Ambient intermolecular [2 + 2] cycloaddition: An example of carbophilicity and oxophilicity competition in Au/Ag catalysis

Article abstract of DOI:10.1021/ol500854m

The gold-catalyzed intermolecular [2 + 2] cycloaddition of propargyl esters was achieved with good stereoselectivity. The silver-free condition was critical for this transformation, while only a trace amount of [2 + 2] products were formed in the presence of silver under otherwise identical conditions.

Full text of DOI:10.1021/ol500854m

Letter
pubs.acs.org/OrgLett
Ambient Intermolecular [2 + 2] Cycloaddition: An Example of
Carbophilicity and Oxophilicity Competition in Au/Ag Catalysis
Yijin Su, Yanwei Zhang, Novruz G. Akhmedov, Jeffrey L. Petersen, and Xiaodong Shi*
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506, United States
S
* Supporting Information
ABSTRACT: The gold-catalyzed intermolecular [2 + 2]
cycloaddition of propargyl esters was achieved with good
stereoselectivity. The “silver-free” condition was critical for this
transformation, while only a trace amount of [2 + 2] products
were formed in the presence of silver under otherwise identical
conditions.
he gold-catalyzed propargyl ester rearrangement has been
well studied during the past decade, both experimentally
formed from this diaryl propargyl ester rearrangement and the
intermolecular allene [2 + 2] cycloaddition at rt. In addition,
the “silver-free” condition is critical in this transformation: in
the presence of silver, even a catalytic amount, dimer 2 was
observed over the [2 + 2] products due to the silver-activated
substitution. Considering the extensive efforts from various
research groups toward understanding the role of silver in gold
catalysis,6 this work provides another type of silver influence as
an oxophilic Lewis acid, which deviates from the gold reaction
pathway.
T
and computationally.1 The reactions typically undergo 3,3-
rearrangement via gold promoted alkyne activation. The allene
intermediates can be further activated by the same gold
catalysts and translated into various products, such as indenes,2
enones,3 and vinyl halides4 (Scheme 1). Recently, special gold
Scheme 1. Gold-Catalyzed Propargyl Ester Activation
The cationic gold complexes are effective carbophilic π-acids,
which can effectively activate both an alkyne and allene.7
According to literature, three types of chemoselective gold
catalyst (activate alkyne over allene) have been reported as
gold-oxo complexes,8 gold-pyridine/Et3N complexes,9 and
gold-1,2,3-triazole complexes (TA-Au).10 Surprisingly, among
all the reported gold-catalyzed propargyl ester rearrangements,
diaryl propargyl esters are not viable substrates. In fact, during
our investigations on triazole-gold (TA-Au) catalyzed allene
synthesis, complex reaction mixtures were observed. To
understand how this particular type of substrate reacts, we
monitored the reactions of compound 1a with various gold
catalysts (Figure 1).
First, treating 1a with LAuCl/AgX (5% loading, L = PPh3,
IPr, XPhos, X = OTf, NTf2 or SbF6) gave complex reaction
mixtures. Through careful examination, dimer 2a was identified
as the major product (50% yield using anhydrous solvent; see
detailed structure analysis in the Supporting Information). With
the triazole gold (TA-Au) catalysts, the reaction was much
cleaner (less polymerization and decomposition). However, in
addition to the dimer 2a (30%), several other products were
observed. Fortunately, the structure of one major product was
catalysts have been reported to achieve high yields of allene
intermediates, including the triazole gold reported by our
group.5 While this chemistry seems well understood, one
“concealed” problem was that most of these transformations
generally lack tolerance for the diaryl substituted internal
alkynes (R1, R2 = aryl groups). For example, simply treating
diphenyl propargyl ester 1a (R1 = R2 = Ph, R = CH3) with
various LAuCl/AgX (L = PPh3, IPr, XPhos; X = TfO−, Tf2N−,
SbF6 , BF4 ) catalysts gave complex reaction mixtures with
little indene or allene obtained. To fill this missing piece of the
puzzle, we conducted detailed investigations on this specific
type of substrate. Herein, we report the different products
−
−
Received: March 21, 2014
Published: April 16, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Cyclobutanes are very attractive building blocks in organic
synthesis, and this reaction is conducted under mild conditions
(rt) from simple starting materials. Thus, the discovery shown
above revealed an interesting new approach to access
substituted cyclobutanes under mild conditions. As shown in
Scheme 2, the allene should be formed prior to either
dimerization or cyclization. This was confirmed by monitoring
the reaction with NMR: allene A was the only product formed
during the first 2 h of reaction when treating 1a with TA-Au
catalysts. Efforts to isolate allene A were unsuccessful due to the
poor stability. To improve the chemoselectivity ([2 + 2] over
dimer) and stereoselectivity (different cyclobutane isomers), we
prepared various propargyl ester derivatives and charged them
under gold catalytic conditions. The results are summarized in
Table 1.
