Gold catalysis: Non-spirocyclic intermediates in the conversion of furanynes by the formal insertion of an alkyne into an aryl-alkyl C-C single bond

Article abstract of DOI:10.1002/chem.201200306

It takes al-kynes: The formation of furyl-substituted heterocycles from furanynes with donor groups on the furan-alkyne tether and mechanistic control experiments indicate the involvement of open-chained carbenium ions in the overall insertion of an alkyne into a C-C bond, rather than the usual spirocyclic intermediates (see scheme). Copyright

Full text of DOI:10.1002/chem.201200306

COMMUNICATION
DOI: 10.1002/chem.201200306
Gold Catalysis: Non-Spirocyclic Intermediates in the Conversion of
Furanynes by the Formal Insertion of an Alkyne into an Aryl–Alkyl
À
C C Single Bond
A. Stephen K. Hashmi,*[a, b] Tobias Hꢀffner,[a] Weibo Yang,[a] Sreekumar Pankajakshan,[b]
Sascha Schꢀfer,[b] Lara Schultes,[a] Frank Rominger,[a] and Wolfgang Frey[b]
The gold-catalyzed transformation of furanynes 1[1] repre-
sents one of the first homogeneous gold-catalyzed conver-
sions with a broad scope; it was only preceded by the Ito–
Sawamura–Hayashi asymmetric aldol reaction[2] and the nu-
À
À
cleophilic addition reactions that form new C N and C O
bonds.[3] The substrates 1 possess a 1,6-enyne substructure
and, for terminal alkynes, are reliably converted to I
(Scheme 1). During the last decade, several new reactivity
patterns have been discovered by varying the substituents
on 1. Furanynes containing a silyl substituent at the 5-posi-
tion of the furan ring lead exclusively to anellated furans II
by a hydroarylation reaction.[4] With an aryloxy group on
the distal position of the alkyne, the chiral, polycyclic com-
pound III can be obtained.[5] An aryl group on the distal po-
sition and a nitrogen atom in the furanyne tether provides
either the anellated products IV or V (the latter from a 1,7-
enyne), depending on the length of the tether.[6] With a two-
carbon tether containing a siloxy group (such as in the 1,5-
enyne VI), the formation of the 7-arylbenzofurans VII can
be observed.[7]
Most of these reactions proceed through a cationic spiro-
intermediate of the generalized type A (Figure 1) following
coordination of the alkyne to gold and the subsequent elec-
trophilic attack of the activated alkyne at the 2-position of
the furan ring.[8] Similar heterocyclic spirocations have been
discussed previously for the synthesis of different anellated
heterocycles; however, the mechanism has usually been pro-
posed as the 2,3-shift of a substituent leading to VII, rather
than the 3,2-shift that is described herein.[9]
Scheme 1. The different known pathways of the gold-catalyzed furanyne
cycloisomerization.
Figure 1. Common intermediate of the gold-catalyzed furanyne cycloiso-
merizations, A.
[a] Prof. Dr. A. S. K. Hashmi, Dipl.-Chem. T. Hꢀffner, W. Yang,
L. Schultes, Dr. F. Rominger
While investigating the substrate 1a, which contains a cy-
clopropyl group at the furfurylic position of the tether, we
observed a new type of product. By using the Gagosz cata-
lyst,[10] the dihydropyrrole 3a was formed in addition to the
expected 2a (Scheme 2), the structure of which was unam-
biguously assigned by X-ray crystal-structure analysis
(Figure 2).[11]
A possible mechanism for the formation of the insertion
product 3 is shown in Scheme 3. Due to the presence of the
donor group R, the cationic intermediate A can re-aroma-
tize by fragmentation. The previous anti-addition of the gold
Organisch-Chemisches Institut
Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax : (+49)6221-54-4205
E-mail: hashmi@hashmi.de
[b] Prof. Dr. A. S. K. Hashmi, S. Pankajakshan, Dipl.-Chem. S. Schꢀfer,
Dr. W. Frey
Institut fꢁr Organische Chemie
Universitꢀt Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200306.
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Table 1. Screening of catalysts for the conversion of 1a.[a]
Entry
Catalyst
Yield[b] [%]
3a 2a
1
2
3
4
5
Et3PAuCl
Ad2nBuPAuNTf2
dppmACTHNUTRGENUG(N AuCl)2
Mes3PAuNTf2
Ph3PAuNTf2
AgNTf2
AgNTf2
29
12
4
58
87
54
37
0
Scheme 2. Formation of the insertion product 3a during gold catalysis of
1a.
35[c]
30[c]
6
AgNTf2 (C1)
6
39
7
8
AgNTf2 (C2)
AgNTf2 (C3)
13[c]
34
0
15
Figure 2. Solid-state molecular structure of the insertion product 3a.
9
AgNTf2 (C4)
AgNTf2 (C5)
25
0
traces
42
species [Au] to the furan results in the gold atom and the
carbenium ion side-chain being properly located on the
same side of the olefin, which then allows the stabilized car-
benium ion in B to react with the vinyl–gold substructure-
10
ACHTUNGTRENNUNG(Scheme 3). Electrophilic attack at the vinyl–gold intermedi-
