Sequential O-H/C-H bond insertion of phenols initiated by the gold(I)-catalyzed cyclization of 1-bromo-1,5-enynes

Article abstract of DOI:10.1021/acs.orglett.5b00738

The development of a sequential O-H/C-H bond functionalization of phenols initiated by the cationic gold(I)-catalyzed cyclization of 1-bromo-1,5-enynes to produce (2-bromocyclopent-2-en-1-yl)phenols is reported. This unprecedented domino transformation efficiently proceeds under mild conditions (5 mol % of (t-Bu)₃PAuNTf₂, CH₂Cl₂, 0-23 °C) via an intermediate aryl alkyl ether which collapses at ambient temperature to undergo a 1,2-hydride shift followed by C-H insertion of the phenol.

Full text of DOI:10.1021/acs.orglett.5b00738

Letter
pubs.acs.org/OrgLett
Sequential O−H/C−H Bond Insertion of Phenols Initiated by the
Gold(I)-Catalyzed Cyclization of 1‑Bromo-1,5-enynes
Klaus Speck, Konstantin Karaghiosoff, and Thomas Magauer*
Department of Chemistry and Pharmacy, Ludwig-Maximilians-University Munich, Butenandtstrasse 5-13, 81377 Munich, Germany
S
* Supporting Information
ABSTRACT: The development of a sequential O−H/C−H
bond functionalization of phenols initiated by the cationic
gold(I)-catalyzed cyclization of 1-bromo-1,5-enynes to produce
(2-bromocyclopent-2-en-1-yl)phenols is reported. This unprece-
dented domino transformation efficiently proceeds under mild
conditions (5 mol % of (t-Bu)3PAuNTf2, CH2Cl2, 0−23 °C) via
an intermediate aryl alkyl ether which collapses at ambient
temperature to undergo a 1,2-hydride shift followed by C−H
insertion of the phenol.
eactions involving the cyclization of 1,n-enynes are highly
valuable as they can generate molecular complexity under
R
mild conditions in one synthetic operation.1 Within this general
reaction class, chemical processes based on the gold(I)-catalyzed
cyclization of 1,5- and 1,6-enynes have emerged as a reliable and
efficient strategy for the synthesis of functionalized cycloalkane
derivatives.2 Although the overall reaction mechanism of these
transformations is strongly dependent upon the exact exper-
imental conditions and reaction partners, a few intermediates
were proposed to play a key-role.3
Figure 1. Selected natural products containing the (cyclopentyl)phenol
structural motif.
As part of our efforts to study the gold(I)-catalyzed addition of
phenols to 1-bromoalkynes for the synthesis of aryl bromoenol
ethers, we discovered that Nolan’s [(IPr)Au(OH)] HBF4·OEt2
catalyst6 (5 mol %) promotes the cycloisomerization of 1-bromo-
6-methylhept-5-en-1-yne 1a followed by C−H insertion of p-
cresol to provide 2a (37%) and traces of the bis-alkylated phenol
3a (Table 1, entry 1). Careful reaction monitoring revealed that
both products had only formed after concentration of the yellow
reaction solution at 50 °C to give the product mixture as a red-
orange residue. The expected trans-addition of p-cresol across
the alkyne, to give the bromo enol ether, was not observed.
Excited by this unexpected result, we evaluated a series of
different catalytic systems to optimize the transformation of
enyne 1a to 2a. We found that the electronic nature of the
spectator ligand (phosphine, phosphite, or N-heterocyclic
carbene ligand) had little effect on the reactivity of the catalyst
(entries 2−4).7 However, exchange of the counterion led to a
dramatic change in reaction yield (entries 1 and 5−7).8 It was
interesting to note that the catalytic system containing either the
triflate or triflimide anion showed similar efficiency, whereas a
sharp drop was observed for hexafluoroantimonate. Chloride
failed to catalyze the transformation at all. Finally, by increasing
the amount of phenol to 5 equiv, the byproduct 3a could be
further diminished to give 2a in 76% yield (entry 8). The recently
The way these transient structures interact with an external
nucleophile has a profound influence on the reaction pathway
and the substitution pattern of the products.2c,4 Carbon (arenes,
heteroarenes, 1,3-dicarbonyls)4d and oxygen (H2O, ROH,
RCOOH) nucleophiles4e−h typically attack the putative
enyne−cyclization intermediates to give products carrying the
former nucleophile in their side-chain (Scheme 1a, Nu = R′OH,
R′ = R = alkyl, aryl).3d
Scheme 1. Gold(I)-Promoted Cyclization of 1,5-Enynes in the
Presence of External Oxygen Nucleophiles
Herein, we describe a mild experimental procedure for the
realization of an unexplored reaction pathway4d that is operative
for 1-halo-1,5-enynes in the presence of phenols (Scheme 1b, Nu
= ArOH, R = Br, Cl). This strategy constitutes a facile entry to
synthetically useful (2-halocyclopent-2-en-1-yl)phenols whose
underlying (cyclopentyl)phenol structural motif can be found in
several biologically active molecules (Figure 1).5
Received: March 13, 2015
Published: March 31, 2015
© 2015 American Chemical Society
1982
DOI: 10.1021/acs.orglett.5b00738
Org. Lett. 2015, 17, 1982−1985

