Gold catalysis: Tandem reactions of diyne-diols and external nucleophiles as an easy access to tricyclic cage-like structures

Article abstract of DOI:10.1002/chem.201001322

Different diyne-diols composed of two terminal homopropargylic alcohol groups were prepared by bi-directional synthesis. Subjection of the syn diastereomers to NAC-gold catalysts (NAC=nitrogen acyclic carbene) in the presence of external nucleophiles such

Full text of DOI:10.1002/chem.201001322

DOI: 10.1002/chem.201001322
Gold Catalysis: Tandem Reactions of Diyne–Diols and External Nucleophiles
as an Easy Access to Tricyclic Cage-Like Structures**
A. Stephen K. Hashmi,*[a] Miriam Bꢀhrle,[a] Michael Wçlfle,[b] Matthias Rudolph,[a]
Marcel Wieteck,[a] Frank Rominger,[a] and Wolfgang Frey[b]
Dedicated to Professor Josꢀ Barluenga on the occasion of his 70th birthday
Abstract: Different diyne–diols com-
posed of two terminal homopropargylic
alcohol groups were prepared by bi-di-
rectional synthesis. Subjection of the
syn diastereomers to NAC–gold cata-
lysts (NAC=nitrogen acyclic carbene)
in the presence of external nucleo-
philes such as water or anilines provid-
ed substituted and highly rigid hetero-
cyclic cages. The corresponding anti
mediate of the reactions of the syn dia-
stereomers could be isolated and even
be characterised by crystal structure
analysis. Overall, eight new bonds are
formed in the reaction, which proceeds
by a multistep sequence of highly selec-
tive hydroalkoxylations and hydrohy-
droxylation or hydroaminations. For
furyl substituents and for internal al-
kynes competing reaction pathways
could be identified. By the cross-cou-
pling of a product with an iodoaryl sub-
stituent, the use of these cage com-
pounds as geometrically defined link-
ing groups by using orthogonal transi-
tion-metal-catalysed
methodology,
Keywords: alcohols
·
alkynes
·
namely, gold and palladium catalysis,
could be demonstrated.
amines · gold · heterocycles
disaACHTUNGTRENNUNGsterACHTUNGTRENNUNGeomers polymerised. An inter-
Introduction
philes as well, thus leading to ketones and acetals as prod-
ucts (Scheme 1a). In the last decades the intermolecular hy-
droalkoxylation and the hydration of alkynes became one of
the benchmark reactions in gold catalysis.[3] In addition to
the intermolecular reactions, a wide range of intramolecular
cyclisations were established, leading to structurally complex
acetals, ketals and spiroketals (Scheme 1b).[4] Furthermore,
In recent years numerous new gold-catalysed reactions have
been reported, and this interesting area of organic chemistry
is still one of the hot topics in current chemistry.[1] The ini-
tial step in most of the gold-catalysed reactions is the activa-
tion of an alkyne by the carbophilic metal centre, followed
by the attack of a nucleophile. The first reports on this reac-
tivity pattern were published nearly 20 years ago by Utimo-
to et al.[2] Besides the addition of nitrogen nucleophiles, they
could show that water and alcohols could serve as nucleo-
[a] Prof. Dr. A. S. K. Hashmi, Dipl.-Chem. M. Bꢀhrle, Dr. M. Rudolph,
M. Wieteck, Dr. F. Rominger
Organisch-Chemisches Institut
Ruprecht-Karls-Universitꢁt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax : (+49)6221-54-4205
E-mail: hashmi@hashmi.de
[b] Dr. M. Wçlfle, Dr. W. Frey
Institut fꢀr Organische Chemie, Universitꢁt Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
[**] The authors thank Umicore AG & Co. KG for the generous donation
of gold salts.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001322.
Scheme 1. Hydroalkoxylation and hydration pathways of alkynes.
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FULL PAPER
combinations of an intramolecular enol ether formation fol-
lowed by a subsequent intermolecular trapping with various
alcohols were described (Scheme 1c).[4b,g,5] A very elegant
and visionary variation of this principle has been reported
by Barluenga et al.[6] Considering the above-mentioned reac-
tion pathways, we were curious to know if it was possible to
use diyne–diols with a suitable distance between the react-
ing groups to induce a selective mono attack of the hydroxyl
groups (Scheme 1d).
A formation of bicyclic bis(enol
ethers) should lead to reactive intermediates that could
allow an entry for further transformations.
Figure 1. Solid-state molecular structure of 2b.
