Exploring the potential of diarylacetylenediols as hydrogen bonding catalysts

Article abstract of DOI:10.1021/jo400926n

In the course of a search for new classes of hydrogen bonding catalysts, we have examined diarylacetylenediols as potential catalysts for the Diels-Alder reaction. General and efficient methods have been developed for the preparation of these diols. Their structures were systematically modified, and increased activity was observed for those possessing an electron-withdrawing group on the aryl groups. The electron-deficient diarylacetylenediol catalysts, while more active, undergo spontaneous cyclization to the corresponding benzo[b]furans. A mechanism is postulated to explain this facile transformation. Computational studies performed on 2-ethynylphenol help to explain the effect of the alkyne on the conformation and hydrogen bond donating ability of the adjacent OH group. Finally, the crystal structure of one of the diols is reported, and it displays an intricate network of intermolecular hydrogen bonds.

Full text of DOI:10.1021/jo400926n

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Article
Exploring the Potential of Diarylacetylenediols as Hydrogen Bonding Catalysts
Yunus Emre Turkmen, and Viresh H. Rawal
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400926n • Publication Date (Web): 19 Jul 2013
Downloaded from http://pubs.acs.org on July 30, 2013
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Exploring the Potential of Diarylacetylenediols as Hydrogen
Bonding Catalysts
Yunus E. Türkmen and Viresh H. Rawal*
Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago, IL 60637,
United States
vrawal@uchicago.edu
O
Cat. 9 (10 mol%)
+
F3C
CF3
d8-toluene, -30 °C
OH
HO
O
9
21 fold rate enhancement
over background
In the course of a search for new classes of hydrogen bonding catalysts, we have examined
diarylacetylenediols as potential catalysts for the Diels-Alder reaction. General and efficient methods
have been developed for the preparation of these diols. Their structures were systematically modified
and increased activity was observed for those possessing an electron-withdrawing group on the aryl
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groups. The electron-deficient diarylacetylenediol catalysts, while more active, undergo spontaneous
cyclization to the corresponding benzo[b]furans. A mechanism is postulated to explain this facile
transformation. Computational studies performed on 2-ethynylphenol help to explain the effect of the
alkyne on the conformation and hydrogen bond donating ability of the adjacent OH group. Finally, the
crystal structure of one of the diols is reported, and it displays an intricate network of intermolecular
hydrogen bonds.
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Introduction
The past decade has witnessed the mushrooming growth of metal-free catalysis. The field has
gone from having representation through isolated examples to a position where it now challenges the
longstanding dominance of metal-based catalysis.1 An important and blossoming subset of this field,
one that shares conceptual similarities to metal-based Lewis acid catalysis, is hydrogen bond catalysis.2
Analogous to metal activation, hydrogen bond formation increases the electrophilicity of a reactant by
lowering its LUMO energy. Moreover, the compatibility of hydrogen bond donors with many functional
groups, such as amines, phosphines, pyridines, etc., makes them excellent partners in bifunctional
organocatalysis.3
In considering different hydrogen bond donor functionalities, we were attracted to the possibility
of using phenols, as such compounds had already been utilized to catalyze reactions. In a seminal 1942
paper, Wassermann noted modest rate acceleration for the Diels-Alder reaction of cyclopentadiene with
benzoquinone in the presence of phenol.4 This area remained more or less dormant until, in their
pioneering studies, Hine and co-workers showed that biphenylenediols, functioning as dual hydrogen
bond donors (Figure 1), catalyze the opening of phenyl glycidyl ether with diethylamine.5 Kelly and co-
workers used a soluble, nitro-substituted biphenylenediol derivative as a catalyst in Diels-Alder
reactions and obtained up to ~30 fold higher conversion over the uncatalyzed reaction with 40 mol%
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catalyst loading.6 Since these early reports, the field has expanded dramatically and numerous other
classes hydrogen bond donors—such as taddols,7 chiral thioureas,3b-d phosphoric acids,2b,2d
guanidines/guanidiniums,8 peptides2h and squaramides9—have been prepared and successfully utilized
in a variety of reactions.2 In addition to these frequently used classes, new hydrogen bond donor
scaffolds have been reported in recent years and applied to catalysis.10
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The remarkable achievements in this area over the past few years have revolutionized our view
of the scope of reactions that can be catalyzed by hydrogen bond donors and Brønsted acids.
Development of new catalyst scaffolds has the potential to expand this scope even further, to include
reactions and functional groups that remain unexplored. We are especially interested in the activation of
carbonyl compounds with dual hydrogen bond donor catalysts. Such binding is expected to not only
provide better activation than the single-point binding but would also result in a rigid, well-organized
complex due to the reduced rotational freedom. The latter aspect is expected to be important in
enantioselective catalysis. The total hydrogen bond strength of a hydrogen-bonded complex depends on
several variables, such as hydrogen bond donating and accepting abilities of the components,11
hydrogen bond distances between them, and the geometric arrangement between the donor and acceptor
groups. As a result, the spatial arrangements of the hydrogens of a dual hydrogen bond donor can, in
principle, be optimized through careful investigation of different scaffolds in order to generate catalysts
with enhanced activities. For instance, our development of the squaramide core as a hydrogen bonding
catalyst was motivated by a desire to explore two-point hydrogen bond donors having larger H-H bond
distance than that found in thioureas, the dominant scaffold for hydrogen bond catalysis.9a Whereas the
H-H bond distance in thiourea core is ca. 2.13 Å, it is 2.72 Å in squaramides, roughly 25% larger.
Although one of the first functional groups to be used for hydrogen-bonding activation, phenols
remain relatively unexplored as catalytic units for carbonyl activation.12 A search for additional
structural support for the interaction between phenolic diols and carbonyl groups uncovered an X-ray
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crystal structure reported by Saied, Simard, and Wuest of a diarylacetylenediol bound to a
cyclohexanone by dual hydrogen bonds (Figure 1).13 We recapitulated the essential features of this
complex in silico using DFT calculations within Spartan'08 molecular modeling program. We also used
this approach to evalute several other diols as potential dual hydrogen bond donors.14 An interesting
aspect of the diphenylacetylenediol is that the alkyne imparts both rigidity and flexibility to the scaffold.
Although the alkyne rigidly holds the two aryl rings in a linear arrangement, the distance between the
two phenolic hydrogens can vary widely, between 2-5 Å, due to free rotation about the single bond.
Despite the ease of synthesis of diarylacetylenediols and their potential to function as dual hydrogen
bond donor catalysts, there are no reports in the literature on the examination of such compounds as
hydrogen bonding catalysts.
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H
N
O
O
H
H
H
H
t-Bu
O
O
t-Bu
O
O
Figure 1. Hydrogen bonded complex of biphenylenediol and a pyridone reported by Hine et al. and
hydrogen bonded complex of a diarylacetylenediol and a cyclohexanone reported by Saied et al.
Results and Discussion
Initial Evaluation of Wuest’s Diol—The objective of the initial studies was to determine if simple
diarylacetylenediols would function as hydrogen bond donor catalysts for activating carbonyl group
containing reactants, potentially through dual hydrogen bonding interactions. The study was initiated
by evaluating the catalysis capability of the known diol 1, which was prepared easily following the
procedure reported by Wuest.15 The Diels-Alder reaction of cyclopentadiene and methyl vinyl ketone
(MVK) to give cycloadduct 2 was selected as the test reaction.16 The reactions were carried out at
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various temperatures in toluene, and conversions were determined at regular intervals by 1H-NMR. The
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rate constants were calculated for both catalyzed and uncatalyzed reactions (Table 1). With 40 mol% of
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diol 1 at 20 °C, the relative rate constant (krel =kobs/kbackground) was found to be 2.8, indicating clear but
low catalytic activity at room temperature (Entry 1).17 This ratio increased noticeably at lower
temperatures. With 20 mol% of the catalyst, a krel value of 6.5 was obtained at 0 °C, and 9.4 at -20 °C
(Entries 2-3). The data convincingly showed that Wuest’s diol functions as a catalyst for the Diels-
Alder reaction.
