1,2,3-triazole as a special "X-factor" in promoting hashmi phenol synthesis

Article abstract of DOI:10.1021/ol902680k

(Figure presented) ³¹PNMR experiments revealed rapid decomposition of the Ph₃PAu⁺TfO^- complex In the presence of the furan-yne, which resulted In poor reactivity as reported In the literature. Therefore, instead

Full text of DOI:10.1021/ol902680k

ORGANIC
LETTERS
2010
Vol. 12, No. 2
344-347
1,2,3-Triazole as a Special “X-Factor” in
Promoting Hashmi Phenol Synthesis
Yunfeng Chen, Wuming Yan, Novruz G. Akhmedov, and Xiaodong Shi*
C. Eugene Bennett Department of Chemistry, West Virginia UniVersity, Morgantown,
West Virginia 26506
xiaodong.shi@mail.wVu.edu
Received November 20, 2009
ABSTRACT
31P NMR experiments revealed rapid decomposition of the Ph3PAu+TfO- complex in the presence of the furan-yne, which resulted in
poor reactivity as reported in the literature. Therefore, instead of tuning different ligands (PR3), the 1,2,3-triazole was applied as a
special X-factor to stabilize the catalyst. The desired phenol products were prepared in excellent yields (1% cat. up to 95% yield) and
chemoselectivity (>20:1).
In the past several years, homogeneous Au catalysis has
become one very important research area in organic synthe-
sis.1 With the discoveries of more and more interesting new
transformations, attention has been drawn to the understand-
ing of the reaction mechanism and the actual catalytic
component.2 We recently reported 1,2,3-triazole bound Au
complexes as effective, thermally stable catalysts in inter-
molecular alkyne hydroaminations.3 Herein, we report the
application of these complexes as effective precatalysts in
promoting chemoselective intramolecular furan-alkyne cy-
clization, which provided (a) clear evidence for the Au(I)
cation as a possible catalyst in this transformation and (b) a
practical alternative solution that allows simple, inexpensive
PPh3 as an effective ligand.
As well-documented in the literature, the cationic Au
activation of alkynes usually proceeded through two com-
petitive reaction paths: (a) Lewis acid (or π-acid) activation
of alkyne for nucleophilic addition and (b) Au back bonding
to alkyne that led to the formation of carbene-like intermedi-
ates. One good example for this interesting dual reactivity
is the Au-catalyzed intramolecular alkyne-furan arrangement,
first reported by Hashmi and co-workers.4
The furan-yne 1 could rearrange to form aromatic substitution
product A and phenol B with the presence of proper Au catalysts
(Scheme 1), although with some debate it was generally
believed that product A was formed through arene addition to
the gold (Lewis acid) activated alkyne (Friedel-Craft-type
addition). The formation of phenol B, on the other hand,
proceeded through the Au-carbene like intermediates followed
by cyclopropane ring opening and gold carbene cyclization.
Compared with reaction path A, the formation of phenol B is
(1) For selected recent reviews on homogeneous Au catalysis, see: (a)
Hashmi, A. S. K.; Rudolph, M. Chem. Soc. ReV. 2008, 37, 1766–1775. (b)
Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. ReV. 2008, 108, 3351–
3378. (c) Arcadi, A. Chem. ReV. 2008, 108, 3266–3325. (d) Jimenez-Nunez,
E.; Echavarren, A. M. Chem. ReV. 2008, 108, 3326–3350. (e) Hashmi,
A. S. K. Chem. ReV. 2007, 107, 3180–3211. (f) Fu¨rstner, A.; Davies, P. W.
Angew. Chem., Int. Ed. 2007, 46, 3410–3449. (g) Jime´nez-Nu´n˜ez, E.;
Echavarren, A. M. Chem. Commun. 2007, 333–346. (h) Zhang, L.; Sun, J.;
Kozmin, S. A. AdV. Synth. Catal. 2006, 348, 2271–2296. (i) Hashmi,
A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45, 7896–7936.