Results and Discussion
(other solid-state structures of syn-diols 2c and 2 f have
been obtained, too).[7] The propargyl side chain shows two
different orientations in the solid state.
With the syn-diols in hand, we first tested the conversion
of 2a with several gold(I) catalysts as well as simple gold-
As a source for possible bis(enol ether) intermediates, the
diols 2 were prepared by a twofold addition of propargyl
Grignard reagent to the readily available 1,2-diketones 1
(Table 1). Products 2 were obtained as a mixture of dia
G
ACHTUNGTREN(NUNG III) chloride. All the reactions were performed in dichloro-
methane saturated with water. One equivalent dodecane
was used as an internal standard and the results are summa-
AHCTUNGTREGrNNUN ised in Table 2. Besides the acetate-coordinated triphenyl-
Table 1. Bidirectional synthesis of diols 2.
Table 2. Catalyst screening.
Entry R1
R2
Crude
d.r.
(syn:anti)
2
a
Yield Isolated
2
d.r.
(syn:anti)
[%][a]
U
Entry
1
Catalyst
Standard:Product
1:1
1
2
3
44:56
50:50
44:56
50
84:16
75:25
91:9
b[c] 25
c[c] 42
4
5
60:40
d
e
42
49
92:8
92:8
2
1:0.65
[b]
–
3
4
5
6
7
8
9
10
Ph3PAuNTf2
AuCl3
nBuAd2PAuNTf2
Ph3PAuOAc/AgNTf2
IPrAuCl/AgNTf2
AgNTf2
1:0.70
1:0.26
1:0.71
1:0
1:0.82
1:0
6
7
50:50
20:80
f[c] 25
80
92:8
g
40:60
[a] Separation conditions optimised for isolation of syn-2. Parts of the anti
isomers were removed by crystallisation during the isolation process.
[b] Complex mixture. [c] X-ray structure determination.[7]
[11]
H-KITPHOSAuNTf2
Cy2BiphenylAuNTf2
1:0.76
1:0.82
[11]
A
phosphine gold(I) complex (Table 2, entry 6), all of the
tested gold compounds (for example, the in situ activated
phosphite-based catalyst (Table 2, entry 2) or the pre-
formed Ph3PAuNTf2 (Table 2, entry 3)) showed significant
reactivity. The best results were obtained by using the acti-
vated NAC–complex (Cat A, Table 2, entry 1; NAC=nitro-
gen acyclic carbene).[9] The conversion with AuCl3 was sig-
nificantly less efficient, and for AgNTf2 only traces of prod-
uct were obtained even after prolonged reaction times.[10]
1:1, the only exception being the methyl-substituted diol 2g
(80%, anti; Table 1, entry 7). Because parts of the anti
isomer could easily be separated by crystallisation (except
for methyl-substituted diol 2g, Table 1, entry 7), the isolated
yields are given for the enriched syn isomers. The structural
assignment of the syn isomers is based on the comparison of
the NMR data and the configuration observed in several X-
ray crystal structure analyses.[7,8] As one representative ex-
ample, Figure 1 displays the solid-state structure of syn-2b
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9847

A. Stephen K. Hashmi et al.
Conversion of the test substrate 2a on a preparative scale
under the optimised conditions allowed the identification of
the reaction product. The product 3a was obtained exclu-
sively in high yield (Table 3, entry 1). Fortunately, the prod-
nation of aryl and alkyl substituents in substrate 2 f also de-
livered the desired product in moderate yield (Table 3,
entry 6). All products are crystalline solids, in addition to 3a
the three products 3b, 3c and 3d could be characterised by
crystal structure analyses.
Finally, substrate 2g that contains a furan–yne substruc-
ture was converted (Scheme 2). In this case two competing
reaction pathways are possible. In addition to the product
Table 3. Substrate scope for the tandem ketalisation.
Entry
1
R1
R2
3
Yield of 3 [%]
a[a]
82
2
3
b[a]
c[a]
75
79
Scheme 2. Competing reaction pathways for substrate 2g.
4
d[a]
69
3g of the domino ketalisation process (initiated by the
oxygen attack, Path A), a competing furan–yne cyclisation
(attack of the furan double bond, Path B) was observed,
leading to significant amounts of phenol 4.[12] Owing to the
syn arrangement of the hydroxyl groups of phenol 4, no fur-
ther cyclisation is possible. Owing to the mild reaction con-
ditions, a gold-catalysed intermolecular addition of water to
the alkyne was also not observed. The structure of 4 is also
based on a crystal structure analysis (Figure 3).
