), 1095
(s) cm−1. HRMS (DART): calcd for [C15H12FOH]+ 227.0867, found
227.0872.
1-Ethynyl-2,4-bis(p-tolyloxy)benzene (11c). Nonpreparative,
6 h Reaction Time. In a reaction flask were added 10 (148 mg, 1.07
mmol) and p-cresol (242 mg, 2.09 mmol). The flask was then purged
with Ar for 5 min. Dry, degassed DMSO (5.0 mL) was then added to
the flask. KOtBu (245 mg, 2.19 mmol) was then added to the reaction
flask, which was heated in an oil bath at 100 °C. After 6 h the reaction
was quenched with an aqueous 1 M HCl solution. The mixture was
then extracted with CH2Cl2 (3 × 80 mL). Then the combined organic
layers were washed with H2O (80 mL) and dried over Na2SO4. Most
of the CH2Cl2 in a small sample of the organic solution was removed
2-tert-Butyl-1-(p-tolyl)-1H-indole (9b). In a reaction flask under
Ar, 7c (196 mg, 1.11 mmol), p-toluidine (237 mg, 2.51 mmol), and
DMSO (3.0 mL) were added. The reaction was started with the
addition of KOtBu (281 mg, 2.51 mmol). The reaction mixture was
stirred in an oil bath at 100 °C for 18 h. The reaction was quenched by
dilution with CH2Cl2 and 1 M HCl. The layers were separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were washed with H2O (20 mL) and dried
over Na2SO4. The solvent was removed in vacuo to give a brown oil.
Purification by silica gel flash chromatography (hexanes → EtOAc/
hexanes, 1/10) gave 162 mg (0.611 mmol, 55%) of 9b as a yellowish
1
in vacuo; the residual brown liquid was dissolved in CDCl3 ,and a H
NMR spectrum was obtained to determine the ratios of the species
present.
15 h Reaction Time. In a reaction flask were added 10 (270 mg,
1.96 mmol) and p-cresol (460 mg, 4.25 mmol). The flask was then
purged with Ar for 5 min. Dry, degassed DMSO (8.0 mL) was then
added to the flask. KOtBu (468 mg, 4.17 mmol) was then added to the
reaction flask, which was heated in an oil bath at 100 °C. After 15 h the
reaction was quenched with an aqueous 1 M HCl solution. The
mixture was then extracted with CH2Cl2 (3 × 80 mL). Then the
1
oil. H NMR (500 MHz, CDCl3): δ 7.66 (d, J = 10 Hz, 1H), 7.36−
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combined organic layers were washed with H2O (80 mL) and dried
over Na2SO4, and the solvent was removed in vacuo. Purification by
silica gel flash chromatography (run twice, EtOAc/hexanes, 2/98) gave
137.6 (t, J = 2.8 Hz), 108.9 (dd, J = 14.7, 6.2 Hz), 104.0 (t, J = 25.8
Hz), 103.8 (t, J = 2.5 Hz), 70.9, 30.8, 28.1. TLC: Rf = 0.48 (hexanes).
IR (thin film): 2970 (s), 2929 (m), 2869 (s), 2900 (s), 2231 (m),
1609 (m), 1587 (m), 1587 (s), 1504 (s), 1475 (s), 1404 (s), 1363 (s),
1246 (s), 1118 (s) cm−1. HRMS (DART): calcd for [C18H20F2H]+
275.1606, found 275.1625.
1
558 mg (1.78 mmol, 91%) of 11c as a yellow liquid. H NMR (500
MHz, CDCl3): δ 7.43 (d, J = 8.5 Hz, 1H), 7.15−7.12 (m, 2H), 6.93−
6.91 (m, 2H), 6.89−6.88 (m, 2H), 6.56 (dd, J = 8.5, 2.4 Hz, 1H), 6.48
(d, J = 2.4 Hz, 1H), 3.19 (s, 1H), 2.32 (s, 6H). 13C NMR (126 MHz,
CDCl3): δ 160.3, 159.6, 153.9, 153.4, 135.0, 133.8, 133.5, 130.4, 130.3,
119.5, 119.2, 111.8, 107.8, 107.8, 80.6, 79.3, 20.7. TLC: Rf = 0.03
(EtOAc/hexanes, 2/98). IR (thin film): 3286 (s), 3031 (m), 2922
(m), 2108 (m), 1889 (w), 1599 (s), 1504 (s), 1418 (s), 1275 (s), 1206
(s), 1100 (s) cm−1. HRMS (DART): calcd for [C22H19O2H]+
315.1380, found 315.1358.