(2) Selected recent examples, see: (a) Cui, L.; Zhang, G.; Peng, Y.;
Zhang, L. Org. Lett. 2009, 11, 1225–1228. (b) Gorske, B. C.; Mbofana,
C. T.; Miller, S. J. Org. Lett. 2009, 11, 4318–4321. (c) Marion, N.; Carlqvist,
P.; Gealageas, R.; de Fremont, P.; Maseras, F.; Nolan, S. P. Chem.sEur.
J. 2007, 13, 6437–6451. (d) Nevado, C.; Echavarren, A. M. Chem.sEur.
J. 2005, 11, 3155–3164.
(3) Duan, H.; Sengupta, S.; Petersen, J. L.; Akhmedov, N. G.; Shi, X.
J. Am. Chem. Soc. 2009, 131, 12100–12102.
(4) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem. Soc. 2000,
122, 11553–11554.
10.1021/ol902680k  2010 American Chemical Society
Published on Web 12/14/2009

chemoselectivity. One hypothesis was that Au(I) under-
went disproportionalization and generated active Au(III)
in situ, which then served as the active catalyst for this
reaction.5i,8 The successful application of Au(I) complexes
as the precatalyst was first reported in 2006, while
Uson-Laguna salt 2b and Schmidbaur-Bayler salt 2c were
used to promote the reaction, giving modest to good yields
(up to 72%) of the phenol products.8 Interestingly, with a
more sterically hindered ligand, catalyst 2c provided better
chemoselectivity, favoring the formation of the phenol (>20:
1). Therefore, very recently, new Au(I) complexes with steric
hindered ligands (such as 2d and 2e) have been applied as
effective catalysts for phenol synthesis. These results led to
the concerns: Were Au(I) cations themselVes effectiVe
catalysts for alkyne 1 actiVation? Was the application of the
rather complicated steric hindered and electron enriched
phosphorus ligands necessary?
It was reasonable to rationalize that Au(III), a better Lewis
acid, should favor alkyne activation in the Friedel-Craft type
cyclization (formation of A). The Au(I) cation, in theory, would
be a better catalyst for carbene intermediate formation due to
its high electron density on the gold atom (d10 for AuI and d8
for AuIII), but this hypothesis was not consistent with current
literature reports. To investigate the reaction mechanism, 31P
NMR studies were performed with substrate 1a and simple
Ph3PAu+·TfO- catalyst as summarized in Figure 2.
Scheme 1. Dual Reactivities of Cationic Au Catalysts
a much more interesting transformation, which involved four
bonds breaking and formation of four new bonds in one step.
Hashmi and co-workers performed extensive investigations of
this transformation (Figure 1).5 Remarkable works have also
Figure 1
synthesis.
. Representative effective gold catalysts for Hashmi phenol
been performed regarding the elucidation of the reaction
mechanism including the successful isolation of several key
intermediates.6 Our interest in spending efforts on this rather
“well-studied” transformation was initiated by the “unconven-
tional” and “picky” ligand effects (vide infra), along with an
unclear argument in the literature whether the Au(I) cation itself
could promote this reaction or the in situ formed Au(III) (from
Au(I) precatalyst decomposition) were the only viable catalysts
for this reaction.
According to the literature, AuCl3 was first reported as
the effective catalyst for the isomerization of 1, giving
phenol B as the major products in good yields.4 Later
developed Au(III)-pyridine complexes (such as 2a) led
to improved reaction efficiency.7 Meanwhile, the Au(I)
complexes, such as Ph3PAuOTf, were reported as less
effective catalysts with “slow reaction rate” and poor
Figure 2.
31P NMR spectra of catalyst Ph3PAu+·TfO- with substrate
1a. Ph3PAuCl (20 mg, 0.04 mmol) was dissolved in 1 mL of CDCl3,
then AgOTf (10 mg, 0.04 mmol) and 1a (24 mg, 0.08 mmol) were
added sequentially (see Supporting Information).