5
6
e
f
58
48
[a] X-ray structure determination.[7]
uct delivered crystals that were suitable for an X-ray crystal
structure analysis.[7] Figure 2 displays the solid-state struc-
ture of 3a, which unambiguously proves the formation of a
Figure 3. Solid-state molecular structure of 4.
Figure 2. Solid-state molecular structure of 3a.
new type of cage-shaped tricyclic ketal. Unfortunately, the
conversion of anti-2a only resulted in decomposition, most
probably due to polymerisation of the intermediate enol
ethers.
To get an impression of the substrate scope, a range of
syn-diols 2 were converted in preparative scales. Both an
electron-donating (Table 3, entry 2) and a bromo substituent
(Table 3, entry 3) at the aromatic system were tolerated.
Switching to the bulkier naphthyl substituent (Table 3,
entry 4) still delivered good yields. Next we investigated
alkyl-substituted diol 2e (Table 3, entry 5), which was also
readily converted, but gave slightly lower yields. The combi-
Encouraged by the results for the ketalisation process, we
considered the possibility of using other external nucleo-
philes than water for incorporation as the bridging atom.
For an initial catalyst screening, we tested the reaction with
substrate 2a and three equivalents of aniline as the nucleo-
phile under different reaction conditions. The results are
presented in Table 4. NHC ligands as well as NAC ligands
showed good conversions with the NTf2 counterion, with
only a minor influence of the solvent. The reaction times for
the aniline additions were longer: after 3 h still no complete
conversion was observed for all of the tested catalyst sys-
tems. The optimum conditions were found to be the NAC–
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Easy Access to Tricyclic Cage-Like Structures
FULL PAPER
Table 4. Catalyst optimisation for intermolecular nitrogen nucleophiles.
Entry Catalyst AgX
Solvent
Standard:Product Standard:Product
after 3 h
after 72 h
1
2
3
4
5
6
7
8
9
IPrAuCl AgNTf2 DCM
Cat A AgNTf2 DCM
IPrAuCl AgNTf2 toluene
Cat A AgNTf2 toluene
IPrAuCl AgNTf2 acetonitrile 1:0.53
Cat A AgNTf2 acetonitrile 1:0.43
IPrAuCl AgSbF6 DCM
Cat A AgSbF6 DCM
IPrAuCl AgSbF6 toluene
Cat A AgSbF6 toluene
1:0.53
1:0.57
1:0.53
1:0.59
1:0.75
1:0.69
1:0.70
1:0.78
1:0.88
1:1
1:0
1:0
1:0
1:0
Figure 4. Solid-state molecular structure of 5a.
1:0
1:0
1:0
1:0
alkyl-substituted anilines. In the cases of a mono substitu-
tion, high yields were obtained for ortho-, meta- and para-
substituted anilines (Table 5, entries 3–7). In the case of o,o-
10
Table 5. Reaction of different substrates 2 with different nitrogen nucleophiles.
catalyst (Cat A) activated with
AgNTf2 in acetonitrile (Table 4,
entry 6). A massive counterion
effect was visible by changing
the counterion to hexafluoroan-
timonate; in these cases no re-
action took place under various
conditions (Table 4, entries 7–
10).
Entry
1
2
a
Nucleophile
Product
Yield [%]
80
Time
16 h
5a[b]
Under the optimised condi-
tions different N nucleophiles
were subjected to the diols 2.
Table 5 gives an impression of
the synthetic potential and the
limitations. Starting with simple
aniline (Table 5, entry 1), we
were pleased to obtain promis-
ing results for N nucleophiles
as well. As in the case of the
water addition, a high yield of
80% was achieved. Once again
the results of the X-ray crystal
structure analysis delivered the
proof for the structural assign-
ment of the resulting tricyclic
system (Figure 4 for 5a).[7]
Changing the substituents at
the starting diols to alkyl dra-
matically reduced the reactivity.
No complete conversion was
observed for the addition of
aniline, even after prolonged
reaction times, and therefore
only 15% of the desired prod-
uct 5b could be isolated
(Table 5, entry 2). As a result,
we switched back to aromatic
diols again. First we tested
2
3
e
a
5b[b]
5c[b]
15[c]
96
16 h
3 d
4
5
a
a
5d
5e
82
81
2 d
5 d
6
7
a
a
5 f[b]
5g[b]
80
85
16 h
16 h
8
9
a
a
5h
18
2 d
2 d
–
unselective
10
11
12
a
a
a
–
no reaction
6 d
5i[b]
5j
76
77
16 h
16 h
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9849

