Gold-Catalyzed Highly Chemo- and Regioselective C-H Bond Functionalization of Phenols with Haloalkynes

Article abstract of DOI:10.1002/ejoc.201900653

A highly chemo- and stereoselective addition of unprotected phenols to haloalkynes was developed. A ligand and counterion controlled process enabled the highly site-selective and chemoselective C-H bond functionalization of phenol derivatives with haloalkynes in moderate to excellent yield at room temperature. The simple availability of the starting materials in combination with the preferred para-C-H functionalization over a competing O-H insertion makes this an attractive protocol. The stereoselectivity of the products depends on the choice of the catalyst. From a synthetic prospective, this method offers an efficient route towards vinyl chlorides, which are valuable precursors for the synthesis of pharmaceutical drugs.

Full text of DOI:10.1002/ejoc.201900653

A Journal of
Accepted Article
Title: Gold-Catalysed Highly Chemo- and Regioselective C-H Bond
Functionalization of Phenols with Haloalkynes
Authors: Tapas Adak, Jürgen Schulmeister, Martin C. Dietl, Matthias
Rudolph, Frank Rominger, and A. Stephen K. Hashmi
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900653
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900653
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201900653
Gold-Catalysed Highly Chemo- and Regioselective C-H Bond Functionalization
of Phenols with Haloalkynes
a
a
a
M.Sc. Tapas Adak, M.Sc. Jürgen Schulmeister, B.Sc. Martin Dietl, Dr. Matthias
a
a
.a,b
Rudolph, Dr. Frank Rominger, Prof. Dr. A. Stephen K. Hashmi*
aOrganisch-Chemisches Institut, Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
E-mail:hashmi@hashmi.de
Homepage: http://www.hashmi.de
bChemistry Department, Faculty of Science
King Abdulaziz University
Jeddah 21589 (Saudi Arabia)
Abstract: A highly chemo- and stereoselective addition of unprotected phenols to
haloalkynes was developed. A ligand and counter ion controlled process enabled the
highly site-selective and chemoselective C-H bond functionalization of phenol
derivatives with haloalkynes in moderate to excellent yield at room temperature. The
simple availability of the starting materials in combination with the preferred para-C-H
functionalization over a competing O-H insertion makes this an attractive protocol. The
stereo-selectivity of the products depends on the choice of the catalyst. From a
synthetic prospective, this method offers an efficient route towards β-haloalkenes
which are valuable precursor for the synthesis of pharmaceutical drugs.
Keywords: addition reactions, alkynes, diastereoselectivity, gold, vinyl halides
Introduction
The development of new synthetic strategies by employing simple and readily
accessible starting materials under mild conditions (e.g. at room temperature) has
great impact on organic chemistry. In this regard gold catalysis has proven to be a
suitable tool for the design and development of new and valuable chemical
[
1]
transformations.
Chemo- and site-selective catalytic transformations are an
[
2]
interesting topic in synthetic chemistry. Here we report the direct chemo- and site-
selective C-H functionalization of unprotected phenols with haloalkynes by using the
readily available cationic IPr-gold(I) complex at room temperature.
[3]
Aryl-substituted alkenes bearing phenol substituents are versatile intermediates in
organic synthesis and important structural motifs in natural products and
[
4]
pharmaceuticals. Drugs that contain such a structural motif are for example
Isocombrestatine A, Bexarotene, Panomifene, Tamoxifen and Ratanhine (Scheme 1).
Moreover, Diarylethenes are present in photo-responsive molecular switch-machines
[
5]
and medicines. Chloroalkenes as synthetic intermediates are very important
synthons due to the presence of an easy transformable synthetic handle. For
examples, chloroalkenes have been exploited as key building blocks for natural
[
6]
products such as a Pan-Bcl-2-Inhibitor (Scheme 1) and Hartellines. Therefore a site-
selective direct C-C coupling of phenols is of high interest.