Organic Letters
Letter
a
Table 1. Gold(I)-Catalyzed Cycloisomerization of 1-Bromo-
Scheme 3. Substrate Scope and Functional-Group Tolerance
1,5-enyne 1a in the Presence of p-Cresol. Optimization of
a
Reaction Parameters
a
entry
catalyst
solvent
yield 2a/3a (%)
b
1
2
3
4
5
6
7
8
9
(IPr)Au(OH), HBF4·OEt2
IPrAuNTf2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
37/6
62/5
64/4
66/4
0
(2,4-t-BuPhO)3PAuNTf2
(t-Bu)3PAuNTf2
(t-Bu)3PAuCl
(t-Bu)3PAuCl, AgSbF6
(t-Bu)3PAuCl, AgOTf
(t-Bu)3PAuNTf2
InI3, AgSbF6
39/4
65
c
76
43/4
a
Reaction conditions: 1 (0.25 mmol), p-cresol (0.38 mmol), catalyst
(5 mol %), CH2Cl2 (1 mL), 23 °C. Yields of 2a/3a were determined
1
by H NMR using 1,3,5-trimethoxybenzene as the internal standard.
b
1 (0.49 mmol), p-cresol (0.54 mmol), catalyst (5 mol %), toluene
c
(1.8 mL), 50 °C. p-Cresol (5 equiv), isolated yield. IPr = (2,6-
diisopropylphenyl)-1,3-imidazol-2-ylidene; NTf2 = bis[(trifluoro-
methane)sulfonyl]amide].
described yneophile diodoindium(II) cation9 promoted this
reaction as well but showed significantly lower conversion (entry
9). For a full analysis of reaction conditions, promoters, and
control experiments, see Table 1 in the Supporting Information.
After having performed these initial experiments, we
speculated that the 1-bromo substituent might exert a unique
steric and electronic effect on this transformation. To prove this
hypothesis, several substrates differing in the alkyne substitution
were prepared (Scheme 2).
Scheme 2. Influence of the Alkyne Substituent on the Overall
Reaction Sequence
a
Reaction conditions according to entry 8 of Table 1. Yields of the
b
isolated product. Average of two runs. p-Fluorophenol (1.05 equiv)
c
was added prior to the addition of 2,4-di-tert-butylphenol. p-
Methoxyphenol, p-fluorophenol, and p-bromophenol were used in
excess (10 equiv).
and 7 the ortho products were predominantly formed. This ratio
was also not altered when the catalyst (2,4-t-BuPhO)3PAuNTf2,
previously reported for the gold(I)-catalyzed site-specific C−H
bond functionalization of phenols,11 was used. When para-
substituted phenols were employed, the ortho C−H functional-
ization products could be isolated in yields up to 76%.
Substrates containing functional groups such as halides (10),
alkyl ethers (11), silyl ethers (12), and esters (14, 17) were also
tolerated under the reaction conditions. Unfortunately, the less
electron-rich compounds 15−17 were formed in low yields even
in the presence of a large excess of phenol (10 equiv).12 For 16,
the O−H insertion product according to the pathway shown in
Scheme 1a could be isolated in 75% yield (see the Supporting
Information for details). However, the low reactivity of p-
fluorophenol in the consecutive C−H insertion step made the
overall transformation inefficient.
The unique behavior of 1a was immediately evident, as
product formation for nonhalogenated substrates could only be
observed for 2g (X = Ph, 8%). Exchange for chlorine decreased
the yield to 56%, whereas only a 6% yield was obtained for 1-
iodoalkyne 1c, which was unstable under the reaction
conditions.10 The reactions of 1d−g led to the formation of
side products (see Supporting Information for details), and for
1h decomposition occurred.
Having established the optimized reaction conditions, the
substrate scope was investigated with a panel of phenols. As
shown in Scheme 3, electron-rich phenols react smoothly to give
2a and 4−13 in good yields. Although exclusive chemoselectivity
was observed for the C−H bond, the site-selectivity was less
predictable. For 5 and 13, the para position was favored, and for 4
1983
DOI: 10.1021/acs.orglett.5b00738
Org. Lett. 2015, 17, 1982−1985