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TABLE 1. Diels-Alder reaction of Cyclopentadiene and MVK catalyzed by diols 1 and 3
OH
HO
O
toluene
+
1
3
O
OH
HO
2
catalyst
entry
cat. mol %
k(obs)/k(back)
T (°C)
20
1
2
3
4
1
1
1
3
40
20
20
20
2.8
6.5
9.4
2.3
0
-20
-20
The working hypothesis was that diol 1 functions through a two-point hydrogen bond to the carbonyl
oxygen. To test this premise, we prepared the known homologous diacetylenic diol 3,15b in which the
two phenol rings are separated by a diyne unit. This diol was expected to have electronic properties
similar to 1 but have a larger distance between the two OH’s. Molecular mechanics calculations show
the two donor oxygen atoms in 3 at their minimum distance to be 6.8 Å apart (vs 3.9 Å in 1), a distance
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that is believed to be too large for a good two-point hydrogen bond. Under the standard reaction
conditions, diol 3 exhibited lower catalytic activity (krel=2.3, Entry 4) than 1. While seemingly
consistent with the original hypothesis, the interpretation of these results is less than straightforward,
explainable through other considerations, including a one-point activation model. Wuest and coworkers
had noted through IR studies that in solution both phenols in 1 are internally hydrogen bonded by O-
H···π interaction to the shared alkyne.15a The presence of two alkynes in 3 means that rather than sharing
an alkyne, each hydroxyl would be internally hydrogen bonded to the proximal alkyne, one alkyne per
hydroxyl. As such, the hydroxyls in 3 are expected to be less available than in 1 for intermolecular
hydrogen bonding activation, consistent with the observed results. These initial results motivated us to
prepare and examine the activity of a wider range of structurally modified diarylacetylenediol catalysts.
Substituted Diphenylacetylene Diols—Having shown that the diarylacetylenediol backbone is
effective for activating the carbonyl group, we next focused on the preparation of several additional
phenols and diphenols, some designed to assess the effect of steric and electronic perturbations on
catalysis activity, and others to serve as controls (Figure 2). We recognized that the ortho-tert-butyl
groups in 1 and 3, through steric compression and entropic constraints, would cause the hydroxyl groups
to be more strongly hydrogen bonded to the alkyne, thereby making the phenols less effective for
intermolecular hydrogen bond activation.15a To tease out the effect of the tert-butyl group on catalyst
activity, we considered the unsubstituted diol 4 available through the route used for 1. Diol 5, having
the electron-withdrawing -CF3 group para to the phenols, was expected to be a more effective catalyst
than those discussed above. Structurally similar mono-phenol derivatives 6 and 7 as well as the diyne-
separated diol 8 were expected to serve as controls. Diol 9, having the -CF3 groups meta to the phenols,
would show the effect of the position of this withdrawing group on catalyst activity.
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OH
HO
OH
HO
OH
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F3C
CF3
F3C
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OH
HO
OH MeO
OH
HO
F3C
CF3
F3C
CF3 F3C
CF3
7
8
9
Figure 2. Substrates considered for evaluation as hydrogen bond donors.
Synthesis of Phenols 4-9—Cross-coupling chemistry enabled the synthesis of nearly all of the
compounds selected for use as catalysts in the present study. The known parent diol 418 was prepared
by a slightly modified route. Diol 5 was prepared through the sequence summarized in Scheme 1.
Lithiation of the MOM-protected phenol derivative 1019 with n-BuLi followed by treatment with iodine
afforded aryl iodide 11 in 98% yield. Sonogashira coupling of 11 with excess ethynyltrimethylsilane
and the subsequent deprotection of the TMS group with TBAF gave 12 in 84% yield over two steps. A
further Sonogashira coupling of 11 with alkyne 12 provided MOM-protected acetylene-diol 13 in 94%
yield. Finally, removal of the MOM groups using HCl in methanol gave diol 5 in 83% yield.
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The mono-ols 6 and 7 and the diyne-separated diol 8, all designed for use as controls, were
prepared as shown in Scheme 2. Sonogashira coupling of 11 with phenylacetylene (93%) and
deprotection of the MOM group afforded 6 (74%). Similarly, mono-methyl protected diol 7 was
obtained by the cross-coupling of 12 with 15 (67%) followed by selective deprotection of the MOM
group (94%). Finally, oxidative coupling of 12 (86%) and subsequent deprotection under acidic
conditions afforded diyne linked diol 8 in high yield (98%).
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Scheme 1. Synthesis of Diol 5
5
6
7
8
OMOM
OMOM
H
OMOM
n-BuLi, THF
-78 °C; then
I2, -78 °C to rt
1.
TMS
PdCl2(PPh3)2
CuI, Et3N, 70 °C
I
9
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98%
2. TBAF, THF
84% for 2 steps
CF3
CF3
CF3
10
11
12
OH
HO
OR
RO
11, PdCl2(PPh3)2
CuI, Et3N, 70 °C
HCl
MeOH
94%
83%
F3C
CF3
F3C
CF3
5
13, R=MOM
Scheme 2. Synthesis of 6, 7, and 8
Ph
H
OMOM
PdCl2(PPh3)2
CuI, Et3N, rt
HCl
MeOH
11
6
93%
74%
F3C
14
1. PdCl2(PPh3)2
CuI , Et3N, 70 °C
67%
OMe
I
OH MeO
12
+
2. HCl, MeOH
94%
CF3
F3C
CF3
15
7
1. CuCl, TMEDA
acetone, O2, 60 °C
86%
OH
HO
2. HCl, MeOH
98%
F3C
CF3
8
The preparation of diol 9, which is isomeric with diol 5, was accomplished as shown in Scheme 3.
Commercially available 3-(trifluoromethyl)phenol was iodinated under basic conditions to afford the 6-
iodinated phenol in 29% unoptimized yield. Protection of the phenol with a MOM group afforded aryl
iodide 16 (75%),20 which upon Sonogashira coupling with ethynyltrimethylsilane and TMS-
deprotection afforded 17 in 64% yield over two steps. A second Sonogashira coupling of 17 and 16 gave
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protected diol 18 almost quantitatively (99%). Finally, deprotection of the MOM groups in acidic
methanol gave diol 9 in 66% yield.
5
6
7
8
9
Scheme 3. Synthesis of Diol 9
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TMS
1.
