Gold(I)-catalyzed asymmetric cyclopropenation of internal alkynes

Article abstract of DOI:10.1021/ja304506g

Highly enantioselective cyclopropenation of internal alkynes with aryldiazoacetates was achieved using the binuclear gold catalyst (S)-xylylBINAP(AuCl)₂, activated by silver hexafluoroantimonate.

Full text of DOI:10.1021/ja304506g

Communication
pubs.acs.org/JACS
Gold(I)-Catalyzed Asymmetric Cyclopropenation of Internal Alkynes
John F. Briones and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
S
* Supporting Information
Table 1. Ag(I)-Catalyzed Cyclopropenation of 1 Using
Various Chiral Ligands
a
ABSTRACT: Highly enantioselective cyclopropenation
of internal alkynes with aryldiazoacetates was achieved
using the binuclear gold catalyst (S)-xylylBINAP(AuCl)2,
activated by silver hexafluoroantimonate.
b
c
entry
ligand
mol % Ag mol % L* yield, % ee, %
1
2
3
4
5
6
7
tBuBOX
pyBOX
PHOX
13
13
10
10
5
14
14
12
41
6
74
NR
79
86
42
81
70
<5

18
7
yclopropenes have broad utility as synthons in organic
C
synthesis.1 Therefore, considerable effort has been placed
in developing new methods for their synthesis.2 One of the
most effective ways for their preparation in a stereoselective
manner is the metal-catalyzed cyclopropenation of alkynes by
diazo compounds.3 The enantioselective cyclopropenation of
terminal alkynes with dirhodium(II) catalysts is well estab-
lished4 and good results were recently obtained with chiral
Co(II) and Ir(II) catalysts.5 Despite these notable advances,
extending asymmetric cyclopropenation reactions to internal
alkynes has been challenging.6 Only one report on the
enantioselective cyclopropenation of internal alkynes has been
published and the observed levels of enantioinduction were low
(below 20% ee).4a Recently, our group reported an effective
method for the synthesis of racemic, highly substituted
cyclopropenes from the reaction of internal alkynes using
silver triflate (AgOTf) as a catalyst (eq 1).7 Aryldiazoacetates
MonoPhos
Brucine
<5
17
<5
(S)-Tol-BINAP
(R)-DTBM-SEGPHOS
10
10
12
12
a
Standard reaction conditions: 2 (0.5 mmol, 1.0 equiv) in degassed
dichloromethane (8 mL) was added to a 2 mL dichloromethane
solution of 1 (2.5 mmol, 5.0 equiv), AgSbF6 and ligand at 23 °C.
Isolated yield of 3. Determined by chiral HPLC.
b
c
1−3) gave poor levels of enantioinduction (up to 18% ee with
Ag(I)/PHOX complex) (Table 1).10,11 When the PyBOX
ligand 6 was used, diazo decomposition did not occur. The
phosphoramidite ligand MonoPhos (7) provided the cyclo-
propene product in good yield and 7% ee (entry 4).12 Silver
hexafluoroantimonate/brucine complex also provided the
cyclopropene in good yield but no asymmetric induction
(entry 5).13 We then used chiral phosphine-based ligands 8 and
9 for the cyclopropenation reaction (entries 6−7). These
ligands are one of the more generally used ligands for chiral
silver catalysis and have been shown to create excellent
asymmetric environments around the silver center.14 Silver(I)−
phosphine chiral complexes have been shown to be effective in
promoting a variety of carbon−carbon bond forming reactions
such as asymmetric allylation, Mannich-type reactions, aldol
reactions, hetero Diels−Alder reactions, and 1,3-dipolar
cycloadditions.15 However, poor levels of enantioinduction
were obtained in the cyclopropenation using (S)-tolBINAP (8)
and (R)-DTBM-SEGPHOS (9) as ligands (17% and <5% ee).