1,5-Diethynyl-2,4-difluorobenzene (12a). In a reaction tube
were added 1,3-dibromo-4,6-difluorobenzene42 (523 mg, 1.92 mmol),
PdCl2(PPh3)2 (31.2 mg, 0.0445 mmol), and CuI (17.8 mg 0.049
mmol). The mixture was purged with Ar for 5 min, and then degassed
trimethylsilylacetylene (1.36 mL, 15.1 mmol) and triethylamine (6
mL) were added in that order. The reaction tube was sealed and
heated to 80 °C for 29 h. The reaction was quenched by loading the
contents onto a silica plug and eluting with EtOAc. The solvent was
removed in vacuo, then 1 M TBAF in THF (2 mL, contains 5% H2O)
was added, and the mixture was stirred for 10 min. Purification by
silica gel flash chromatography (hexanes) gave 178.0 mg (1.10 mmol,
57%) of 12a as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.62 (t, J
= 7.7 Hz, 1H), 6.88 (t, J = 8.9 Hz, 1H), 3.28 (s, 2H). 13C NMR (126
MHz, CDCl3): δ 163.3 (dd, J = 259.4, 12.1 Hz), 138.7 (t, J = 2.8 Hz),
107.6 (dd, J = 14.4, 6.5 Hz), 104.7 (t, J = 25.5 Hz), 82.9 (t, J = 2.6 Hz),
75.0. TLC: Rf = 0.40 (hexanes). IR (KBr pellet): 3299 (m), 3286 (m),
2120 (w), 1802 (w), 1618 (s), 1586 (s), 1493 (s), 1409 (s), 1299 (m),
1156 (s), 1081 (s) cm−1. HRMS (DART): calcd for [C10H4F2H]+
163.0354, found 163.0356.
1,5-Bis(n-butylethynyl)-2,4-difluorobenzene (12d). In a sealed
reaction vial were added 1,3-dibromo-4,6-difluorobenzene (1.19 g,
4.37 mmol), PdCl2(PPh3)2 (165 mg, 0.235 mmol), and CuI (90.7 mg
0.476 mmol). The mixture was purged with Ar for 5 min, and then
degassed 1-hexyne (2.50 mL, 21.6 mmol), DMF (6 mL), and
triethylamine (6 mL) were added. The mixture was stirred under Ar
for 1 h at room temperature, sealed, then heated to 80 °C for 40 h.
The reaction was quenched by dilution with EtOAc and aqueous
NH4Cl. The layers were separated, and the aqueous phase was
extracted with EtOAc (20 mL). The combined organic layers were
flashed through a plug of silica gel with EtOAc (400 mL). The solvent
was removed in vacuo to give a brown oil. Purification by silica gel
flash chromatography (hexanes) gave 1.03 g (3.74 mmol, 86%) of 12d
1
as a yellow oil. H NMR (500 MHz, CDCl3): δ 7.42 (t, J = 7.9 Hz,
1H), 6.79 (t, J = 9.1 Hz, 1H), 2.42 (t, J = 7.0 Hz, 4H), 1.63−1.57 (m,
4H), 1.53−1.44 (m, 4H), 0.95 (t, J = 7.3 Hz, 6H). 13C NMR (126
MHz, CDCl3): δ 161.9 (dd, J = 255.1, 11.8 Hz), 137.5 (t, J = 2.9 Hz),
109.0 (dd, J = 14.7, 6.2 Hz), 104.1 (t, J = 25.8 Hz), 95.9 (t, J = 2.6 Hz),
72.3, 30.6, 21.9, 19.2, 13.6. TLC: Rf = 0.57 (hexanes). IR (thin film):
3064 (w), 2960 (s), 2934 (s), 2874 (s), 2238 (m), 2208 (m), 1712 (s),
1679 (m), 1589 (m), 1504 (s), 1407 (s), 1221 (m) cm−1. HRMS
(DART): calcd for [C22H13F2H]+ 275.1606, found 275.1616.