1. I2, Na2CO3
THF, H2O
29%
OMOM
OH
PdCl2(PPh3)2
CuI, Et3N, 80 °C
I
2. TBAF, THF
64% over 2 steps
2. MOMCl
i-Pr2NEt, CH2Cl2
75%
CF3
CF3
16
OMOM
OR
RO
16, PdCl2(PPh3)2
CuI, Et3N, 70 °C
F3C
CF3
99%
CF3
18: R=MOM
9: R=H
17
MeOH
HCl
66%
Activity of New Phenolic Catalysts—The relative activity of Wuest’s diols, the newly synthesized diols,
and the control compounds as hydrogen bond donor catalysts was investigated and the results are
summarized in Table 2. The kinetics studies were carried out under pseudo first order conditions at -30
°C using 10 mol% of diol catalysts and 20 mol% of mono-phenols, and conversions were determined by
1H-NMR. Under the new kinetics protocol, the relative rate constant for Wuest’s diol 1 was found to be
3.5 (Entry 1), whereas that for the diyne-separated diol was 1.3 (Entry 2).21 The parent
diphenylacetylene diol 4 was found to catalyze the DA reaction with higher efficiency than the ortho-
tert-butyl-substituted diol, 1 (Entry 3). This result is consistent with the expectation that the tert-butyl
groups enforce a stronger O–H···π interaction, thereby making the phenols less effective hydrogen bond
donors. In addition, the tert-butyl groups prevent the “OH-out” conformation (OH away from the
alkyne), whereas in the absence of tert-butyl groups such a conformation is possible, and the catalyst
may function in this form. Finally, compared to the unsubstituted diol, 4, the electron-donating effect of
the two alkyl groups on each aryl ring in 1 are expected to decrease the acidity of the phenols. For
example, the pKa of 4-Me phenol is 18.9, while that of unsubstituted phenol is 18.0 in DMSO.22 Entries
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4-7 illustrate the effect of electron-withdrawing groups on the aryl units. As expected, the electron-
withdrawing CF3 groups in 5 increased the activity of the diol catalyst, giving a krel value of 16.7 (entry
4). To the extent that diol 5 promotes the cycloaddition through two-point hydrogen bond activation,
the analogous mono-phenolic compounds 6 and 7 were expected to serve as controls, as they would
form a one-point hydrogen bond. Phenols 6 and 7 were utilized at 20 mol% loading (to have equal
Brønsted acid concentration) and found to be less effective as catalysts than 5, giving krel values of 5.0
and 2.7, respectively (entries 5-6). The differences in the catalytic activities of 6 and 7 can be
understood by considering their stable conformations, wherein the phenolic hydroxyls are expected to
be stabilized through hydrogen bonding interactions, as drawn in entries 5 and 6. Although too far for a
good hydrogen bond, the methoxy group oxygen in 7 can provide weak electrostatic stabilization to the
phenol. Also, resonance contribution by the methoxy group will render the alkyne more electron-rich,
strengthening the hydrogen bond to the phenolic hydroxyl. Interestingly, the alkyne-expanded diol 8,
while less active than 5, was more effective as a catalyst than the alkynyl control compounds, mono-
phenols 6 and 7, and even 4-trifluoromethylphenol (19, entries 5-8). Catalyst 9 with CF3 groups at the
meta position to OH showed a further increase in catalyst activity (krel=21.8, Entry 9), whereas 3-
trifluoromethyl phenol (20) gave a krel value of 10.3 (20 mol%, entry 10). Overall, the kinetics data
provides clear evidence that phenolic hydrogen bond donors catalyze the Diels-Alder reaction between
cyclopentadiene and methyl vinyl ketone. Diarylacetylene diols designed to provide two-point
hydrogen bonding were more effective at accelerating the cycloaddition reaction compared to the mono-
phenols, but only moderately so.
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6
7
8
9
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Table 2. Diels-Alder reaction of cyclopentadiene and MVK at -30 °Ca
O
catalyst
+
d8-toluene
-30 °C
O
2
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b
Cat
krel
Δδ in 13C
Entry
1
Catalyst
(ppm)c
mol % (kobs/kback
)
OH
HO
10
11
12
13
14
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16
17
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10
3.5
0.14
1
OH
HO
2
10
10
10
20
1.3
9.6
0.09
1.49
2.55
0.72
3
OH
OH
O
HO
3
4
4
HO
16.7
5.0
F3C
CF3
5
H
5
6
F3C
6
CH3
O
H
O
20
2.7
0.23
F3C
CF3
7
OH
HO
7
8
9
10
20
10
10.0
7.7
2.22
2.17
2.68
F3C
CF3
8
F3C
OH
19
OH
HO
F3C
CF3
21.8
9
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OH
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10
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10.3
2.09
CF3
20
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aThe catalytic reactions were carried out using cyclopentadiene (1.0 M), MVK (0.1
M) and the catalyst (10 or 20 mol%) in d8-toluene at -30 °C. bkrel= kobs/kbackground is
c
the average of at least two runs. Δδ represents the chemical shift change of the
carbonyl carbon of MVK (0.06 M) upon addition of 100 mol% diol or 200 mol%
phenol, in d8-toluene.
Correlation of Catalyst Activity with NMR Chemical Shifts—We have sought to correlate the
activities of the different catalysts with the strength of their interaction with the dienophile. On the far
right column of Table 2 are presented the chemical shift changes upon complexation of the different
catalysts with MVK. In each case, a 1:1 mixture of the diol, 0.06 M,23 and MVK was prepared in d8-
toluene and their 13C-NMR spectra were recorded. The chemical shift differences of the MVK carbonyl
carbon in these solutions with that in the blank MVK solution were determined. While diols 1 and 3
induced very small changes (0.14 and 0.09 ppm, respectively; entries 1 and 2), the catalytically active
diols 5 and 9 gave Δδ values of 2.55 and 2.68 ppm, respectively (Entries 4 and 9). For comparison
purposes, mono-phenol derivatives were also investigated, but with a 2:1 phenol/MVK ratio (0.12 M
phenol concentration). As expected, the mono-phenols gave smaller Δδ values than their diol analogues,
indicative of poorer binding (Entries 5, 6, 8 and 10). When these values are compared with the observed
krel values, they clearly show a close relation between the chemical shift changes upon complexation
and the activity of the catalyst.
Computational Studies—We next investigated computationally the effect of the alkyne moiety on the
conformation and hydrogen bond donating ability of the -OH group in 2-alkynyl phenols. While the
steric effect of the alkynyl group is expected to be small, it can influence the properties of the nearby
phenol through hydrogen bonding interactions.24 Indeed, based on IR stretches, Wuest and co-workers
had proposed that in the absence of a hydrogen bond acceptor the two OH’s of 1 make intramolecular
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hydrogen bonds to the triple bond.15a In order to determine whether such an interaction is playing a role
in the hydrogen bonding capability of the phenols, we carried out calculations on 2-ethynylphenol using
Spartan'08. Single point energies were calculated at AM1, HF 6-31G** and DFT B3LYP 6-31G**
levels of theory at each 20° increment in the H1-O1-C1-C2 dihedral angle between 0-180° (Figure 3).
The energy difference between the 0° and 180° conformations was found to be 2.16 kcal/mol by AM1,
while HF 6-31G** and DFT B3LYP 6-31G** gave 3.57 and 3.90 kcal/mol, respectively (Figure 3a).
The last value is in excellent agreement with the report of Mulder and co-workers,24d who had
determined the ΔHintra-HB of 2-ethynylphenol to be -3.8 kcal/mol by DFT calculations. In addition to the
energy profile, molecular electrostatic potential (ESP) surfaces were calculated for each conformation.
These potentials have been used in the literature as measures of hydrogen bond donating or accepting
abilities of different functional groups.25 According to DFT calculations, the electrostatic potential of
the OH hydrogen decreases from + 65.0 to + 44.5 kcal/mol (ΔESP = 20.5 kcal/mol) when the dihedral
angle changes from 180 to 0° (Figure 3b). The same calculation was also carried out using AM1 and HF
6-31G**, and the ESP differences between two conformers were found to be 10.4 and 21.8 kcal/mol,
respectively.26 When considered together, these two results indicate that the orientation of the OH
hydrogen toward the alkyne is favored energetically by 3.90 kcal/mol and this orientation is expected to
diminish the hydrogen bond donating ability of the hydroxyl group. It should be noted that such a
conformational preference might be a result of an attractive interaction between the alkyne and the OH
group or a repulsive interaction between the oxygen lone pairs and alkyne π-bond(s), or a combination
of both of these effects.