(5) See examples: (a) Hashmi, A. S. K.; Rudolph, M.; Huck, J.; Frey,
W.; Bats, J. W.; Hamzic, N. Angew. Chem., Int. Ed. 2009, 48, 5848–5852.
(b) Hashmi, A. S. K.; Loos, A.; Littmann, A.; Braun, I.; Knight, J.; Doherty,
S.; Rominger, F. AdV. Synth. Catal. 2009, 351, 576–582. (c) Hashmi,
A. S. K.; Scha¨fer, S.; Bats, J. M.; Frey, W.; Rominger, F. Eur. J. Org.
Chem. 2008, 73, 4891–4899. (d) Hashmi, A. S. K.; Salathe´, R.; Frey, W.
Chem.sEur. J. 2006, 12, 6991–6996. (e) Hashmi, A. S. K.; Blanco, M. C.;
Kurpejovic, E.; Frey, W.; Bats, J. W. AdV. Synth. Catal. 2006, 348, 709–
713. (f) Hashmi, A. S. K.; Weyrauch, J. P.; Kurpejovic, E.; Frost, T. M.;
Miehlich, B.; Frey, W.; Bats, J. W. Chem.sEur. J. 2006, 12, 5806–5814.
(g) Carrettin, S.; Blanco, M. C.; Corma, A.; Hashmi, A. S. K. AdV. Synth.
Catal. 2006, 348, 1283–1288. (h) Hashmi, A. S. K.; Ding, L.; Bats, J. W.;
Fischer, P.; Frey, W. Chem.sEur. J. 2003, 9, 4339–4345. (i) Hashmi,
A. S. K.; Frost, T. M.; Bats, J. W. Org. Lett. 2001, 3, 3769–3771.
To ensure the accuracy of these NMR experiments, the
H3PO4 in a sealed capillary tube was applied as the internal
standard (0 ppm signal). The Ph3PAu+·TfO- sample was freshly
prepared. As shown in Figure 2B, the Ph3PAu+, though it
decomposed over time (up to 10 h at rt), could be prepared in
good purity. The integration ratio of the signals provided direct
measurement of PPh3Au+ cation concentration. Upon the
addition of 2.0 equiv of alkyne 1a, formation of gold-mirror
occurred instantly. A new 43.5 ppm signal was observed in
Org. Lett., Vol. 12, No. 2, 2010
345

NMR (Figure 2C), which likely was attributable to the corre-
sponding phosphorus oxidation products. The decomposition
of the Ph3PAu+·TfO- occurred much faster with the presence
of alkyne 1a and almost no Ph3PAu+ left after 2 h (Figure 2E).
Importantly, 1a was completely consumed, and the products
3a (26% NMR yield) and 4a (28% NMR yield) were both
formed, though with low yields and poor chemoselectivity.
Upon addition of extra 1a into the fully decomposed sample
(Figure 2E), a slower reaction of 1a was observed, which was
consistent with literature reports that in situ formed Au(III) or
Au(0) from Au(I) decomposition could still catalyze this
transformation, though with a slower reaction rate. These NMR
experiments indicated that (a) the reaction between
Ph3PAu+·TfO- and 1a was fast and (b) the resulting low yields
were caused by the decomposition of the Au(I) catalyst,
especially with the presence of 1a. These results were also in
agreement with the facts that more bulky phosphorus ligands
(i.e., 2d, 2e) gave better yields due to the improved stability of
Au(I) cations.
Figure 4.
31P NMR Spectra of Complex 2g with Substrate 1a. 2g
(30 mg, 0.04 mmol) was dissolved in 1 mL of CDCl3, and then 1a
(24 mg, 0.08 mmol) was added (see Supporting Information).