1,5-Diethynyl-2,4-bis(p-tolyloxy)benzene (13a). In a reaction
flask under Ar, 12a (163 mg, 1.01 mmol), p-cresol (236 mg, 2.19
mmol), and DMSO (3.0 mL) were added. The reaction was started
with the addition of KOtBu (240 mg, 2.13 mmol). The reaction
mixture was stirred in an oil bath at 60 °C for 6 h. The reaction was
quenched by dilution with CH2Cl2 and 1 M HCl. The layers were
separated, and the aqueous phase was extracted with CH2Cl2 (3 × 80
mL). The combined organic layers were washed with H2O (80 mL)
and dried over Na2SO4. The solvent was removed in vacuo to give a
brown oil. Purification by silica gel flash chromatography (hexanes →
CH2Cl2/hexanes, 1/4) gave 318 mg (0.940 mmol, 93%) of 13a as a
white solid. 1H NMR (500 MHz, CDCl3): δ 7.70 (s, 1H), 7.08 (d, J =
8.1 Hz, 4H), 6.84 (d, J = 8.5 Hz, 4H), 6.30 (s, 1H), 3.19 (s, 2H), 2.29
(s, 6H). 13C NMR (126 MHz, CDCl3): δ 160.1, 153.6, 139.5, 133.6,
130.2, 118.8, 108.8, 107.6, 81.3, 78.1, 20.7. TLC: Rf = 0.11 (CH2Cl2/
hexanes, 1/9). IR (KBr pellet): 3280 (s), 2923 (m), 2107 (m), 1889
(m), 1597 (s), 1561 (s), 1504 (s), 1535 (s), 1387 (s), 1294 (s), 1207
(s), 1082 (s) cm−1. HRMS (DART): calcd for [C24H19O2H]+
339.1380, found 339.1389.
1,5-Bis(phenylethynyl)-2,4-difluorobenzene (12b). In a re-
action tube were added 1,3-dibromo-4,6-difluorobenzene (1.41 g, 5.18
mmol), PdCl2(PPh3)2 (216 mg, 0.308 mmol), and CuI (113 mg 0.595
mmol). The mixture was purged with Ar for 5 min, and then degassed
phenylacetylene (2.80 mL, 25.5 mmol), DMF (6 mL), and
triethylamine (6 mL) were added. The mixture was stirred under Ar
for 1 h at room temperature, and then the reaction tube was sealed and
heated to 80 °C for 40 h. The reaction was quenched by dilution with
EtOAc and aqueous NH4Cl. The layers were separated, and the
aqueous phase was extracted with EtOAc (20 mL). The combined
organic layers were flashed through a plug of silica gel with EtOAc
(400 mL). The solvent was removed in vacuo to give a brown oil.
Purification by silica gel flash chromatography (hexanes) gave 1.43 g
1
(4.54 mmol, 88%) of 12b as a white solid. H NMR (500 MHz,
CDCl3): δ 7.71 (t, J = 7.8 Hz, 1H), 7.57−7.53 (m, 4H), 7.38−7.36 (m,
6H), 6.93 (t, J = 9.0 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 162.3
(dd, J = 257.9, 11.9 Hz), 137.3 (t, J = 2.7 Hz), 131.7, 128.8, 128.4,
122.5, 108.8 (dd, J = 14.5, 6.4 Hz), 104.6 (t, J = 25.6 Hz), 94.6 (t, J =
2.6 Hz), 80.9. TLC: Rf = 0.20 (hexanes). IR (KBr pellet): 3059 (m),
2230 (w), 1681 (w), 1594 (m), 1581 (m), 1506 (s), 1406 (s), 1233
(s), 1144 (s) cm−1. HRMS (DART): calcd for [C22H12F2H]+
314.0907, found 314.0922.
1,5-Bis(tert-butylethynyl)-2,4-difluorobenzene (12c). In a
reaction tube were added 1,3-dibromo-4,6-difluorobenzene (1.85 g,
6.80 mmol), PdCl2(PPh3)2 (246 mg, 0.351 mmol), and CuI (133 mg
0.701 mmol). The mixture was purged with Ar for 5 min, and then
degassed tert-butylacetylene (4.30 mL, 34.6 mmol), DMF (6 mL), and
triethylamine (6 mL) were added. The mixture was stirred under Ar
for 1 h at room temperature, and then the reaction tube was sealed and
heated to 80 °C for 40 h. The reaction was quenched by dilution with
EtOAc and aqueous NH4Cl. The layers were separated, and the
aqueous phase was extracted with EtOAc (20 mL). The combined
organic layers were flashed through a plug of silica gel with EtOAc
(400 mL). The solvent was removed in vacuo to give a brown oil.