1
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European Journal of Organic Chemistry
10.1002/ejoc.201900653
Scheme 1. Drugs and natural compounds containing aryl olefins
In the past decade, many indirect methodologies for the C-C coupling of phenols have
[
7]
been developed, these are based on introduction of directing groups. Nevertheless,
the improvement of a direct C-C coupling of unprotected phenols would significantly
enhance the synthetic potential. Recently, Bedford investigated a Rh-catalysed direct
ortho-selective C-H arylation of phenols by using catalytic amounts of phosphite as
[
8]
traceless directing group. Dong and co-workers reported a Pd-catalysed ortho
[
9]
arylation of phenols by using carbamate as directing group. Another pioneering work
by Larrosa includes a palladium-catalysed meta-selective C-H arylation of phenols by
[
10]
using carbon dioxide as traceless relay directing group.
Zhang developed a
and Shi’s groups
[
11]
[12]
[13]
B(C
6
F
5
)
3
-catalyzed ortho-alkylation.
Very recently, Zhang’s
developed a gold-catalysed site-selective C-H functionalization of phenols with highly
reactive gold carbenes derived from aryl diazo-acetate precursors. The C-O coupling
of chloroalkynes and phenols under basic conditions has been reported by many
[
14]
groups (Scheme 2a).
However the direct C-H arylation of phenols with an
electrophile is quite challenging because of a competitive O-H bond insertion in the
[
15]
presence of various transition metal like Pd, Cu, Rh, Fe, Ir (Scheme 2b). Recently,
Nolan’s group also reported a gold-catalysed C-O coupling of phenols and alkyne
[
16]
(Scheme 2b).
Herein we present the site-selective para-addition of phenols to
[
17]
chloroalkynes (Scheme 2c). Because of the carbophilic -acidic nature
appeared promising the for a site-selective C-C coupling of haloalkynes and phenols.
gold
2
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European Journal of Organic Chemistry
10.1002/ejoc.201900653
Scheme 2. Different reactivity modes for alkynes and phenols
Results and discussion
We started our investigation by exploring the reactivity of (chloroethynyl)benzene (1a)
with phenol (2a) at room temperature as a model reaction. We were pleased to
observe 46% yield of the para-addition product in a 3:5 (E:Z)-ratio in the presence of
IPrAuCl (5 mol%) and AgNTf
IPrAuCl to PPh AuCl, the yield of the reaction increased to 53% in a 9:10 (E:Z)-ratio
entry 2). A switch to bulkier ligands, improved the yield but not the (E:Z)-ratio in the
2
(10 mol%) after 16 h in DCM (entry 1). By changing
3
(
[
18]
-
case of AgNTf as co-catalyst. By changing the counter ion to BARF in combination
2
with IPr as ligand we were not only obtained 74% NMR yield (entry 4), but at the same
time achieved a perfect diastereoselectivity at room temperature. From a brief
-
screening of other ligands with BARF , we concluded that IPr was the best ligand for
our protocol. A screening of solvent revealed that DCE (78% yield, entry 5) was more
effective than DCM. Other polar solvents like acetonitrile, nitromethane (entries 7 and
8
) were less effective. It is also noteworthy that in the presence of NaBARF as co-
catalyst we were able to isolated a minor amount of C-O coupled product 4a (entry 4),
whereas in the presence of AgNTf only a trace amount of C-O coupled product was
2
observed at room temperature. We only isolated 77% acetate coupled product in
presence of JohnPhosAuCl and acetic acid as solvent (entry 12) at 60 °C. Neither in
the presence of NaBARF alone nor with only MsOH the reaction proceeded under
these conditions (entries 13 and 14).