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H
H
O
H
O
H
∆E = 3.90 kcal/mol
ESP(max) = 44.5 kcal/mol
ESP(max) = 65.0 kcal/mol
Figure 3. Dependence of (a) relative energy and (b) maximum electrostatic potential on the dihedral
angle for 2-ethynylphenol.
Synthesis and Chemistry of Diol 21—The significant increase in catalyst activity by the introduction of
–CF3 groups (diols 5 and 9) prompted us to prepare diol catalysts with even stronger electron
withdrawing groups. Among the common groups considered, the cyano unit was expected to provide the
required electron-withdrawing ability without adding steric factors. In particular, we decided to prepare
diol 21, with CN groups at the para positions. In their work on biphenylene diols, Kelly and coworkers
had found the nitro-substituted derivatives to be poorly soluble, and had prepared a diol with propyl
groups ortho to the hydroxyls.6 We decided to follow a similar strategy in the case of the cyano-
substituted diarylacetylenediol (Scheme 4). Phenol 22 was prepared in three steps from the
commercially available 4-cyanophenol, following a reported procedure.27 Iodination of 22 under basic
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conditions (83%) followed by MOM protection afforded cleanly the aryl iodide 23 (93%). The
Sonogashira coupling of 23 with ethynyltrimethylsilane (91%) and its subsequent desilylation with
TBAF gave quantitatively acetylene 24. The protected diol 25 was obtained in 93% yield by a second
Sonogashira coupling. The final deprotection step, however, proved to be problematic. Treatment of 25
with HCl in methanol at room temperature resulted in complete formation of the benzo[b]furan
derivative 26.28,29 The use of BBr3 in CH2Cl2 at room temperature didn’t provide an improvement.
However, when 25 was treated with BBr3 at -78 °C for 45 min and quenched with half saturated
NaHCO3 solution, a mixture of 21 and 26, in a 1:2 ratio, was obtained (determined by 1H-NMR). After
the solvent was evaporated and the sample was kept at room temperature for 3 h, TLC showed that it
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had completely converted to 26, the structure of which was further confirmed by HRMS, H, and C-
NMR. This observation suggests that diol 21 spontaneously converts to benzo[b]furan 26 at room
temperature. A plausible mechanism for the benzo[b]furan formation is shown in Scheme 5.
Scheme 4. Studies on the Synthesis of Diol 21
1.
TMS
PdCl2(PPh3)2, CuI
Et3N, 70 °C, 91%
OMOM
OH
1. I2, Na2CO3
THF, H2O, 83%
I
2. TBAF, THF
quant.
2. MOMCl
i-Pr2NEt, CH2Cl2
93%
CN
CN
22
23
OMOM
OMOM
CN
23, PdCl2(PPh3)2
CuI, Et3N, 70 °C
93%
NC
MOMO
CN
24
25
CN
NC
OH
HO
BBr3, CH2Cl2
-78 °C
O
+
HO
NC
CN
26
21
~1:2
room temp.
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Proposed Mechanism for the Benzo[b]furan formation—2-alkynylphenol derivatives have been shown
to be useful substrates for the synthesis of benzo[b]furans by the use of transition metals,18,30 various
electrophiles,31 Brønsted acids,32 and bases.33 In addition, diarylacetylenediols have been observed, by
us and others, to undergo a facile transformation to the corresponding benzo[b]furans under acidic and
basic conditions.18,28,34 In our hands, this conversion was more common with diols having electron
withdrawing groups, wherein some substrates cyclized spontaneously to the benzo[b]furans. For
instance, diols 535 and 9 undergo a slow but clear transformation to the corresponding benzo[b]furans,
even when stored in the refrigerator (~0 °C). Additionally, as described in the previous section, we were
unable to prepare diol 21, due to its fast conversion to 26.36
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A plausible mechanism to rationalize the facile transformation of diarylacetylenediols to the
benzo[b]furans under acidic and basic conditions is presented inScheme 5. The ortho-hydroxyl is
expected to increase the basicity of the alkyne, so that under acidic conditions it can be protonated to
form a protonated allenone type species. In this intermediate, the planes of the two six-membered rings
are perpendicular to each other and the phenol –OH lies in proximity to the π* of the allenone moiety.
The high electrophilicity of the protonated allenone, coupled with the rearomatization driving force,
would lead to a fast 5-exo-dig-cyclization to give the protonated benzo[b]furan which would regenerate
the acid catalyst upon deprotonation. It should be noted that the acidic diols with strong electron
withdrawing groups would act as acid catalysts by themselves and would not require an external acid,
which would explain the spontaneous decomposition of some of the diols studied.37
Scheme 5. Proposed mechanism for the formation of benzo[b]furan under (a) acidic and (b) basic
conditions
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a)
b)
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OH
HO
OH
OH
OH
-A-
-H+
H
9
O
O
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HO
H
H
A
O
HO
OH
HO
O
-B-
H
B-
HO
B-
H
B
OH
O
O
H
B-H
O
O
O
A similar mechanism can be written for the base catalyzed benzo[b]furan formation (Scheme
5b). This time, the initially formed phenolate upon deprotonation would increase the electron density of
the alkyne reducing its barrier to protonation, whether inter- or intramolecularly, to give an allenone.
Nucleophilic addition of the second phenol or phenolate would result in cyclization and give the
benzo[b]furan phenolate, the protonation of which would regenerate the base catalyst.
Crystal Structure of Diol 5—A search of the literature showed that, surprisingly, the crystal structure of
a diarylacetylenediol has not been reported, except for the co-crystal shown in Figure 1. In order to get
some insight on the structural parameters and conformation of a free diarylacetylenediol, good quality
crystals of diol 5 were obtained and its X-ray crystal structure was determined. As shown in Figure 4,
both hydroxyl groups in the molecule lie in the same plane but on opposite sides of the alkyne, with the
hydrogens of the OH groups facing away from the triple bond. All the hydrogens and oxygens of the
hydroxyl groups participate in hydrogen bonding in an efficient way to form a 3D hydrogen bonded
network. From the pattern analysis, its graph set was determined as R 44 (22).38 Due to the symmetry in
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the molecular network, all the hydrogen bonds are equivalent with an O···O distance of 2.76 Å and O-
H···O angle 167.9°. There is also a weak C-H···F-C short contact39 with H···F and C···F distances of
2.58 and 3.43 Å, respectively, and C-H···F angle 148.3°.
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a)
b)
Figure 4. Different views of the crystal structure of diol 5: (a) Hydrogen bonded network showing the
R 44 (22) motif; (b) side view of the hydrogen bonded network.
Conclusions
In this study, we demonstrated the first use of diarylacetylenediols as hydrogen bond donor
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catalysts. General and efficient methods were developed for the preparation of various
diarylacetylenediols. Of the different diols examined, diols 5 and 9 were found to be among the better
catalysts for the Diels-Alder reaction of cyclopentadiene and MVK, resulting in up to 21-fold rate
enhancement over the background reaction. It is likely that such diols can be used for the promotion of
other reactions involving carbonyl group activation. The diols studied showed higher catalytic activities
than their mono-phenol counterparts in control experiments. However, the differences were small,
indicating that the contribution from dual hydrogen bond activation may be limited with this scaffold.