Purification by silica gel flash chromatography (hexanes) gave 1.79 g
(6.52 mmol, 96%) of 12c as a clear, colorless oil. 1H NMR (500 MHz,
CDCl3): δ 7.42 (t, J = 8.0 Hz, 1H), 6.77 (t, J = 9.1 Hz, 1H), 1.31 (s,
18H). 13C NMR (126 MHz, CDCl3): δ 161.7 (dd, J = 255.2, 11.7 Hz),
1,5-Bis(phenylethynyl)-2,4-bis(p-tolyloxy)benzene (13b). In
a reaction flask under Ar, 12b (314 mg, 0.999 mmol), p-cresol (230
mg, 2.13 mmol), and DMSO (3.0 mL) were added. The reaction was
started with the addition of KOtBu (237 mg, 2.11 mmol). The
reaction mixture was stirred in an oil bath at 60 °C for 6 h. The
reaction was quenched by dilution with CH2Cl2 and 1 M HCl. The
layers were separated, and the aqueous phase was extracted with
CH2Cl2 (3 × 80 mL). The combined organic layers were washed with
H2O (80 mL) and dried over Na2SO4. The solvent was removed in
vacuo to give a brown oil. Purification by silica gel flash
chromatography (hexanes → CH2Cl2/hexanes, 1/4) gave 235 mg
1
(0.887 mmol, 89%) of 13b as a white, sticky solid. H NMR (500
MHz, CDCl3): δ 7.78 (s, 1H), 7.39−7.37 (m, 4H), 7.32−7.29 (m,
6H), 7.12 (d, J = 8.1 Hz, 4H), 6.91 (d, J = 8.6 Hz, 4H), 6.51 (s, 1H),
2.31 (s, 1H). 13C NMR (126 MHz, CDCl3): δ 158.6, 154.2, 138.1,
133.1, 131.5, 131.5, 130.2, 128.2, 123.2, 118.4, 110.6, 109.3, 93.9, 84.1,
20.7. TLC: Rf = 0.21 (CH2Cl2/hexanes, 1/10). IR (KBr pellet): 3075
(w), 3028 (w), 2208 (m), 1897 (w), 1590 (s), 1496 (s), 1392 (s),
1236 (s), 1192 (s), 1071 (s) cm−1. HRMS (DART): calcd for
[C36H27O2H]+ 491.2006, found 491.2006.
1,5-Bis(tert-butylethynyl)-2,4-bis(p-tolyloxy)benzene (13c).
In a reaction flask under Ar, 12c (280 mg, 1.02 mmol), p-cresol
(238 mg, 2.20 mmol), and DMSO (3.0 mL) were added. The reaction
J
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Article
was started with the addition of KOtBu (241 mg, 2.15 mmol). The
reaction mixture was stirred in an oil bath at 80 °C for 20 h. The
reaction was quenched by dilution with CH2Cl2 and 1 M HCl. The
layers were separated, and the aqueous phase was extracted with
CH2Cl2 (3 × 80 mL). The combined organic layers were washed with
H2O (80 mL) and dried over Na2SO4. The solvent was removed in
vacuo to give a brown oil. Purification by silica gel flash
chromatography (hexanes → CH2Cl2/hexanes, 1/4) gave 399 mg
with H2O (20 mL) and dried over Na2SO4. The solvent was removed
in vacuo to give a brown oil. Purification by silica gel flash
chromatography (hexanes → EtOAc/hexanes, 4/6) gave 81 mg
1
(0.17 mmol, 38%) of 14 as an off-white solid. H NMR (500 MHz,
DMSO-d6): δ 7.85 (s, 6H), 7.27−7.21 (m, 14H), 7.10−7.19 (m, 4H),
6.89 (s, 1H), 2.33 (s, 6H). 13C NMR (126 MHz, CDCl3): δ 140.8,
138.2, 136.6, 136.3, 133.1, 129.8, 128.7, 128.0, 127.7, 126.8, 125.1,
110.1, 103.3, 90.4, 21.1. TLC: Rf = 0.73 (EtOAc/hexanes, 3/7). IR
(ATR): 3035 (w), 1604 (m), 1542 (m), 1512 (s), 1474 (m), 1438
(m), 1388 (s), 1292 (m), 1245 (m), 1212 (s), 1107 (m) cm−1. HRMS
(DART): calcd for [C36H28N2H]+ 489.2325, found 489.2337.