Table 1. Reaction Optimization
3
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European Journal of Organic Chemistry
10.1002/ejoc.201900653
Entry
Catalyst
Solvent
Time (h)
Yield (%)a
3
a (E:Z)b
46 (3:5)
4ab
1
2
3
IPrAuCl (5 mol%)
AgNTf (10 mol%)
PPh AuCl (5 mol%)
AgNTf (10 mol%)
JohnPhosAuCl (10
mol%)
DCM
DCM
DCM
16
16
16
trace
2
3
53 (9:10) trace
2
49 (3:7)
trace
AgNTf (10 mol%)
2
4
5
IPrAuCl (5 mol%)
NaBARF (10 mol%)
IPrAuCl (5 mol%)
NaBARF (10 mol%)
IPrAuCl (2 mol%)
NaBARF (3 mol%)
JohnPhosAuCl (5
mol%)
DCM
DCE
DCE
DCE
3
3
74
(>99% Z)
10
9
78
(>99% Z)
83 (79),
(>99% Z)
37
6c
7
3
9
24
ND
NaBARF (10 mol%)
8
PPh
3
AuCl (5 mol%)
DCE
24
24
24
24
24
trace
ND
ND
ND
ND
NaBARF (10 mol%)
IPrAuCl (5 mol%)
NaBARF (10 mol%)
IPrAuCl (5 mol%)
NaBARF (10 mol%)
JohnPhosAuCl (5
mol%)
1
0
1
CH
3
CN
-
-
-
1
CH
3
NO
2
1
2d
ACOH
13
NaBARF (10 mol%)
MSOH (10 mol%)
DCE
DCE
-
-
ND
ND
14
Reaction Conditions: 0.2 mmol (1a), 0.24 mmol (2a) in 1 mL solvent at room
a
temperature. NMR yield using benzaldehyde as internal standard. Numbers in
b
1
parentheses are isolated yields. Calculated from the H NMR of the crude reaction
c
d
o
mixture. 1.2 equiv of 1a. Reaction carried out at 60 C
We must stress that under most of the other conditions an (E/Z)-mixture of the product
was formed. This even applies to the Brettphos ligand, which in our hands provided a
1
:1 mixture of diastereomers (Figure 1). Thus our results do not confirm the findings
[
3]
reported in the recent literature.
4
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European Journal of Organic Chemistry
10.1002/ejoc.201900653
Figure 1. Comparison of the pure diasteromer (Z)-3a obtained by the optimized
condition with the IPrAuBARF catalyst (top, blue) and the 1:1 mixture of the
diastereomeric (E/Z)-mixture obtained with BrettPHOSAuBARF (bottom, red).
After recognizing this, we had to explore a possible subsequent but undesired
rearrangement of the pure (Z)-3a obtained under our reaction conditions. Figure 2
(
bottom) shows (Z)-3a at room temperature with 2 mol% of our catalyst in CD
even after 12 h at room temperature (i.e. exactly the conditions for the synthesis of
Z)-3a) no isomerization to (E)-3a was observed. Finally, to be on the safe side, we
2
Cl
2
,
(
heated this reaction mixture in a sealed NMR tube to 50°C for 4 h (i.e. the conditions
used in the literature for the BrettPhosAuCl/NaBARF system), only traces of the (E)-
diastereomer were detected.
5
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European Journal of Organic Chemistry
10.1002/ejoc.201900653
Figure 2. (Z)-3a with additional signals from 2 mol% IPrAuCl/ 4 mol% NaBARF in
CD Cl at RT: a) after 1 min (bottom); b) after 12 h (middle); c) at 50° C after 4 h.
2
2
Then we studied the reaction with the BrettPhosAuCl/NaBARF system in order to see
whether also pure (Z)-3a is formed initially, but subsequently is rearranged to the
observed (Z)/(E) mixture. The spectra show that even after 10 minutes when the
conversion is not complete (E)-3a is already present ((Z)/(E) = 3:1). This stays the
same until after 30 minutes the consumption of the starting materials is complete, then
over the next hour a complete equilibration to (Z)/(E) = 1:0.93 is achieved, which does
not change any more even after 2 h. This equilibrium ratio is in accord with our
computations (vide infra). This experiment clearly demonstrates, that with the known
BrettPhosAuCl/NaBARF system even at low conversion of the starting materials no
pure diastereomers can be obtained.
6
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European Journal of Organic Chemistry
10.1002/ejoc.201900653
starting material is consumed
product being formed
2
h
1.5 h
1
h
3
0 min
0 min
2
1
0 min
min
1
Figure 3. Conversion of (Z)-3a with 2 mol% BrettPhosAuCl / 4 mol% NaBARF in
CD Cl at 40°C followed by time from 1 min to 2 h.