The PPh3AuCl/AgOTf catalysts gave only dimer 2 with no
cycloaddition product 3 observed (entry 1). The silver-free TA-
Au catalyst produced the desired [2 + 2] products as mixtures
of isomers. With the NH-triazole (TA-H) as ligand, 43% dimer
was obtained (entry 2). The amount of dimer was decreased
when N-methyl triazole (TA-Me) was used (entry 3), likely
caused by the elimination of an acidic proton on NH-triazole
(activating OAc leaving group). Switching acetate to benzoylate
resulted in the exclusive formation of a dimer due to the better
propargyl leaving group (PhCOO− vs CH3COO−). Finally,
application of pivalate achieved excellent chemoselectivity,
giving the [2 + 2] products in good yields (>85% combining all
isomers, entry 5). Moreover, the bulky pivalate group also gave
significantly improved stereoselectivity with only two major
cycloaddition products obtained (3 and 3′) in a 5:1 ratio. The
structure of the minor isomer, 3′, was also confirmed by the X-
ray crystallography. The silver-free gold oxo catalyst
[(PPh3Au)3O]OTf could also promote this reaction effectively
(entry 6), though with a slightly lower reaction rate compared
with that using TA-Au.
Figure 1. Analyzing the propargyl rearrangement of 1a.
determined by X-ray crystallography as the [2 + 2] cyclo-
addition product 3a. Other minor products were identified as
the stereoisomers generated from the [2 + 2] cycloaddition.
This result was exciting since it was the first example of an
intermolecular allene [2 + 2] reaction through propargyl ester
rearrangement. Notably, indene was not observed in this case.
The successful confirmation of the dimer and the [2 + 2]
cycloaddition products greatly enhance our understanding of
this reaction. A proposed reaction mechanism is shown in
Scheme 2.
Scheme 2. Propargyl Ester Activation
Silver salt was crucial in this transformation. As shown in
entry 7, the addition of 2% AgOTf led to the formation of only
dimer 2 without any cycloaddition product 3 obtained. Using a
silver catalyst alone (entry 8) gave the same dimer product with
a slower reaction rate, likely due to the decreased reactivity of
a
Table 1. Optimization of Gold(I)-Catalyzed Allene [2 + 2]
b
yield (%)
b
entry
1
cat. (%)
R
temp (°C)
time (h)
conv (%)
2
3
3′
other isomer
PPh3AuCl/AgOTf (5%)
[PPh3Au(TA-H)]OTf (1%)
[PPh3Au(TA-Me)]OTf (1%)
[PPh3Au(TA-Me)]OTf (1%)
[PPh3Au(TA-Me)]OTf (1%)
[(PPh3Au)3O]OTf (1%)
[PPh3Au(TA-Me)]OTf (1%) + 2% AgOTf
AgSbF6 (5%)
CH3
CH3
CH3
Ph
rt
rt
rt
rt
rt
rt
rt
rt
rt
80
1
100
100
100
100
100
100
100
100
60
67
trace
10
trace
8
−
35
c
2
12
12
12
16
20
1
43
12
53
<5
trace
63
45
0
d
3
16
13
50
4
5
6
7
8
9
trace
68
trace
12
trace
<5
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
69
14
<5
trace
trace
0
trace
trace
0
trace
trace
0
16
16
16
HOTf (5%)
e
10
PtCl2 (5%)
100
0
56
14
<5
a
b
1
Reaction conditions: 1 (0.2 mmol) and catalyst in DCM (0.8 mL), rt, time. Determined by H NMR using 1,3,5-trimethoxybenzene as internal
c
d
e
standard. TA-H = benzotriazole. TA-Me = N-methyl benzotriazole. 15% yield of (E)-1-phenyl-3-(p-tolyl)prop-2-en-1-one.
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Organic Letters
Letter
the silver catalyst toward alkyne activation (compared with gold
catalyst). Triflate acid did not promote the rearrangement at all,
giving only the propargyl ester decomposition over time (entry
9). Finally, the silver-free PtCl2 catalyst gave a similar
cycloaddition reaction, though at elevated temperature (entry
10). In view of these results, it is clear that the propargyl
rearrangement is the initiation step. The reactivity of the three
well-known π-acids follows the general trend Au(I) > AgX >
PtCl2 in this transformation. Besides alkyne activation, the silver
cation (more oxophilic) can also activate the acetate as a leaving
group, giving dimer 2 as the only product. The silver-free TA-
Au catalyst indicated excellent reactivity toward alkyne
activation over the undesired oxygen activation, which led to
the successful cycloaddition of allene for the first time. The
reaction substrate scope is shown in Figure 2.