A. Stephen K. Hashmi et al.
revealed unselective reactivity
(Table 5, entry 9). Next we ex-
plored the functional-group tol-
Table 5. (Continued)
Entry
2
Nucleophile
Product
Yield [%]
85
Time
16 h
13
a
5k
erance. Although
a
second
amino functionality was not tol-
erated (Table 5, entry 10), no
problems occurred with elec-
tron-deficient trifluoromethyl-,
nitrile- and bromo-substituted
anilines, all of them delivering
high yields (Table 5, entries 11–
13). In that series, a nitro sub-
stituent was the limit (Table 5,
entry 14). Probably due to the
slow
decomposition
14
15
a
a
–
–
11 d
5 d
no reaction
16
17
18
19
20
a
a
a
a
a
–
no reaction
2 d
5l[b]
5m
5n
5o
59
52
84
45
28 d
2 d[a]
16 h
16 h
strong
electron-withdrawing
effect, only minor conversion
and poor selectivity was ob-
served. Substrates with addi-
tional unprotected hydroxy
functions were also not suitable
(Table 5, entries 15 and 16).
Surprisingly, no reaction took
place even after several days.
Most probably this is caused by
a reduction of the catalyst by
the substrate; the silyl-protect-
ed derivatives (Table 5, en-
tries 17 and 18), as well as a
21
22
a
a
5p[b]
81
16 h
4 d
–
no reaction
23
24
a
a
5q
88
33
39
16 h
14 d
5r[b] and
methyl
ether
derivative
(Table 5, entry 19), could, how-
ever, be converted in reasona-
ble yields. Although an unpro-
tected acid moiety as well as a
ketone were tolerated at the
para position of the aromatic
ring (Table 5, entries 20 and
21), p-aminobenzoic acid ethyl
ester (Table 5, entry 22) showed
no reactivity. Changing the aro-
matic system of the nucleophile
was also possible; a-naphthyl-
25
26
27
a
a
a
–
6
–
no reaction
25[c]
4 d
7 d[a]
1 d
unselective
28
29
a
c
5s
5t
99
71
16 h
2 d
AHCTUNGTRENNUNG
entry 23), and even electron-de-
ficient 2-aminopyridine showed
moderate conversion after pro-
longed reaction times (Table 5,
entry 24). In the case of 2-ami-
nopyridine, we were able to iso-
late significant amounts of bicy-
clic double enol ether 6. The
solid-state structure of this in-
termediate (see below) nicely
shows the open-cage structure
30
31
a
a
5u
5v
63
52
16 h
16 h
[a] 608C. [b] X-ray structure determination.[7] [c] Incomplete conversion.
disubstituted anilines, a significant drop in yield was ob-
served for the dimethyl case (Table 5, entry 8) and the reac-
tion with sterically more demanding isopropyl groups only
of these systems. Although adamantyl amine showed no re-
activity (Table 5, entry 25), intermediate 6 could be isolated
with phenethylamine as the nucleophile (Table 5, entry 26)
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but incomplete conversion,
even under elevated tempera-
tures, limited the yield. Still,
this is a unique case because 6
represents one of the few cases
in which intermediates of gold-
catalysed conversions can be
isolated and fully character-
ised.[13] The conversion of tosyl-
ACHTUNGTRENNUNGamide failed probably owing to
its decreased nucleophilicity
(Table 5, entry 27). Finally, we
tested hydrazine derivatives as
nucleophiles. Good to excellent
results were obtained for ben-
zylcarbazate (Table 5, entries 28
and 29), and tert-butyl carba-
zate as well as tosylhydrazine
also delivered satisfying results
(Table 5, entries 30 and 31).
This opens the possibility for
further functionalisation at
these positions.
Scheme 3. Further modifications of tricycles 5 through cross-coupling.
By the incorporation of p-io-
doaniline in the resulting tricy-
cle 5w, a substrate that can
easily be modified through
cross-coupling methods, was ob-
tained (Scheme 3). To demon-
strate the access to complex
molecular structures by using
the orthogonality of two metals,
5w was converted under Sono-
gashira conditions. Coupling
with ethynylestradiole accom-
plished the modified tricycle 5x
in 60% yield.
Overall, many of the sub-
strates could be characterised
by single-crystal structure anal-
Scheme 4. Mechanistic hypothesis for the tandem cyclisation.
yses, namely, 5b, 5c, 5 f, 5g, 5i, 5 l, 5p and 5r.