1
(0.887 mmol, 87%) of 13c as a white solid. H NMR (500 MHz,
CDCl3): δ 7.50 (s, 1H), 7.07 (d, J = 8.1 Hz, 4H), 6.81 (d, J = 8.6 Hz,
4H), 6.53 (s, 1H), 2.29 (s, 6H), 1.14 (s, 18H). 13C NMR (126 MHz,
CDCl3): δ 157.2, 154.9, 138.1, 132.3, 129.9, 117.6, 112.0, 111.1, 103.4,
73.6, 30.7, 28.0, 20.6. TLC: Rf = 0.08 (CH2Cl2/hexanes, 1/10). IR
(KBr pellet): 2971 (s), 2867 (s), 2222 (m), 1982 (w), 1595 (s), 1506
(s), 1390 (s), 1327 (s), 1261 (s), 1109 (s) cm−1. HRMS (DART):
calcd for [C32H35O2H]+ 451.2632, found 451.2649.
6-Fluoro-2-phenyl-5-(phenylethynyl)-1-(p-tolyl)-1H-indole
(15). In a reaction flask under Ar, 12b (28.0 mg, 0.0891 mmol), p-
toluidine (9.72 mg, 0.0891 mmol), and DMSO (0.8 mL) were added.
The reaction was started with the addition of KOtBu (21.4 mg, 0.178
mmol). The reaction mixture was stirred in an oil bath at 100 °C for
18 h. The reaction was quenched by dilution with CH2Cl2 and 1 M
HCl. The layers were separated, and the aqueous phase was extracted
with CH2Cl2 (3 × 20 mL). The combined organic layers were washed
with H2O (20 mL) and dried over Na2SO4. The solvent was removed
in vacuo to give a brown oil. Purification by silica gel flash
chromatography (run twice, hexanes → CH2Cl2/hexanes, 3/7) gave
1,3-Bis(n-butylethynyl)-4,6-bis(p-tolyloxy)benzene (13d). In
a reaction flask under Ar, 12d (267 mg, 0.975 mmol), p-cresol (224
mg, 2.08 mmol), and DMSO (3.0 mL) were added. The reaction was
started with the addition of KOtBu (231 mg, 2.05 mmol). The
reaction mixture was stirred in an oil bath at 60 °C for 6 h. The
reaction was quenched by dilution with CH2Cl2 and 1 M HCl. The
layers were separated, and the aqueous phase was extracted with
CH2Cl2 (3 × 80 mL). The combined organic layers were washed with
H2O (80 mL) and dried over Na2SO4. The solvent was removed in
vacuo to give a brown oil. Purification by silica gel flash
chromatography (hexanes → CH2Cl2/hexanes, 1/4) gave 159 mg
1
10 mg (0.029 mmol, 26%) of 15 as an off-white solid. H NMR (500
MHz, CDCl3): δ 7.74 (d, J = 6.8 Hz, 1H), 7.54−7.48 (m, 2H), 7.32−
7.23 (m, 3H), 7.21−7.13 (m, 7H), 7.07−7.01 (m, 2H), 6.91 (d, J =
10.2 Hz, 1H), 6.67 (s, 1H), 2.34 (s, 3H). 13C NMR (126 MHz,
CDCl3): δ 160.5 (d, J = 228 Hz), 142.2 (d, J = 3.75 Hz), 139.1, 139.0,
137.7, 135.2, 132.0, 131.6, 130.7, 128.7, 128.3, 128.2, 128.0, 127.5,
127.4, 125.0, 125.0, 124.4, 123.6, 105.2 (d, J = 18.2 Hz), 103.2, 97.5
(d, J = 26.3 Hz), 92.1, 84.4, 21.2. TLC: Rf = 0.37 (CH2Cl2/hexanes, 3/
7). IR (ATR): 3064 (w), 2921 (m), 2852 (w), 2220 (w), 1736 (w),
1620 (m), 1606 (m), 1511 (s), 1465 (s), 1457 (s), 1380 (s), 1323 (s),
1261 (s), 1177 (s), cm−1. HRMS (DART): calcd for [C29H20FNH]+
402.1653, found 402.1682.