Because of the disappointing results obtained using silver
catalysts, we turned our attention to the use of chiral gold
catalysts. Previous reports involving gold-catalyzed reactions of
diazo compounds have been limited to the use of achiral gold
complexes, primarily with ethyl diazoacetate as the carbenoid
source.16,17 Our studies focused on the use of Au(I) catalysts,
containing various BINAP-type ligands which have been
popularized by Toste and co-workers (Figure 2).18 These
Au(I) catalysts have been found to promote effectively a variety
are the optimum carbenoid precursors for this chemistry. The
resulting silver-bound donor/acceptor carbenoids offer com-
plementary reactivity to the established rhodium carbenoids in
that they display increased electrophilicity and are less sterically
demanding than their rhodium counterparts.8 Given the recent
demonstrations that the silver carbenoids of donor/acceptor-
substituted diazo compounds have broad synthetic potential,7,8
we have initiated a program to identify enantioselective variants
of this chemistry. In this paper we describe our studies, which
led to the discovery that chiral digold catalysts display similar
reactivity to the achiral silver catalysts, leading to the highly
enantioselective cyclopropenation of internal alkynes by donor/
acceptor carbenoids.
Our exploratory studies began using 1-phenyl-1-propyne 1
and methyl phenyldiazoacetate 2 as suitable test substrates. We
initially examined different chiral ligands generally employed
with silver(I) catalysts in Lewis acid mediated C−C bond
forming reactions.9 Oxazoline-based ligands 4 and 5 (entries
Received: May 17, 2012
Published: July 9, 2012
© 2012 American Chemical Society
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Communication
Table 3. Au(I)-Catalyzed Asymmetric Cyclopropenation of
a
Disubstituted Alkynes
b
c
entry
product
R1
R2
% yield
% ee
1
2
3
4
5
6
7
8
g
13a
13b
13c
13d
13e
13f
13g
13h
13i
H
Me
Et
81
68
70
83
72
62
78
58
76
93
90
94
86
90
98
92
96
89
93
H
H
iBu
Cy
nBu
H
H
H
CH2OTBS
CH2Cy
CH2CHCH2
nBu
Figure 1. Chiral ligands for Ag(I)-catalyzed transformations.
H
H
p-Br
o-Me
10
13j
nBu
75
a
b
Standard reaction conditions: Same as Table 2. Isolated yield of
c
13a−j. Determined by chiral HPLC.
Scheme 1. Au(I)-Catalyzed Cyclopropenation of
Electronically Activated Alkyl Alkynes
Figure 2. Structure of digold complexes.
Table 2. Cyclopropenation of 1 with 2 Using Various Au(I)
a
Chiral Complexes
b
c
entry
Au(l)
temp (°C) % yield
% ee
1
2
3
4
5
6
(S)-tolBINAP(AuCl)2
(S)-tolBINAP(AuCl)2
(S)-xylylBINAP(AuCI)2
(S)-DTBMSEGPHOS(AuCl)2
(S)-BINAP(AuCl)2
23
0
69
74
81
40
62
16
64
0
87
92
0
93
0
−91
92
0
(entry 8). The levels of enantioselectivity does not vary over a
range from 0.5 to 2.0 ratio of (S)-xylylBINAP(AuCl)2/AgSbF6
(see Supporting Information).
(S)-MONOPHOS(AuCl)
(S)-xylylBINAP(AuCl)2
(S)-xylylBINAP(AuCl)2
0
−14
94
d
7
e
0
8
23
0
a
The scope of the cyclopropenation reaction with various
disubstituted alkynes was explored using (S)-xylylBINAP-
(AuCl)2 (10) (12 mol %) activated by AgSbF6 (10 mol %).
The reaction proved to be applicable to a wide range of 1-
arylalkynes and the desired cyclopropenes were obtained in
moderate to good yields and with excellent levels of
enantioinduction (Table 3). The absolute configuration of the
cyclopropene 13a was assigned unambiguously by X-ray
crystallographic analysis.19 The absolute configuration of the
other cyclopropene products was assigned by analogy to 13a.