While the activity of the diols was found to increase with the introduction of electron-withdrawing
groups, the observed tendency to undergo spontaneous cyclization to the corresponding benzo[b]furans
may limit the range of modifications that can be carried out on these catalysts. A mechanism involving
an allenone type intermediate is proposed to rationalize the formation of the benzo[b]furan products. We
have also shown through computational studies that 2-ethynylphenol prefers the internally hydrogen
bonded conformation by 3.90 kcal/mol, and this conformation reduces the electrostatic potential on OH
hydrogen by 20.5 kcal/mol. Finally, the crystal structure of diol 5 was obtained and found to possess an
intricate network of intermolecular hydrogen bonds.
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Experimental Section
General Information. All air sensitive reactions were performed using oven dried glassware under N2
or Ar atmosphere. Reactions were monitored by TLC on silica gel 60 Å F254 plates visualized by UV
and KMnO4 staining solution. Flash column chromatography was performed on 32-63 µm Flash silica
1
gel. NMR spectra were measured at 500 MHz for H spectra and 125 MHz for 13C spectra and
calibrated from residual solvent signals (chloroform at 7.26 ppm, toluene at 6.98 ppm, acetone at 2.05
ppm, acetonitrile at 1.94 ppm and methanol at 3.31 ppm for 1H spectra; chloroform at 77.0 ppm, toluene
13
at 20.4, acetone at 206.68 ppm and acetonitrile at 118.69 ppm for C spectra). Infrared spectra were
measured on NaCl plates. Melting points are uncorrected. High-resolution mass spectra (ESI) were
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obtained using an ion trap mass analyzer.
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9
Dichloromethane (CH2Cl2), toluene, benzene and tetrahydrofuran (THF) were purified by
passage over activated alumina using a solvent purification system. Cyclopentadiene was obtained by
cracking dicyclopentadiene at 170 °C and distillation under nitrogen before every use. Methyl vinyl
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ketone was distilled under nitrogen and stored at –10 °C. Triethylamine (HPLC grade) was stored over
KOH pellets. CuI and PdCl2[P(C6H5)3]2 were stored in a desiccator. CAUTION: The reactions in
sealable pressure tubes were carried out in a well-ventilated fume hood behind a blast shield.
Diols 115a and 315b were prepared according to the reported procedures.
2-Iodo-1-(methoxymethoxy)-4-(trifluoromethyl)benzene (11): To a solution of 1019 (1.70 g, 8.22
mmol) in 40 mL of anhydrous THF at -78 °C was added slowly n-BuLi (1.6 M solution in hexanes, 6.2
mL, 9.9 mmol) and the resulting solution was stirred at -78 °C for 30 min. In a separate round-bottom
flask, I2 (3.13 g, 12.3 mmol) was dissolved in 10 mL of anhydrous THF under argon and added
dropwise to the reaction mixture via syringe. The resulting reddish brown mixture was allowed to warm
to room temperature and stirred under nitrogen for 22 h. The reaction mixture was quenched with
saturated Na2S2O3 solution and stirred until the color turned light yellow. The aqueous phase was
extracted twice with Et2O, and the combined organic extracts were dried over MgSO4, filtered and
concentrated in vacuo to afford 11 (2.68 g, 98%) as a yellow oil, which was used in the next step
without further purification. 1H NMR (500 MHz, CDCl3): δ 8.03 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.5,
1.5 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 5.29 (s, 2H), 3.50 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 158.5,
136.5 (q, JC-F = 3.8 Hz), 126.8 (q, JC-F = 3.8 Hz), 125.4 (q, JC-F = 32.8 Hz), 123.1 (q, JC-F = 270.4 Hz),
113.9, 94.7, 86.5, 56.5; IR (film): 2960, 2911, 2830, 1604, 1496, 1396, 1324, 1297, 1124, 1081, 1036,
982, 821, 667 cm-1; HRMS (ESI) Calcd for C9H8F3IO2Na (M+Na)+ : 354.9413, Found: 354.9415.
2-Ethynyl-1-(methoxymethoxy)-4-(trifluoromethyl)benzene (12): Compound 11 (365 mg,
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1.10 mmol) was dissolved in 3.0 mL of Et3N in a sealable tube fitted with a septum, at room
temperature, under nitrogen. PdCl2(PPh3)2 (46 mg, 0.066 mmol), CuI (21 mg, 0.11 mmol) and
ethynyltrimethylsilane (457 µL, 3.30 mmol) were added sequentially and the system was briefly
evacuated and filled with nitrogen three times after each addition. The tube was sealed by the
replacement of the septum with the screw cap, heated to 70 °C and stirred at this temperature for 18 h.
After cooling down to room temperature, the reaction mixture was quenched with a 1:1 brine-H2O
mixture and the aqueous layer was extracted three times with Et2O. The combined organic extracts were
dried over MgSO4, filtered and concentrated to afford a brown oil. This crude oil was dissolved in 10
mL of anhydrous THF under nitrogen and cooled to 0 °C. TBAF (1.0 M solution in THF, 2.2 mL, 2.2
mmol) was added slowly and the reaction mixture was stirred for 30 min. The mixture was then
quenched with 10 mL of H2O and diluted with 40 mL of Et2O. The two phases were partitioned in a
separatory funnel and the organic phase was washed with 20 mL of brine, dried over MgSO4, filtered
and concentrated to afford a brown oil. Purification by flash column chromatography (EtOAc:hexanes =
1:19) gave 12 (212 mg, 84% over 2 steps) as a light yellow oil. 1H NMR (500 MHz, CDCl3): δ 7.73 (d,
J = 2.0 Hz, 1H), 7.53 (dd, J = 8.5, 2.0 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 5.31 (s, 2H), 3.52 (s, 3H), 3.35
(s, 1H); 13C NMR (125 MHz, CDCl3): δ 160.6, 131.3 (q, JC-F = 3.8 Hz), 127.1 (q, JC-F = 3.8 Hz), 124.0
(q, JC-F = 33.8 Hz), 123.7 (q, JC-F = 270.0 Hz), 114.5, 112.9, 94.7, 82.4, 78.5, 56.4; IR (film): 3304,
2962, 2913, 2832, 2113, 1614, 1503, 1421, 1336, 1274, 1252, 1131, 1086, 985, 827 cm-1; HRMS (ESI)
Calcd for C11H10F3O2 (M+H)+ : 231.0627, Found: 231.0630.
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1,2-Bis[2-(methoxymethoxy)-5-(trifluoromethyl)phenyl]ethyne (13): Compound 11 (143 mg,
0.43 mmol) was dissolved in 1.0 mL of Et3N in a sealable tube fitted with a septum, at room
temperature, under nitrogen. PdCl2(PPh3)2 (18 mg, 0.026 mmol), CuI (8 mg, 0.043 mmol) and a solution
of alkyne 12 (109 mg, 0.47 mmol) in 1.0 mL of Et3N were added sequentially and the system was
briefly evacuated and filled with nitrogen three times after each addition. The tube was sealed by the
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replacement of the septum with the screw cap, heated to 70 °C and stirred at this temperature for 18 h.
After cooling down to room temperature, the reaction mixture was quenched with a 1:1 brine-H2O
mixture and the aqueous layer was extracted three times with Et2O. The combined organic extracts were
dried over MgSO4, filtered and concentrated in vacuo to afford a brown oil. Purification by flash
column chromatography (15% to 20% EtOAc in hexanes) gave 13 (175 mg, 94%) as a white solid. mp
9
10
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100-101 °C; H NMR (500 MHz, CDCl3): δ 7.79 (d, J = 2.0 Hz, 2H), 7.54 (dd, J = 8.5, 2.0 Hz, 2H),
7.24 (d, J = 8.5 Hz, 2H), 5.34 (s, 4H), 3.55 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 160.0, 130.7 (q, JC-F
= 3.8 Hz), 126.9 (q, JC-F = 3.8 Hz), 124.1 (q, JC-F = 33.8 Hz), 123.8 (q, JC-F = 270.0 Hz), 114.8, 114.0,
94.8, 89.4, 56.4; IR (film): 2966, 2913, 2834, 1615, 1511, 1441, 1349, 1312, 1271, 1246, 1205, 1129,
1086, 992, 828 cm-1; HRMS (ESI) Calcd for C20H16F6NaO4 (M+Na)+ : 457.0845, Found: 457.0844.