2
2
With the optimal reaction conditions in hand, we investigated the scope of the gold-
catalysed ortho/para selective C-H bond functionalization of chloroalkyne 1a with
varying phenols derivatives (Scheme 2). In a first series of ortho-substituted phenols,
alkyl (3b, 3c), methoxy (3d), allyl (3e) and aryl (3f) groups all delivered exclusively the
para-addition products in good yields and with only one diastereomer (the one shown
in Table 2). An additional substituent in meta-position was equally efficient (3g). In the
case of only meta-substituted phenols, mixtures of ortho- and para-addition products
were observed and yields were lower (3h, 3i). 1,2-Dimethlyphenol delivered a better
yield but also in low selectivity (3j). As expected a very efficient reaction (96% yield)
was observed for 2,6-dimethylphenol (3k). Interestingly, 3,5-dimethlylphenol delivered
only the para-addition product (3l). Catechol delivered an excellent yield of the
para/meta product (3m). In a series of phenols with blocked para-position always
ortho-addition at the sterically less hindered position was observed in yields ranging
from 65%-98% (3n-3t).
Table 2. Scope with respect to the phenols
7
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10.1002/ejoc.201900653
Cl
Cl
Cl
Cl
tBu
OH
OMe
OH
OH
OH
3a (79%)
3b (84%)
3c (86%)
3d (93%)
Cl
Cl
Cl
Ph
OH
OH
OH
3f (77%)
3g
3e (68%)
(
73%)
Cl
Cl
Cl
OH
OMe
Cl
OH
OH
OH
3h (51%)
OMe
3
h' (35%)
3i (32%)
3i' (59%)
Cl
Cl
Cl
OH
Cl
OH
OH
OH
3
j' (32%)
3j (60%)
3k (96%)
3l (78%)
Cl
Cl
Cl
Cl
OH
OH
OH
OH
OH
OMe
3o (80%)
Ph
3m (98%)
3n (73%)
3
p (77%)
Cl
Cl
OH
Cl
Cl
OH
OH
OH
O
OMe
OMe
3q (89%)
3r (98%)
3s (77%)
3t (65%)
General reaction conditions: 1a (0.24 mmol), phenol (0.2 mmol), IPrAuCl (2 mol%),
NaBARF (3 mol%) in 1 mL DCE at room temperature for 3-6 hours. Isolated yields
are reported.
The scope with respect to the chloroalkynes was also investigated (Table 3). The
substitution of the phenyl group of chloroalkyne 1a has only a slight effect on the yield
and selectivity of the reaction. Both electron-withdrawing and donating substituents at
the chloroalkyne reacted smoothly with phenol (2a) to give the desired products (Table
3
, entries 5a-o) in good to excellent yields (49-94%). The reaction well tolerated
functional groups including ester (5j), methoxy (5e), trifluoromethyl (5i) and halogens
5c, 5f, 5g, 5h). Electron-deficient substituents at the phenyl ring of the chloroalkyne
(
showed better results (5f-i) than electron-rich phenyl rings (5a-b, 5d-e) and our
protocol also well tolerates ortho- and meta-substituents at the arene ring attached to
8
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European Journal of Organic Chemistry
10.1002/ejoc.201900653
the alkyne (5b-c, 5n). Finally, it is noteworthy that chloroalkynes showed better
reactivity than bromo alkynes (5o), which can be attributed to the higher
electronegativity. The corresponding iodo alkyne did not react any more.
Table 3. Scope with respect to the haloalkynes
Cl
Cl
Cl
OH
OH
F
5
OH
5a (61%)
5b (68%)
c (62%)
Cl
Cl
Cl
OH
MeO
OH
5d (74%)
F
OH
5e (54%)
5f (82%)
Cl
Cl
Cl
Cl
OH
Br
OH
F3C
OH
5g (85%)
5h (92%)
5i (68%)
Cl
Cl
Cl
MeOOC
OH
MeO
OH
OH
5j (62%)
5k (59%)
5l (92%)
Cl
Br
Cl
F3C
OH
OH
Ph
OH
CF3
5o (49%)
5m (94%)
5n (63%)
General reaction conditions: Chloroalkyne (0.24 mmol), 2a (0.2 mmol), IPrAuCl (2
mol%), NaBARF (3 mol%) in 1 mL DCE at room temperature for 3-12 hours. Isolated
yields are reported.