Recently, we reported the application of triazole-Au
complexes as thermally stable catalysts in challenging alkyne
activation under harsh conditions.3 The working hypothesis
was that triazole compounds could form dynamic coordina-
tion with Ph3PAu+ cation, which allowed the effective
activation of alkyne with much improved gold cation
stability. This discovery was very interesting since it provided
an alternative strategy in tuning the Au catalyst reactivity
(Figure 3): instead of changing different phosphorus ligands,
isomerization products 3a and 4a were formed in modest
yields (Table 1, entry 1). Detailed screening of the reaction
conditions is shown in Table 1.
Table 1. Screening of Reaction Conditions
yield (%)a
Figure 3
reactivity.
. X-factor: an alternative strategy in tuning gold catalyst
loading
(%)
[C] time convn
mol/L (h)
(%) 3a 4a 3a:4ab
cat.
soln
1
2
3
4
5
6
7
8
9
2f
2g
2f
2f
2f
2.0
2.0
2.0
2.0
2.0
2.0
2.0
5.0
1.0
0.5
1.0
CH2Cl2 0.2
CH2Cl2 0.2
4
4
4
4
4
4
4
8
8
100 24 28
100 30 34
100 35 30
1:1.2
1:1.1
1.2:1
the catalyst reactiVity could be adjusted by the X ligands
through controlling the equilibrium process.
DCE
Tol
0.2
0.2
95 45 trace >20:1
Considering the main problem for simple Ph3PAu+·TfO-
in promoting Hashmi phenol synthesis was the decomposi-
tion of catalysts, we wondered whether the X-ligand coor-
dination strategy could be applied. This would provide an
alternative solution to promote this useful transformation with
the very simple, inexpensive PPh3 ligand. The NMR experi-
ments between triazole-Au complex 2g and 1a were then
performed to evaluate the stability of the triazole-Au
complex (Figure 4).
CH3CN 0.2
CH3NO2 0.2
CH3NO2 0.2
CH3NO2 0.02
CH3NO2 0.05
100 54
100 56
100 59
96 90
73 68
65 63
100 96
7
0
0
0
0
0
0
8:1
2f
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
2g
2g
2g
10 2g
11 2g
CH3NO2 0.075 21
CH3NO2 0.075 12
a Yields determined by NMR with 1,3,5-trimethoxybenzene as internal
standard. b Ratio determined by NMR of crude reaction mixtures.
To our great delight, no triazole Au decomposition was
observed with the presence of 1a even after 24 h, and
As shown in Table 1, with application of triazole, the catalyst
2f could effectively promote alkyne 1a rearrangement, giving
3a and 4a in modest yields. The chemoselectivity (3a:4a) was
poor when the reaction was conducted in dichloromethane.
However, the selectivity was significantly improved with
nitromethane as the solvent, giving phenol 3a as the dominant
product (entry 6). Catalyst 2g gave slightly improved yield
(entry 7), which was likely due to the improved catalyst stability.
Notably, the crude reaction NMR indicated that the only side
(6) (a) Hashmi, A. S. K.; Rudolph, M.; Weyrauch, J. P.; Wo¨lfle, M.;
Frey, W.; Bats, J. W. Angew. Chem., Int. Ed. 2005, 44, 2798–2801. (b)
Hashmi, A. S. K.; Kurpejovic, E.; Wo¨lfle, M.; Frey, W.; Bats, J. W. AdV.
Synth. Catal. 2007, 349, 1743–1750. (c) Hashmi, A. S. K.; Rudolph, M.;
Siehl, H.; Tanaka, M.; Bats, J. W.; Frey, W. Chem.sEur. J. 2008, 14, 3703–
3708.
(7) Hashmi, A. S. K.; Weyrauch, J. P.; Rudolph, M.; Kurpejovic, E.
Angew. Chem., Int. Ed. 2004, 43, 6545–6547.