2,2'-(Ethyne-1,2-diyl)bis[4-(trifluoromethyl)phenol] (5): Compound 13 (121 mg, 0.28 mmol)
was dissolved in 3 mL MeOH and 2 mL CH2Cl2 and the resulting clear solution was treated with 0.3 mL
concentrated HCl. The reaction mixture was stirred at room temperature, under air for 22 h. It was then
quenched with water and the aqueous phase was extracted once with CH2Cl2 and twice with EtOAc.
The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford a
yellowish white solid. Purification by flash column chromatography (2% MeOH in CHCl3) gave 5 (80
1
mg, 83%) as a white solid. mp 172-174 °C; H NMR (500 MHz, CDCl3): δ 7.73 (d, J = 1.5 Hz, 2H),
7.56 (dd, J = 8.5, 2.0 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 6.29 (br s, 2H); 13C NMR (125 MHz, Acetone-
d6): δ 161.9, 130.8 (q, JC-F = 3.8 Hz), 128.3 (q, JC-F = 3.8 Hz), 123.2 (q, JC-F = 267.5 Hz), 122.5 (q, JC-F
= 32.5 Hz), 117.3, 111.7, 90.5; IR (film): 3341 (br), 1444, 1394, 1342, 1273, 1123, 1072, 900 cm-1;
HRMS (ESI) Calcd for C16H7F6O2 (M-H)- : 345.0356, Found: 345.0360.
1-(Methoxymethoxy)-2-(phenylethynyl)-4-(trifluoromethyl)benzene (14): Compound 11
(217 mg, 0.65 mmol) was dissolved in 3.0 mL of Et3N in a round-bottom flask under nitrogen.
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PdCl2(PPh3)2 (28 mg, 0.04 mmol), CuI (12 mg, 0.065 mmol) and phenylacetylene (108 µL, 0.98 mmol)
were added sequentially and the system was briefly evacuated and filled with nitrogen three times after
each addition. The reaction mixture was stirred at room temperature for 22 h and then quenched with
H2O. The aqueous layer was extracted three times with Et2O and the combined organic extracts were
dried over MgSO4, filtered and concentrated in vacuo to afford a brown oil. Purification by flash column
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chromatography (5% EtOAc in hexanes) gave 14 (185 mg, 93%) as a yellow oil. H NMR (500 MHz,
CDCl3): δ 7.77 (d, J = 2.5 Hz, 1H), 7.57-7.55 (m, 2H), 7.51 (dd, J = 8.5, 2.0 Hz, 1H), 7.37-7.35 (m,
3H), 7.22 (d, J = 9.0 Hz, 1H), 5.32 (s, 2H), 3.54 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 159.9, 131.7,
130.6 (q, JC-F = 3.8 Hz), 128.6, 128.5, 126.5 (q, JC-F = 3.8 Hz), 124.1 (q, JC-F = 32.5 Hz), 123.9 (q, JC-F
=
270.0 Hz), 123.0, 114.7, 114.3, 94.8, 94.5, 84.2, 56.4; IR (film): 2960, 2830, 2221, 1612, 1598, 1505,
1338, 1270, 1243, 1150, 1115, 1085, 984, 904, 825, 757 cm-1; HRMS (ESI) Calcd for C17H14F3O2
(M+H)+ : 307.0940, Found: 307.0942.
2-(Phenylethynyl)-4-(trifluoromethyl)phenol (6): To a solution of 14 (39 mg, 0.13 mmol) in 2
mL MeOH was added 0.1 mL concentrated HCl. The reaction mixture was stirred at room temperature,
under air for 5.5 h, quenched with water and the aqueous phase was extracted three times with CH2Cl2.
The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford a
brown oil. Purification by flash column chromatography (EtOAc:hexanes 1:9) gave 6 (25 mg, 74%) as a
white solid. mp 61-62 °C; 1H NMR (500 MHz, CDCl3): δ 7.70 (d, J = 2.0 Hz, 1H), 7.55-7.53 (m, 2H),
7.50 (dd, J = 8.5, 1.5 Hz, 1H), 7.40-7.37 (m, 3H), 7.06 (d, J = 9.0 Hz, 1H), 6.13 (s, 1H); 13C NMR (125
MHz, CDCl3): δ 158.9, 131.7, 129.3, 129.1 (q, JC-F = 3.8 Hz), 128.6, 127.4 (q, JC-F = 3.8 Hz), 123.9 (q,
JC-F = 270.0 Hz), 123.0 (q, JC-F = 32.5 Hz), 121.7, 115.2, 110.2, 97.5, 81.5; IR (film): 3317 (br), 2962,
2219, 1722, 1616, 1597, 1491, 1431, 1340, 1271, 1116, 905, 829, 757 cm-1; HRMS (ESI) Calcd for
C15H8F3O (M-H)- : 261.0533, Found: 261.0535.
2-iodo-1-methoxy-4-(trifluoromethyl)benzene
(15):
To
a
solution
of
p-
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(trifluoromethyl)anisole40 (500 mg, 2.84 mmol) in 15 mL of anhydrous THF was added slowly n-BuLi
(2.5 M solution in hexanes, 1.4 mL, 3.4 mmol) at -78 °C. The resulting solution was stirred at 0 °C for
45 min, cooled back to -78 °C and a solution of I2 in 6.0 mL of anhydrous THF was added dropwise.
The resulting mixture was allowed to warm to room temperature and stirred under nitrogen overnight. It
was then quenched with saturated Na2S2O3 solution and stirred until the color turned light yellow. The
aqueous phase was extracted three times with Et2O and the combined organic extracts were dried over
MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (2% EtOAc in
hexanes) gave 15 (403 mg, 47%) as a colorless oil.41 1H NMR (500 MHz, CDCl3): δ 8.02 (d, J = 2.0 Hz,
1H), 7.58 (dd, J = 8.5, 1.5 Hz, 1H), 6.86 (d, J = 9.0 Hz, 1H), 3.94 (s, 3H); 13C NMR (125 MHz, CDCl3):
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δ 160.6, 136.6 (q, JC-F = 3.8 Hz), 127.0 (q, JC-F = 3.8 Hz), 124.5 (q, JC-F = 33.8 Hz), 123.3 (q, JC-F
=
270.0 Hz), 110.2, 85.6, 56.6; IR (film): 3014, 2971, 2947, 2845, 1605, 1499, 1463, 1399, 1323, 1270,
1121, 1081, 1044, 896, 816, 666 cm-1; HRMS (APPI) Calcd for C8H6F3IO (M)+ : 301.9410, Found:
301.9407.