1
(0.440 mmol, 45%) of 13d as a clear, viscous, yellow oil. H NMR
(500 MHz, CDCl3): δ 7.51 (s, 1H), 7.06 (d, J = 8.3 Hz, 4H), 6.81 (d, J
= 8.6 Hz, 4H), 6.42 (s, 1H), 2.32 (t, J = 7.0 Hz, 4H), 2.29 (s, 6H),
1.49−1.42 (m, 4H), 1.40−1.35 (m, 4H), 0.87 (t, J = 7.3 Hz, 6H). 13C
NMR (126 MHz, CDCl3): δ 157.7, 154.6, 138.2, 132.6, 130.0, 118.0,
111.6, 109.9, 94.9, 75.1, 30.6, 21.8, 20.6, 19.3, 13.6. TLC: Rf = 0.10
(CH2Cl2/hexanes, 1/10). IR (thin film): 3031 (m), 2957 (s), 2930
(s), 2233 (m), 1881 (w), 1735 (m), 1598 (s), 1505 (s), 1487 (s), 1392
(s), 1308 (s), 1216 (s), 1168 (s), 1132 (s) cm−1. HRMS (DART):
calcd for [C32H34O2H]+ 451.2632, found 451.2653.
ASSOCIATED CONTENT
■
S
* Supporting Information
1,5-Diethoxy-2,4-bis(phenylethynyl)benzene (13e). In a
reaction flask under Ar, 60% NaH in mineral oil (20.1 mg, 0.521
mmol) was added followed by hexanes (2.0 mL), and the mixture was
stirred at room temperature for 20 min. The dispersion was allowed to
settle, and the hexanes was removed via syringe. DMSO (1.0 mL) and
EtOH (0.030 mL, 0.521 mmol) were added, and the mixture was
stirred at room temperature for 30 min. Concurrently, 12b (74 mg,
0.24 mol) was dissolved in DMSO (1.0 mL). At the end of the 30 min
time period, the DMSO solution of 12b was added, and the contents
of the flask were sealed and heated for 18 h at 60 °C. At the end of 18
h, the reaction was quenched by the addition of 1 M HCl and CH2Cl2.
The reaction mixture was further diluted with CH2Cl2 to a volume of
20 mL, and the aqueous layer was separated and discarded. The
organic phase was washed with H2O (2 × 20 mL) and brine (20 mL),
dried over Na2SO4, and concentrated in vacuo to give a brown solid.
Purification by silica gel flash chromatography (EtOAc/hexanes, 2/8)
Text and figures giving details of rate measurements and
calculation of substituent constants and H and 13C NMR
1
spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail for J.L.K.: jlkatz@colby.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This material is based upon work supported by the National
Science Foundation (CHE-0640729, CHE-0552292, CHE-
1062944), the Dreyfus Foundation, and Colby College.
1
gave 70.5 mg (0.197 mmol, 82%) of 13e as a white solid. H NMR
(500 MHz, CDCl3): δ 7.65 (s, 1H), 7.55−7.52 (m, 4H), 7.37−7.31
(m, 6H), 6.46 (s, 1H), 4.17 (q, J = 7.0 Hz, 4H), 1.53 (t, J = 7.0 Hz,
6H). 13C NMR (126 MHz, CDCl3): δ 160.9, 137.6, 131.4, 128.2,
127.8, 123.9, 105.4, 97.5, 92.4, 85.1, 64.7, 14.7. TLC: Rf = 0.60
(EtOAc/hexanes, 2/8). IR (KBr pellet): 2979 (w), 2884 (w), 2214
(w), 1611 (m), 1592 (m), 1517 (m), 1421 (m), 1338 (s), 1257 (s),
1095 (m), 1044 (m) cm−1. HRMS (DART): calcd for [C26H22O2]+
366.1620, found 366.1630.
REFERENCES
■
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9568. (b) Majumdar, K. C.; Ray, K. Synthesis 2011, 23, 3767−3783.
(c) Slavin, S.; Burns, J.; Haddleton, D. M.; Becer, C. R. Eur. Polym, J.
2011, 47, 435−446.
(2) (a) Katritzky, A. R.; Taylor, R. J. K. Alkynes. Comprehensive
Organic Functional Group Transformation II; Elsevier: Amsterdam,
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(14). In a reaction flask under Ar, 12b (137 mg, 0.436 mmol), p-
toluidine (207 mg, 1.91 mmol), and DMSO (2.0 mL) were added.
The reaction was started with the addition of KOtBu (213 mg, 1.91
mmol). The reaction mixture was stirred in an oil bath at 100 °C for
18 h. The reaction was quenched by dilution with CH2Cl2 and 1 M
HCl. The layers were separated, and the aqueous phase was extracted
with CH2Cl2 (3 × 20 mL). The combined organic layers were washed
K
dx.doi.org/10.1021/jo400668v | J. Org. Chem. XXXX, XXX, XXX−XXX

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