(8) Hashmi, A. S. K.; Blanco, M. C.; Kurpejovic, E.; Frey, W.; Bats,
J. W. AdV. Synth. Catal. 2006, 348, 709–713.
346
Org. Lett., Vol. 12, No. 2, 2010

reaction was the polymerization of 1a. Therefore, to further
improve the reaction performance, dilution was applied (favor-
ing the desired intramolecular rearrangement over the compet-
ing intermolecular polymerization). As expected, excellent
yields were received when the reaction was performed at lower
concentration even with reduced catalyst loading, though slower
reaction rates were associated (entries 8-11). Combining the
effect of dilution and decreasing catalyst loading, 1% catalyst
with 0.075 M concentration was selected as the practical,
optimal condition, with the formation of product in nearly
quantitive yield (entry 11).
[Ph3P-Au-triazole]+ was the actual catalyst rather than the
Ph3PAu+ cation. The kinetic triazole titration experiments were
therefore performed as shown in Figure 6.
With this 1,2,3-triazole coordination, eVen the simple PPh3
bound Au(I) cation could become a highly efficient catalyst
for this transformation. To evaluate the generality of this
simple precatalyst, some representative furan-alkynes were
tested, and the phenol products were obtained in excellent
yields as shown in Figure 5.
Figure 6. Reaction kinetic profiles with various amounts of triazoles
in the system. General reaction conditions: 1a and catalyst 2g in
CH3NO2, concentration was 0.04 mol/L, room temperature. Yields
of 3a were determined by the NMR of the reaction mixture at given
time with 1,3,5-trimethoxybenzene as internal standard. A: 1% 2g.
B: 1% 2g + 1% triazole. C: 1% 2g + 4% triazole. D: 1% 2g +
9% triazole.
The reaction kinetic profile indicated a significant decrease
in reaction rate with increase of triazoles. These experiments
provided strong evidence that the actual Au(I) catalyst was likely
the Ph3PAu+ cation, which was under equilibrium with
[Ph3P-Au-triazole]+.
In conclusion, the NMR experiments revealed that the reason
for simple Au(I) catalyst as a poor catalyst in promoting Hashmi
phenol synthesis was the rapid decomposition of the gold
catalyst. Therefore, instead of tuning the phosphorus ligands,
an alternative strategy was developed by using the 1,2,3-triazole
as a coordination factor to stabilize the catalyst. Excellent yields
and chemoselectivity were obtained. This new approach not
only provided a simple solution for the reported transformation
but also, more importantly, revealed a new strategy in fine-
tuning catalyst reactivity. Influences on the reactivities of other
gold-catalyzed transformations by this X-factor effect are
expected and currently under investigation.
Figure 5. Representative substrates with triazole-Au catalysts.
Reaction performed at room temperature and with the concentration
0.075 mol/L in nitromethane. Isolated yields.
As shown in Figure 5, this triazole-Au precatalyst was
suitable for all of the tested furan-alkyne substrates, giving
the desired phenol products in excellent yields. For the
R-unsubstituted alkyne 1f, two different cyclization products,
3f and 3f′, were obtained, which was consistent with the
proposed reaction mechanism in the literature.
According to the literature, it was generally believed that
Au(I) complexes possessed two coordination sites with a 180°
bond angle. However, some recent reports suggested that it was
possible to have a “third coordination” of highly electron-rich
substrates through static charge interaction.2b One recent
example was the chiral anion controlled enantioselective Au(I)-
catalyzed intramolecular hydroamination reported by Toste.9
Owing to the significantly improved reactivity of the
[Ph3P-Au-triazole]+·TfO- catalyst, we wondered whether
Acknowledgment. We thank the NSF (CHE-0844602),
DOE (DE-FC26-04NT42136), and ACS-PRF-47843-G1 for
financial support.
Supporting Information Available: Experimental details
and spectrographic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(9) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007,
317, 496–499.
OL902680K
Org. Lett., Vol. 12, No. 2, 2010
347