Organic Letters
Letter
For sterically hindered phenols, which reacted sluggishly with
1a, we could take advantage of this observation. Addition of 2,4-
di-tert-butylphenol (5 equiv) to the aforementioned O−H
insertion product in the presence of catalyst gave 9 in good
yield.13 The electron-poor substrates p-(trifluoromethyl)phenol,
methyl p-hydroxybenzoate, and p-hydroxyacetophenone were
unreactive under the reaction conditions, and for substrates
containing nitrogen (18) or acid-labile groups (19), no C−H
insertion could be observed.
Scheme 5. Synthesis of Aryl Ether 25 and Monitoring Its
Conversion to 2a via 1H NMR Spectroscopy (CD2Cl2, 400
MHz)
To obtain a more detailed insight into the reaction
mechanisms, the deuterium-labeled 1-bromo-1,5-enyne 20 was
exposed to the standard reaction conditions (Scheme 4a).
Scheme 4. Mechanistic Investigations
Scheme 6. Proposed Catalytic Cycle
Isolation of 21 confirmed that deuterium underwent a [1,2]-shift
2
prior to C−H insertion. The HR-MS and H NMR analysis of
the product mixture obtained from the reaction of 1a with
phenol-d6 revealed that incorporation of deuterium has occurred
as depicted for 23 and 24 (Scheme 4b). These results are
consistent with a reaction pathway that includes a protodeaur-
eation step after enyne cyclization and the occurrence of a
transient isopropyl cation. The latter would be in equilibrium
with an isopropenyl group which, in the presence of traces of
DNTf2, accounts for the formation of 24.14
Further evidence for the pathway leading to 24 was obtained
from a time-resolved 1H NMR experiment (Scheme 5).
Lowering the reaction temperature to −30 °C led to the
formation of aryl alkyl ether 25 as a single compound. Rapid
purification by flash column chromatography on silica gel gave 25
in 51% yield. When a solution of 25 in dichloromethane-d2 was
treated with gold(I) complex (t-Bu)3PAuNTf2 at 23 °C, clean
formation of 26 and 2a could be observed within 15 min.
A proposed reaction mechanism that is consistent with the
experimental data and literature3,4g,h is provided in Scheme 6.
Site-selective addition of p-cresol to the gold-stabilized
carbocation15 27 or 28,16 obtained via the enyne−cyclo-
isomerization of 1a produces the aryl alkyl ether 25.17
Monitoring the reaction via 1H and 31P NMR revealed that the
catalyst was fully regenerated after the formation of 25 at low
temperature (−30 °C). The unstable alkyl aryl ether collapses
under the reactions conditions at ambient temperature with
concomitant expulsion of p-cresol to give 26 which, in the
presence of traces of acid, is in equilibrium with 29.
leads to 2a. In a separate experiment, it was found that the overall
rearrangement from 25 to 2a can be promoted in the presence of
catalytic amounts of HNTf2 (5 mol %, 51% yield).14,18 This
explains why the overall reaction outcome is dominated by the
counterion and not the ligand on the gold(I) catalyst.
The site-selectivity is controlled by the substrate structure. The
unique feature that only 1-halo-1,5-enynes 1a and 1b efficiently
undergo this transformation is noteworthy, too.19 However, the
exact role of the halogen substituent is still unclear.
In summary, we have developed a domino transformation
which converts 1-halo-1,5-enynes in the presence of phenols to
2-(halocyclopent-2-en-1-yl)phenols which are valuable precur-
sors for the elaboration of more complex structures. This
The subsequent [1,2]-hydride shift of 29 should be favored
due to the formation of a tertiary allylic cation (not shown) which
could be further stabilized by the adjacent bromine substituent.
Addition of p-cresol (C−H insertion step) to the allylic system
1984
DOI: 10.1021/acs.orglett.5b00738
Org. Lett. 2015, 17, 1982−1985