A gram-scale reaction of chlorophenyl acetylene 1a (820 mg, 6 mmol) and phenol 2a
(471 mg, 5 mmol ) was carried out with 2 mol% of gold catalyst and 3 mol% of
NaBARF, furnishing 819 mg (71%) of the desired product 3a (Scheme 3).
Scheme 3. Gram-scale synthesis
Table 4. Preliminary mechanistic study
9
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European Journal of Organic Chemistry
10.1002/ejoc.201900653
a) Kinetic study
(
D)H
Cl
OD
H(D)
H(D)
OH
D
D
D
D
1a
H(D)
OH
Standard conditions
(D)H
D
k /k = 1
H D
50% H
2
a (2 equiv)
b) H/D exchange reaction
>99% H)
2
a- d (2 equiv)
6
(
(>65% D)
Cl
Cl
IPrAuCl
NaBARF
IPrAuCl
NaBARF
D
D
D
1
a
C H OH
C5D5OD
DCM, RT
OH
6 5
CD Cl , RT
2
2
D
OH
D O (1 equiv)
2
IPrAuCl
NaBARF
C D OH
IPrAuCl
NaBARF
RT
IPrAuCl
NaBARF
5
5
DCM
RT
PhOD
DCM
RT
(>99% H)
(>98% H)
Cl
(54% D)
Cl
Cl
D
D
OD
OH
D
OH
D
To gain mechanistic insight, several control experiments were carried out (Table 4).
The observed ortho/para and (E/Z)-selectivity was confirmed by 2D NMR spectra (for
details see supporting information) and by the results of the X-ray single crystal
[
19]
structure analysis (Figure 4).
Figure 4. Solid state molecular structure of 5m
In a preliminary competitive kinetic study no kinetic isotope effect was observed (Table
4a, for details see Supporting Information), revealing that the C-H bond cleavage of
phenol is not involved in the rate determining step. Therefore a CH activation of the
phenol by the gold is unlikely and the reaction should proceed via the nucleophilic
addition of the phenol onto the -activated alkyne. A series of experiments with
deuterated starting materials and solvents revealed that no direct transfer of the proton
released from the Wheland complex takes place instead exchange processes with
either the acidic phenol group or traces of water in the reaction media take place.
Based on the results we propose that the gold directly coordinates to the chloro
1
0
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European Journal of Organic Chemistry
10.1002/ejoc.201900653
substituted alkyne carbon which leads to the more stable -activated alkyne A/vinyl
cation B. Then the phenol attacks the highly electrophilic alkyne. The addition of a
neutral phenol is only possible because of the acceptor substitution of the alkyne.
Other known additions with gold use phenolates which to the higher nucleophilicity of
[
17]
the oxygen leads to the O-addition products. In line with that less electron-deficient
bromoalkynes delivered poorer results. The observed para-selectivity should result
from both steric and electrostatic repulsion between the polarised alkyne and the OH-
moiety. Only if this favoured position is blocked selective ortho-coupling is feasible.
Ar
Cl
LAu+
Cl
LAu+
Carbocationic nature
Cl
AuL
3a
Ar
Ar
A
B
PhOH
HO
Cl
H
[Au]
Ar
Scheme 4. Plausible reaction mechanism
Both ortho- and para-coupled products can serve as versatile intermediates towards
bioactive compound or natural products. For example, the ortho-coupling procedure
was efficiently used for the late-stage modification of estrone 5 (Scheme 5) to
benzofuran 7 in 70% yield. The vinyl chloride subunit of 3a also proved to be a useful
synthetic precursor for a Suzuki coupling and coupling product 8 was obtained in
excellent yield (88%). Furthermore, a variant of this method was also applicable to a
one pot synthesis of 2-chlorovinyl furan derivative 10 in an excellent yield (86%)
without further optimisation. In this process the intramolecular OH addition to the
alkyne takes place first and then the addition of the benzofuran unit onto the
chloroalkyne terminates the cascade.