cycloaddition products in good yields. The electron-donating
group modified substrate (3i) gave the dimer as one of the
major products with TA-Au catalysts, likely due to the
improved ability to form a propargyl carbon cation. This
problem was overcome by using [(PPh3Au)3O]OTf as the
catalyst with a longer reaction time. Steric hindrance was not an
issue in this transformation considering the fact that ortho-
substituted substrates (3l−3n) worked fine under the optimal
conditions with the formation of desired [2 + 2] cycloaddition
products in excellent yields and similar isomer ratios. Poor
selectivity was observed with naphthalene substituted derivative
3o (1.8:1). This result implied the plausible π−π stacking
during the [2 + 2] cycloaddition process.
A greater electronic effect was observed at the alkyne
terminal Ar2 position. The electron-donating p-methoxyphenyl
substituted alkyne gave the desired cyclobutane 3p in excellent
yield when [(PPh3Au)3O]OTf was used as the catalyst.
However, an electron-withdrawing group reduced the reaction
rate for propargyl ester rearrangement due to either the poor
reactivity of alkyne toward π-acid activation (lower electron
density) or the unfavored 3,3-migration (over the electronically
preferred 1,2-rearrangement). Increasing the reaction temper-
ature to 80 °C (with DCE as solvent) gave the allenes in low
yields (<20%), along with a significant amount of unidentified
side products. These results suggest that the ambient [2 + 2]
cycloaddition is substrate-dependent, which raises the concern
whether gold catalysts were involved in the cycloaddition
process. To verify the potential role of gold catalysts in the
cycloaddition step, we monitored the reaction as shown in
Figure 3.
The reaction tolerates a good substrate scope on the
propargyl aryl position (Ar1). Electron-withdrawing groups (3h,
3k) were suitable for this reaction, giving the desired
Figure 3. Investigation on the role of Au in [2 + 2] step.
Treating propargyl ester 1c with silver-free BrettPhosAuNTf2
(0.5%) gave rapid rearrangement (5 min) to allene 4 in
quantitative NMR yield. Since allene 4 will decompose upon
condensation, it is hard to isolate 4 in pure form. Thus, the
reaction mixture was divided into two parts. One part
continued to react under the identical conditions (in the
presence of the gold catalyst). The other part was filtered
through a silica plug to completely remove the gold catalyst.
The resulting solvent was condensed to ensure a concentration
that was identical to that in the case with the gold catalyst. As
reviewed by NMR, for both cases, similar reaction rates were
observed, which confirmed that the allene [2 + 2] cycloaddition
was a thermal reaction and gold activation was not required.11
In conclusion, with the silver-free gold catalyst, the selective
[2 + 2] cycloaddition was achieved with high efficiency under
mild conditions (rt, open flask). Although the minor isomers
were obtained, the fact that only two isolatable cyclobutane
isomers were obtained highlighted the good selectivity and high
efficiency of this transformation. The silver-free condition was
identified as the crucial factor for the success of this
transformation. The strong influence of silver salts (even a
catalytic amount) raised a viable concern for future
a
Figure 2. Reaction Scope of [2 + 2] Cycloadditiona,b Reaction
conditions: 1 (0.2 mmol) and [PPh3Au(TA-Me)]OTf in DCM (0.8
mL). Determined by 1H NMR using 1,3,5-trimethoxybenzene as
b
internal standard. c 1 mol % of [(PPh3Au)3O]OTf was used instead of
[PPh3Au(TA-Me)]OTf.
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Organic Letters
Letter
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investigations on gold catalysis, especially when an oxophilic
catalyst may be involved.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, NMR data, and crystal data CCDC
992259−992261 (2a, 3c, and 3c′). This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
(11) Thermal [2 + 2] cycloaddition of allene: (a) Skraba, S. L.;
Johnson, R. P. J. Org. Chem. 2012, 77, 11096. (b) Tejedor, D.;
*E-mail: Xiaodong.Shi@mail.wvu.edu.
Notes
Men
́
dez-Abt, G.; Gonzal
́
ez-Platas, J.; Ramírez, M. A.; García-Tellado,
F. Chem. Commun. 2009, 2368. (c) Christl, M.; Groetsch, S.; Gunther,
K. Angew. Chem., Int. Ed. 2000, 39, 3261. (d) Alcaide, B.; Almendros,
P.; Aragoncillo, C. Chem. Soc. Rev. 2010, 39, 783.
̈
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSF (CHE-0844602) and NSFC (No.
21228204) for financial support. We also thank NSF-MRI
(CHE-1228336, CHE-1336071) for the support on the new
NMR and X-ray instruments.
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