Organic Letters
Letter
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carbon−carbon bond-forming reaction is catalyzed by cationic
gold(I) complexes, proceeds via a sequential O−H/C−H
functionalization of phenols, and extends the product range
typically observed for simple 1,5-enynes. An application of this
method for the synthesis of bioactive molecules is currently
underway in our laboratories.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, compound characterization data, and
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: thomas.magauer@lmu.de.
Notes
(10) 1-Fluoroalkynes are known to be highly unstable and were not
investigated: Viehe, H. G.; Merenyi, R.; Oth, J. F.; Valange, P. Angew.
Chem. 1964, 76, 888. 1-Iodoalkynes have been successfully used in gold
catalysis: (a) Mader, S.; Molinari, L.; Rudolph, M.; Rominger, F.;
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the Fonds der
Chemischen Industrie (Sachkostenzuschuss to T.M. and
■
Hashmi, A. S. K. Chem.Eur. J. 2015, 21, 3910−3913. (b) Nosel, P.;
̈
Muller, V.; Mader, S.; Moghimi, S.; Rudolph, M.; Braun, I.; Rominger,
̈
Doktorandenstipendium to K.S.), the Dr. Klaus Romer-
̈
F.; Hashmi, A. S. K. Adv. Synth. Catal. 2015, 357, 500−506. (c) Chary, B.
C.; Kim, S.; Shin, D.; Lee, P. H. Chem. Commun. 2011, 47, 7851−7853.
(11) Yu, Z.; Ma, B.; Chen, M.; Wu, H.-H.; Liu, L.; Zhang, J. J. Am.
Chem. Soc. 2014, 136, 6904−6907.
Foundation (Romer Fellowship to K.S.), and the Deutsche
̈
Forschungsgemeinschaft (Emmy-Noether Fellowship to T.M.).
We thank Dr. Pascal Ellerbrock (LMU Munich) and Dr. Kevin
Mellem (Midasyn, Inc.) for helpful discussions during the
preparation of this manuscript.
(12) p-Fluorophenol showed high reactivity in a related Friedel−Crafts
allylation reaction: Coutant, E.; Young, P. C.; Barker, G.; Lee, A.-L.
Beilstein J. Org. Chem. 2013, 9, 1797−1806.
(13) See the mechanistic discussion and Scheme 6 for further details.
(14) Dang, T. T.; Boeck, F.; Hintermann, L. J. Org. Chem. 2011, 76,
9353−9361.
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