1
1
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European Journal of Organic Chemistry
10.1002/ejoc.201900653
Scheme 5. Demonstrating synthetic utility
Overall four isomers of the addition product could be formed, namely the two
diastereomers of the C-C coupling ((Z)-3a and (E)-3a) and the two diastereomers of
the C-O coupling ((Z)-4a and (E)-4a, constitutional isomers of the diastereomers of
3a). We conducted a small computational study of the relative energies of these four
species (Figure 5). The results clearly indicate that the C-C coupling provides the more
stable products; (Z)-3a and (E)-3a are about 34 kcal/mol lower in energy than (Z)-4a
and even about 44 kJ/mol lower than (E)-4a. Between the two diastereoisomers (Z)-
4a and (E)-4a the unvavorable interaction of two -donor substituents located trans at
the double bond is most pronounced, leading to an energy difference of 10 kJ/mol. In
the diastereomeric pair (Z)-3a and (E)-3a the much larger distance of the donor atoms
leads to a smaller difference in energy for this pair of diastereomers. The small energy
difference of only 0.4 kJ/mol for (Z)-3a and (E)-3a is smaller than the error of the
computation, based on this data the two diastereomers of 3a energetically are
equivalent, which fully confirms the equilibration to a 1:0.93 mixture discussed for
Figure 3. The computations also make clear that an attack at the ortho-position with
respect to the phenolic hydroxyl group, which would lead to (Z)-11a and (Z)-11a,
expectedly would provide products 7-10 kJ/mol higher in energy than the observed
products.
1
2
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European Journal of Organic Chemistry
10.1002/ejoc.201900653
B3LYP/cc-pVTZ
all energies given in kJ/mol
Cl
Cl
Cl
O
OH
H = 0
G = 0
reference)
H = +33.9
G = +34.1
H = +6.8
G = +6.9
(
OH
(
Z)-3a
(Z)-4a
(Z)-11a
Cl
Cl
Cl
OH
H = +44.5
G = +43.8
O
H = +10.1
G = +9.5
H = +0.4
G = +0.1
OH
(
E)-4a
(
E)-3a
(E)-11a
Figure 5. Relative energies of the four isomers which can be expected (B3LYP/cc-
pVTZ; all energies given in kJ/mol)
Conclusion
In summary we developed a straightforward gold-catalysed intermolecular C-addition
of phenols to haloalkynes in good to excellent regio-selectivity and diastereoselectivity.
Noteworthy, no competing OH-additions were observed which can be attributed to the
base-free conditions that are enabled by the high electrophilicity of the applied
alkynes. The features of this reaction include mild conditions, good substrate scope
and easy available starting materials. The obtained products are of high value as
synthetic intermediates for organic chemists. As demonstrated even late stage
modifications of bio-active molecules are feasible.
Experimental Section
General procedure for the gold-catalysed synthesis of chlorovinyl derivatives
In a dried schlenk tube IPrAuCl (2 mol %), NaBARF (3 mol %) was stirred for 5 min.
in DCE (0.2 mL) and chloroalkyne (0.24 mmol, 1.2 equiv) was added under a nitrogen
atmosphere at room temperature. Finally, phenol (0.2 mmol, 1.0 equiv) was added to
reaction mixture and stirred for 3 hours at room temperature. After completion, the
mixture was passed through a short silica gel and then concentrated under reduced
pressure reaction mixture and the residue was purified by silica gel flash column
chromatography using petroleum ether and ethyl acetate as eluent to give the desired
product.
Acknowledgement: T.A. thanks to DAAD for a scholarship. We thank Umicore AG &
CO. KG for the generous donation of gold.
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European Journal of Organic Chemistry
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TOC Entry
TOC Text
Two simple building blocks in an easy-to-conduct gold catalysed reaction provide
diastereomerically pure trisubstituted alkenes.
Key Topic
Selective gold catalysis
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