In general, 1,2-dialkyl alkynes gave poor yields of the desired
cyclopropene products. Electronically activated systems,
however, such as in the case of diyne 14 and enyne 17,
provided the desired cyclopropene products 16 and 18,
respectively, in good yields and with excellent levels of
enantioinduction (Scheme 1).
For the majority of substrates, the chiral gold(I)-complex
provided similar types of products to the achiral silver(I)-
catalyzed reactions, although a few exceptions were found. An
unexpected result was observed in the gold-catalyzed cyclo-
propenation of 1,2-diaryl alkynes (Scheme 2), even though
these substrates provide the desired cyclopropene products
under silver catalysis.7 The use of alkyne 19 as substrate in a
gold catalyzed reaction gave a complex mixture and the major
Standard reaction conditions: 2 (0.5 mmol, 1.0 equiv) in degassed
dichloromethane (8 mL) was added to a 2 mL dichloromethane
solution of 1 (2.5 mmol, 5.0 equiv), AgSbF6 and Au(I) catalyst at
specified temp (°C). Isolated yield of 3. Determined by chiral
HPLC. Reaction was conducted under standard conditions except
b
c
d
1.25 mol % of AgSbF6 and 1.5 mol % of Au(I) catalyst were used.
e
Reaction was conducted under standard conditions except no AgSbF6
was added.
of alkyne and allene transformations.18 However, we have seen
no examples of the use of these catalysts for the reactions of
diazo compounds. It became immediately apparent that digold
complexes when activated by AgSbF6 are excellent catalysts for
asymmetric cyclopropenation with donor/acceptor carbenoids.
Cyclopropenation of 1 with 2 using different Au(I) catalysts
bearing the BINAP ligands provided the cyclopropene 3 with
very high levels of enantioinduction (up to 93% ee with (S)-
xylylBINAP(AuCl)2 (10), entry 3) (Table 2). In contrast to the
results with the chiral digold complexes, mononuclear Au(I)
catalyst with (S)-MonoPhos (7) (entry 6) provided the
cyclopropene product in very poor yield and enantioselectivity
(16% yield, 14% ee). A very similar level of enantioselectivity
was obtained when 1.5 mol % of the digold complex was used
(entry 7). No reaction was observed in the absence of AgSbF6
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Communication
Scheme 2. Au(I)-Catalyzed Reaction of 1,2-Diarylalkyne 19
Table 4. Au(I)-Catalyzed Cyclopropenation of 1 Using
Various Aryl Diazoacetates
a
Scheme 3. Au(I)-Catalyzed Cyclopropenation of
Electronically Activated Alkyl Alkynes
a
b
Standard reaction conditions: Same as Table 2 Isolated yield of
c
24a−i. Determined by chiral HPLC.
conducted to confirm the regiochemistry of the product. The
chiral influence of the catalyst was lost during the trans-
formation affording the product in only 18% ee.
Various aryldiazoacetates were also screened for the
cyclopropenation reaction using 1-phenyl-1-propyne 1 as the
representative alkyne trap (Table 4). Cyclopropene products
24a−i were obtained in moderate to good yields with excellent
levels of enantioinduction when (S)-xylylBINAP(AuCl)2 (10)
was used as catalyst. The reaction is compatible with aryl
halides and aryl triflates. For entries 1−3, the enantioinduction
can be improved further by using (S)-DTBM-SEGPHOS-
(AuCl)2 (12) as the catalyst. The absolute configuration of
cyclopropene 24a was confirmed by X-ray crystallographic
analysis.19
In summary, these studies reveal that chiral digold cationic
complexes are capable of high asymmetric induction in the
cyclopropenation of internal alkynes by donor/acceptor
carbenoids.21 The reactivity of the gold carbenoids is similar
to the silver carbenoids. Most notably, the gold carbenoids have
a very different reactivity profile compared to the correspond-
ing rhodium carbenoids, and are much less susceptible to steric
interference. Therefore, we anticipate that the chiral gold
catalysts will open up new synthetic opportunities for donor/
acceptor carbenoids. Further studies are in progress to explore
the range of the new synthetic opportunities of gold-stabilized
donor/acceptor carbenoids and to determine the actual
structure of the chiral catalysts involved in this chemistry.
product was the indene derivative 20, obtained in 37% yield.