OMOM
CF3
F3C
MeO
27
1-methoxy-2-((2-(methoxymethoxy)-5-(trifluoromethyl)phenyl)ethynyl)-4-(trifluoromethyl)
benzene (27): Compound 15 (191 mg, 0.63 mmol) was dissolved in 1.5 mL of Et3N in a sealable tube
fitted with a septum, at room temperature, under nitrogen. PdCl2(PPh3)2 (18 mg, 0.025 mmol), CuI (8
mg, 0.042 mmol) and a solution of alkyne 12 (97 mg, 0.42 mmol) in 1.5 mL of Et3N were added
sequentially and the system was briefly evacuated and filled with nitrogen three times after each
addition. The tube was sealed by the replacement of the septum with the screw cap, heated to 70 °C and
stirred at this temperature for 16 h. After cooling down to room temperature, the reaction mixture was
quenched with a 1:1 brine-H2O mixture and the aqueous layer was extracted three times with Et2O. The
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combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford a
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brown oil. Flash column chromatography (10% to 20% EtOAc in hexanes) followed by recrystallization
9
1
from heptane gave 27 (114 mg, 67%) as white crystals. mp 88-89 °C; H NMR (500 MHz, CDCl3): δ
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7.80 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 8.5, 2.0 Hz, 1H), 7.54 (dd, J = 8.5, 2.0
Hz, 1H), 7.24 (d, J = 9.0 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 5.35 (s, 2H), 3.97 (s, 3H), 3.56 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ 162.2, 160.0, 130.8-130.6 (m, 2C), 127.1 (q, JC-F = 3.8 Hz), 126.8 (q, JC-F
=
3.8 Hz), 124.1 (q, JC-F = 33.8 Hz), 122.9 (q, JC-F = 33.8 Hz), 114.8, 114.0, 112.9, 110.6, 94.9, 89.42,
89.37, 56.5, 56.2; IR (film): 2958, 1613, 1509, 1340, 1331, 1267, 1121, 981, 820 cm-1; HRMS (ESI)
Calcd for C19H14F6NaO3 (M+Na)+ : 427.0739, Found: 427.0736.
2-((2-methoxy-5-(trifluoromethyl)phenyl)ethynyl)-4-(trifluoromethyl)phenol (7): To
a
solution of 27 (80 mg, 0.20 mmol) in 2 mL MeOH and 2 mL CH2Cl2 was added 0.3 mL concentrated
HCl. The reaction mixture was stirred at room temperature, under air for 20 h. It was then quenched
with water and the aqueous phase was extracted once with CH2Cl2 and twice with EtOAc. The
combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. Purification by
flash column chromatography (EtOAc:hexanes 1:4) gave 7 (67 mg, 94%) as a white solid. mp 85-86 °C;
1H NMR (500 MHz, CDCl3): δ 7.72 (d, J = 2.0 Hz, 1H), 7.66 (s, 1H), 7.61 (dd, J = 8.5, 2.0 Hz, 1H),
7.52 (dd, J = 8.5, 2.0 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H), 7.07 (s, 1H), 7.02 (d, J = 9.0 Hz, 1H), 4.03 (s,
1
3H); H NMR (500 MHz, CD3OD)42: δ 7.80 (d, J = 2.0 Hz, 1H), 7.66-7.64 (m, 2H), 7.50 (dd, J = 8.5,
13
2.0 Hz, 1H), 7.21 (d, J = 9.0 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 4.00 (s, 3H); C NMR (125 MHz,
CDCl3): δ 161.7, 159.8, 128.8 (q, JC-F = 3.8 Hz), 127.7 (q, JC-F = 3.8 Hz), 127.6-127.4 (m, 2C), 123.5 (q,
JC-F = 33.8 Hz), 122.8 (q, JC-F = 33.8 Hz), 115.0, 112.0, 110.4, 109.8, 93.0, 86.6, 56.4; IR (film): 3416
(br), 1612, 1504, 1456, 1330, 1267, 1118, 1023, 930, 818 cm-1; HRMS (APPI) Calcd for C17H10F6O2
(M)+ : 360.0580, Found: 360.0574.
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OMOM
MOMO
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F3C
CF3
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1,4-bis(2-(methoxymethoxy)-5-(trifluoromethyl)phenyl)buta-1,3-diyne (28): The following
procedure was adapted from the work of Wuest and co-workers.15b To a suspension of CuCl (116 mg,
1.17 mmol) in 2.0 mL of anhydrous acetone was added TMEDA (65 µL, 0.43 mmol) and the resulting
mixture was stirred at room temperature, under nitrogen for 1 h. In a separate flask, alkyne 12 (100 mg,
0.43 mmol) was dissolved in 4.0 mL of anhydrous acetone under an atmosphere of oxygen. The CuCl
suspension was filtered and the filtrate was added onto the alkyne solution. The resulting mixture was
heated to 60 °C and stirred under oxygen for 45 min. The reaction mixture was then cooled to room
temperature and quenched with H2O (10 mL). The aqueous phase was extracted with Et2O (3x20 mL)
and the combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo.
Purification by flash column chromatography (EtOAc:hexanes 1:9 to 1:4) gave 28 (86 mg, 86%) as a
white solid. mp 104-105 °C; 1H NMR (500 MHz, CDCl3): δ 7.77 (d, J = 1.5 Hz, 2H), 7.55 (dd, J = 9.0,
1.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 5.32 (s, 4H), 3.54 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 161.3,
131.5 (q, JC-F = 3.8 Hz), 127.6 (q, JC-F = 2.5 Hz), 124.1 (q, JC-F = 33.8 Hz), 123.6 (q, JC-F = 270.0 Hz),
114.6, 112.6, 94.7, 78.5, 77.5, 56.5; IR (film): 3009, 2977, 1611, 1503, 1320, 1272, 1251, 1158, 1132,
1080, 923, 887 cm-1; HRMS (ESI) Calcd for C22H16F6NaO4 (M+Na)+ : 481.0845, Found: 481.0842.
2,2'-(buta-1,3-diyne-1,4-diyl)bis(4-(trifluoromethyl)phenol) (8): Compound 28 (44 mg, 0.095
mmol) was dissolved in 2 mL MeOH and 1 mL CH2Cl2 and the resulting clear solution was treated with
0.2 mL concentrated HCl. The reaction mixture was stirred at room temperature, under air for 24 h, at
which time additional concentrated HCl solution (0.1 mL) was added. At the end of 31 h, it was
quenched with water and the aqueous phase was extracted once with CH2Cl2 and twice with EtOAc.
The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. Purification
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by flash column chromatography (EtOAc:hexanes 1:2) gave 8 (35 mg, 98%) as a white solid. mp 139-
141 °C; 1H NMR (500 MHz, CDCl3): δ 7.71 (d, J = 1.0 Hz, 2H), 7.56 (dd, J = 8.5, 2.0 Hz, 2H), 7.07 (d,
5
6
7
8
9
J = 9.0 Hz, 2H), 6.08 (br s, 2H); 13C NMR (125 MHz, CDCl3): δ 160.5, 130.4 (q, JC-F = 3.8 Hz), 128.8
(q, JC-F = 3.8 Hz), 123.6 (q, JC-F = 270.0 Hz), 123.5 (q, JC-F = 33.8 Hz), 115.9, 108.3, 80.3, 76.7; IR
(film): 3321 (br), 1614, 1501, 1333, 1280, 1162, 1126, 1075, 902 cm-1; HRMS (APPI) Calcd for
C18H8F6O2 (M)+ : 370.0423, Found: 370.0420.
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OH
I
CF3
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2-Iodo-5-(trifluoromethyl)phenol (29): To a solution of 3-(trifluoromethyl)phenol (20) (1.22 g,
7.55 mmol) in 8 mL of THF were added H2O (8 mL), Na2CO3.H2O (1.12 g, 9.0 mmol) and I2 (2.3 g,
9.06 mmol) sequentially. The resulting brown mixture was stirred for two days at room temperature,
covered with an aluminum foil. The mixture was then quenched with a 1:1 mixture of saturated Na2S2O3
and NH4Cl solutions and the aqueous phase was extracted three times with Et2O. The combined organic
extracts were dried over MgSO4, filtered and concentrated in vacuo to afford a light yellow oil.