Our mechanistic hypothesis is illustrated in Scheme 4. As
mentioned in the introduction, the first intramolecular hy-
droalkoxylation by the tethered hydroxyl function is initiat-
ed by the p coordination of the gold catalyst. The tether
length of the second hydroxyl moiety in the resulting enol
ether
I now circumvents the usual reaction pathway
(Scheme 1b). Instead of the more reactive, activated[14] enol
ether part (which would lead to acetal formation), the
tether length means that the molecule is predestined for a
second intramolecular nucleophilic attack to the alkyne, the
second hydroalkoxylation, to form intermediate 6. As men-
tioned above, we indeed succeeded in isolating 6 and even
characterising this crucial intermediate[13] by an X-ray crystal
structure analysis (Figure 5). The open-book effect in 6 then
directs the gold catalyst to the exo face of the enol ether
and thus the intermolecular attack of the nucleophile to
Figure 5. Solid-state molecular structure of 6.
form hemi-acetal/-aminal II by a hydrohydroxylation or hy-
droamination occurs from the endo face. Another, now in-
tramolecular hydroalkoxylation or hydroamination of the in-
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9851

A. Stephen K. Hashmi et al.
corporated nucleophile finally delivers tricyclic products as
single diastereomers. To ensure that intermediate 6 is not
only a side product, isolated 6 was re-subjected to the reac-
tion conditions (Table 6). Although Cat A led to complete
Table 6. Conversion of isolated intermediate 6 with H2O.
Figure 6. Solid-state molecular structure of 8.
Entry
Catalyst
Result
1
2
3
Cat A
p-TsOH
–
complete conversion to 3a
decomposition of the starting material
no conversion
formation of 3a, decomposition was observed with para-tol-
uenesulfonic acid[15] and no conversion took place in the ab-
sence of any catalyst. This stresses the fact that not only the
additions to the alkynes, but also the additions to the enol
ether substructures of the intermediates are only efficient
and selective if converted under the mild conditions of gold
catalysis.
Additional proof for the importance of terminal alkynes
for the reaction was obtained by the conversion of non-ter-
minal diyne–diol 7, which was easily available by a Sonoga-
shira coupling. In this case two products were obtained: the
tricyclic ketals 9, and acetal formation and subsequent water
addition delivered product 8 (Scheme 5). Both structural as-
signments could be verified by the results of a crystal struc-
ture analysis (Figure 6 and Figure 7).
Figure 7. Solid-state molecular structure of 9.
Conclusion
Readily available syn-diyne–diols syn-2 with adequate tether
length provide an easy and highly selective access to highly
reactive double enol ether intermediates upon subjection to
the new NAC-gold catalysts. In a domino cyclisation process,
various functionalised intermolecular nucleophiles can be in-
corporated in these open-book-like structures, finally lead-
ing to extremely rigid cage-like assembly in a highly selec-
tive reaction. By using the orthogonality of gold and palladi-
um, a subsequent cross-coupling of the resulting tricycles
could be demonstrated. To get an impression of the rigidity
of the framework created by this methodology, Figure 8
shows a superimposition of two representative examples of
the new substrate class. In these geometrically very similar
structures, only a slight torsion of the attached aromatic
moieties is visible. The incorporation of other types of nu-
cleophiles and further variations of the starting diyne–diols,
for example, by introduction of functional groups for cross-
coupling reactions orthogonal
The selectivity-determining step of the reaction is most
probably the initial attack of the tethered oxygen, which in
the non-terminal case delivers intermediates III and IV de-
rived from
a
5-exo-dig or 6-endo-dig[16] cyclisation
(Scheme 6). Intermediate III now once again favours the 5-
exo-dig process versus the 4-exo-trig enol ether attack,
which results in the formation of product 9. In the case of
intermediate VI, the distance between the enol ether part
and the hydroxyl group enables the nucleophilic attack of
the hydroxyl group at the more reactive enol ether part, and
no 6-endo-dig or 5-exo-dig attack at the alkyne takes place
in this intramolecular competition. Finally, water attacks at
the remaining alkyne and delivers product 8.
to the gold-catalysis are under
investigation and will be pub-
lished in due course. Especially
the use as a core group in mate-
rial science, placing electroni-
cally/photochemically active p
systems at well-defined distan-
Scheme 5. Reaction of non-terminal alkynes.
ces is a focus of these efforts.
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FULL PAPER
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Yi, J. H. Lee, New J. Chem. 2007, 31, 835–837; b) for a comparison
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[12] For representative examples of the gold-catalysed phenol synthesis,
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Received: May 15, 2010
Published online: July 14, 2010
9854
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9846 – 9854