The structure of 20 was confirmed by X-ray crystallographic
analysis.19 This product is probably derived from the initial
attack of the alkyne at the gold carbenoid leading to the
cationic species I. Electrophilic attack of the aryl ring to the
vinyl cation I and subsequent release of the gold catalyst leads
to structure II. This intermediate can then undergo 1,5-
sigmatropic rearrangements to afford the indene product. The
formation of indenes from reaction of aryldiazoacetates and
terminal alkynes has been previously observed when achiral
copper catalysts were used.20
Another interesting transformation showcasing the high
electrophilic character of the Au(I) carbenoid was observed
when the aryl alkyne 21 was used as substrate for the
cyclopropenation reaction (Scheme 3). Instead of formation of
the expected cyclopropene product 22 (which was obtained in
92% yield with AgOTf), the bicyclic product 23 was generated
in 83% yield. The alkyne is considered to attack the metal
carbenoid to form the ionic species I. The pendant aromatic
ring then attacks the vinyl cation to form the bicyclic
intermediate II which then rearranges to norcaradiene III.
The diene undergoes a 6π electrocyclic ring-opening to afford
the cycloheptatriene derivative 23. NOE studies were
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Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
* Supporting Information
Synthetic details and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
hmdavie@emory.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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Llabres I Xamena, F. X.; Sanchez, F. Chem.Eur. J. 2010, 16, 9789−
9795.
(17) For other reactions involving Au(I) carbenoid derived from
diazo compounds please see: (a) Ricard, L.; Gagosz, F. Organometallics
2007, 26, 4704−4707. (b) Li, Z.; Ding, X.; He, C. J. Org. Chem. 2006,
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(18) (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem.
Soc. 2004, 126, 4526−4527. (b) Staben, S. T.; Kennedy-Smith, J. J.;
Toste, F. D. Angew. Chem., Int. Ed. 2004, 43, 5350−5352. (c) LaLonde,
R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. J. Am. Chem. Soc. 2007,
129, 2452−2453. (d) Johansson, M. J.; Gorin, D. J.; Staben, S. T.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 18002−18003. (e) Watson, I.
D. G.; Ritter, S.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 2056−2057.
(f) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007,
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(19) The crystal structures of 13a, 20, and 24a have been deposited
at the Cambridge Crystallographic Data Centre, and the deposition
numbers CCDC 875151, 875157, and 875152 were allocated.
(20) Park, E. J.; Kim, S. H.; Chang, S. J. Am. Chem. Soc. 2008, 130,
17268−17269.
(21) At this stage, the exact structure of the active catalyst has not
been determined. It is well known that the role of combining a silver
salt with a gold chloride pre-catalyst can be more significant than
simply removal of the halide and generation of a gold cation catalyst.
For further discussions, see: Wang, D.; Cai, R.; Sharma, S.; Jirak, J.;
Thummanapelli, S. K.; Akhmedov, N. G.; Zhang, H.; Liu, X.; Petersen,
J. L.; Shi, X. J. Am. Chem. Soc. 2012, 134, 9012−9019. In our case, on
mixing the P2Au2Cl2 complex with AgSbF6, a persistent P2Au2AgCl2
complex is observed by mass spectrometry, suggesting the possibility
that a mixed gold−silver complex may be involved in the catalysis (see
Supporting Information for details).
■
This work was supported by the National Science Foundation
(CHE-1213246), We thank Ken Hardcastle and John Bacsa for
the X-ray crystallographic structural determination.
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NOTE ADDED AFTER ASAP PUBLICATION
■
The version published ASAP July 9, 2012 contained errors in
Tables 2 and 3 and Scheme 2. They were corrected and this
reposted July 12, 2012.
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