Purification by flash column chromatography (EtOAc:hexanes 1:7) gave 29 (640 mg, 29%) as a white
solid. mp 48-49 °C; 1H NMR (500 MHz, CDCl3): δ 7.79 (dd, J = 8.5, 0.5 Hz, 1H), 7.23 (d, J = 1.5 Hz,
13
1H), 6.94 (ddd, J = 8.0, 1.5, 0.5 Hz, 1H), 5.48 (s, 1H); C NMR (125 MHz, CDCl3): δ 155.2, 138.9,
132.8 (q, JC-F = 33.8 Hz), 123.4 (q, JC-F = 271.3 Hz), 118.8 (q, JC-F = 3.8 Hz), 112.0 (q, JC-F = 3.8 Hz),
89.8; IR (film): 3483 (br), 1436, 1418, 1333, 1277, 1172, 1128, 1074, 913 cm-1; HRMS (ESI) Calcd for
C7H3F3IO (M-H)- : 286.9186, Found: 286.9190.
1-Iodo-2-(methoxymethoxy)-4-(trifluoromethyl)benzene (16): To a solution of 29 (458 mg,
1.59 mmol) in 10 mL of anhydrous CH2Cl2 were added N,N-diisopropylethylamine (554 µL, 3.18
mmol) and MOMCl (181 µL, 2.38 mmol) sequentially at room temperature, under nitrogen. The
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resulting clear solution was stirred for 17 h and quenched with saturated NaHCO3 solution. The aqueous
layer was extracted three times with CH2Cl2 and the combined organic extracts were dried over over
MgSO4, filtered and concentrated in vacuo to afford a yellow oil. Purification by flash column
chromatography (3% EtOAc in hexanes) gave 16 (398 mg, 75%) as a colorless oil. 1H NMR (500 MHz,
CDCl3): δ 7.89 (d, J = 8.5 Hz, 1H), 7.29 (s, 1H), 7.01 (d, J = 8.0 Hz, 1H), 5.28 (s, 2H), 3.52 (s, 3H); 13C
5
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NMR (125 MHz, CDCl3): δ 156.4, 140.0, 132.0 (q, JC-F = 32.5 Hz), 123.6 (q, JC-F = 270.0 Hz), 120.0 (q,
JC-F = 3.8 Hz), 111.2 (q, JC-F = 3.8 Hz), 95.1, 91.5, 56.6; IR (film): 2960, 2913, 2834, 1596, 1581, 1481,
1427, 1388, 1328, 1159, 1132, 1082, 987, 923, 880, 818, 740 cm-1; HRMS (ESI) Calcd for
C9H8F3IO2Na (M+Na)+ : 354.9413, Found: 354.9413.
1-Ethynyl-2-(methoxymethoxy)-4-(trifluoromethyl)benzene (17): Compound 16 (222 mg,
0.67 mmol) was dissolved in 2.5 mL of Et3N in a sealable tube fitted with a septum, at room
temperature, under nitrogen. PdCl2(PPh3)2 (28 mg, 0.040 mmol), CuI (13 mg, 0.067 mmol) and
ethynyltrimethylsilane (278 µL, 2.0 mmol) were added sequentially and the system was briefly
evacuated and filled with nitrogen three times after each addition. The tube was sealed by the
replacement of the septum with the screw cap, heated to 80 °C and stirred at this temperature for 20 h.
After cooling down to room temperature, the reaction mixture was quenched with a 1:1 brine-H2O
mixture and the aqueous layer was extracted three times with Et2O. The combined organic extracts were
dried over MgSO4, filtered and concentrated to afford a brown oil. This crude oil was dissolved in 5 mL
of anhydrous THF under nitrogen and cooled to 0 °C. TBAF (1.0 M solution in THF, 1.34 mL, 1.34
mmol) was added slowly and the reaction mixture was stirred for 30 min. The mixture was then
quenched with H2O and diluted with Et2O. The two phases were partitioned in a separatory funnel and
the organic phase was washed once with brine, dried over MgSO4, filtered and concentrated to afford a
brown oil. Purification by flash column chromatography (4% EtOAc in hexanes) gave 17 (99 mg, 64%
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over 2 steps) as a colorless oil. H NMR (500 MHz, CDCl3): δ 7.56 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H),
7.23 (d, J = 8.0 Hz, 1H), 5.30 (s, 2H), 3.53 (s, 3H), 3.39 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 158.5,
134.4, 131.8 (q, JC-F = 32.5 Hz), 123.5 (q, JC-F = 271.3 Hz), 118.4 (q, JC-F = 3.8 Hz), 116.2, 111.8 (q, JC-
6
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= 3.8 Hz), 95.0, 83.2, 78.7, 56.4; IR (film): 3296, 2963, 2916, 2832, 2113, 1614, 1575, 1505, 1431,
F
1393, 1328, 1238, 1158, 1121, 1085, 990, 830, 739 cm-1; HRMS (ESI) Calcd for C11H10F3O2 (M+H)+ :
231.0627, Found: 231.0626.
1,2-Bis[2-(methoxymethoxy)-4-(trifluoromethyl)phenyl]ethyne (18): Compound 16 (138 mg,
0.42 mmol) was dissolved in 1.0 mL of Et3N in a sealable tube fitted with a septum at room
temperature, under nitrogen. PdCl2(PPh3)2 (12 mg, 0.017 mmol), CuI (5.5 mg, 0.029 mmol) and a
solution of alkyne 17 (67 mg, 0.29 mmol) in 1.0 mL of Et3N were added sequentially and the system
was briefly evacuated and filled with nitrogen three times after each addition. The tube was sealed by
the replacement of the septum with the screw cap, heated to 70 °C and stirred at this temperature for 21
h. After cooling down to room temperature, the reaction mixture was quenched with a 1:1 brine-H2O
mixture and the aqueous layer was extracted three times with Et2O. The combined organic extracts were
dried over MgSO4, filtered and concentrated in vacuo to afford a brown solid. Purification by flash
column chromatography (5% to 10% EtOAc in hexanes) gave 18 (125 mg, 99%) as a white solid. mp
1
88-89 °C; H NMR (500 MHz, CDCl3): δ 7.62 (d, J = 8.0 Hz, 2H), 7.40 (s, 2H), 7.27 (d, J = 8.0 Hz,
2H), 5.33 (s, 4H), 3.56 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 157.9, 133.8, 131.7 (q, JC-F = 32.5 Hz),
123.6 (q, JC-F = 271.3 Hz), 118.5 (q, JC-F = 3.8 Hz), 117.3, 112.2 (q, JC-F = 3.8 Hz), 95.2, 90.4, 56.5; IR
(film): 3080, 2965, 2916, 2832, 1614, 1574, 1519, 1431, 1328, 1229, 1160, 1125, 1080, 981, 912, 825,
739 cm-1; HRMS (ESI) Calcd for C20H16F6NaO4 (M+Na)+ : 457.0845, Found: 457.0844.
6,6'-(Ethyne-1,2-diyl)bis[3-(trifluoromethyl)phenol] (9): Compound 18 (75 mg, 0.17 mmol)
was dissolved in 2 mL MeOH and 1 mL CH2Cl2 and the resulting clear solution was treated with 0.2 mL
concentrated HCl. The reaction mixture was stirred at room temperature, under air for 8.5 h. It was then
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