ate and elimination of the cationic gold catalyst yields the
new product type by a formal insertion of the alkyne into
11
12
/AgNTf2 (C6)
AgNTf2 (C7)
0
0
42
À
a C C bond. This pathway is likely to be preferred in the
case of substituents R that can stabilize a cationic center.
Overall, the formation of the new heterocyclic ring sug-
gests the existence of “open-chained” non-spirocyclic inter-
mediates of type B in addition to intermediates A. A direct,
concerted, 1,3-sigmatropic shift from A to C is only allowed
as a suprafacial/antarafacial process, a mechanism that was
excluded by control experiments (see below).
traces
13
AgNTf2 (C8)
AgNTf2 (C9)
14
36
As the selectivity for 3a with the Gagosz catalyst was low,
other catalysts were tested for this reaction (Table 1). All
catalysts allowed complete conversion of the substrate, but
the selectivity towards 3a/2a was often low and significant
amounts of unidentified, polar, oligomeric material were
formed. By using alkyl phosphane ligands (Table 1, entries 1
and 2), a dinuclear gold catalyst (Table 1, entry 3), or the
Mes3P ligand (Table 1, entry 4), inferior results were ob-
tained. The highest yield of 3a was indeed obtained with the
Gagosz catalyst[10] (Table 1, entry 5); however, with the use
of catalyst C3, a better selectivity for 3a (and an almost
identical yield) was detected (Table 1, entry 8). Other phos-
phite catalysts (C2 and C4) show a higher selectivity in
favor of 3a, but the yield was poor due to unselective side
14
19
25
15
16
17
18
AuCl
0
24
28
0
94
36
31
0
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
AgSbF6
AgPF6
AgOTs
[a] All reactions were carried out with 5 mol% of the catalyst in CH2Cl2;
[b] Yield determined by NMR spectroscopy; [c] Isolated yield. Tf=tri-
fluoromethylsulfonyl, dppm=bis(diphenylphosphino)methane, Mes=
1,3,5-trimethylbenzyl, Ts=4-toluenesulfonyl.
Scheme 3. A possible mechanism for the formation of the insertion product 3.
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Au-Catalyzed Alkyne Insertion
COMMUNICATION
Table 2. Screening of solvents for the conversion of 1a with Ph3PAuNTf2
(5 mol%).
reactions and decomposition of the starting material
(Table 1, entries 7 and 9). Catalysts with Buchwald-type li-
gands (Table 1, entries 10–12) only gave phenol 2a in mod-
erate yields. Phosphoramidite-based catalysts show similar
selectivity and reactivity to favor phenol 2a (Table 1, en-
tries 13 and 14). Surprisingly, the most simple gold(I) cata-
lyst, AuCl, gave the best yield of phenol 2a in a clean and
selective reaction (Table 1, entry 15). There was no signifi-
cant counter ion effect: the optimum result of the reaction
Entry
Solvent
Yield[a] [%]
2a
3a
1
2
3
4
5
6
7
dichloromethane
nitromethane
acetonitrile
ethanol/water (2:1)
acetone
35[b]
21
30[b]
37
17
–
13
–
[c]
[c]
0
0
traces
traces
complex mixture
toluene
chloroform
À
with the NTf2 counterion (Table 1, entry 5) was not im-
À
[a] Yield determined by NMR spectroscopy; [b] Isolated yield; [c] No re-
action, catalyst insoluble.
proved when investigating the corresponding SbF6 (Table 1,
À
entry 16), PF6 (Table 1, entry 17), or OTsÀ (Table 1,
entry 18) salts. Control experiments with only silver salts or
with p-TsOH gave neither 2a nor 3a.
Next, we investigated the influence of the solvent, but the
CH2Cl2 used initially (Table 2) was the optimal choice and
no improvement could be achieved.
Other substrates were also converted completely but, as
mentioned above, mixtures of polar oligomers were formed
as side products. The substrate 1b, with a vinyl-substituted
oxygen tether, was found to react slowly and highly unselec-
tively. The reaction was finished after 7 h at RT, and the in-
sertion product 3b was isolated in a low yield of 20%
(Table 3, entry 1). The substrate 1c with a phenyl substituent
on the tether was more reactive; the reaction was finished
in 5 min at RT, but again the yield of the expected product
3c was low (30%; Table 3, entry 2), and the crude NMR
Table 3. Formation of the insertion product 3 or phenol 2.
Entry
Substrate 1
Catalyst[a,b]
Insertion Product 3
Yield of 3 [%]
Phenol 2
Yield of 2 [%]
1
1b
1c
B
3b
3c
20
–
–
–
2
3
B
B
30
44
–
–
1d
1e
3d
3e
–
–
4
5
B
43
22
–
1 f
A
3 f
2 f
29
6
7
8
9
1g
1h
1i
A
A
A
A
3g
3h
3i
23
32
36
51
2g
–
42
–
2i
–
39
–
1j
3j
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A. S. K. Hashmi et al.
Table 3. (Continued)
Entry
Substrate 1
Catalyst[a,b]
Insertion Product 3
Yield of 3 [%]
Phenol 2
Yield of 2 [%]
10
1k
A
3k
51
–
–
11
12
1l
A
A
3l
75
42
–
–
–
–
1m
3m
13
14
15
1n
1o
1p
A
A
A
3n
3o
3p
78
85
83
–
–
–
–
–
–
16
1q
A
3q
87
–
–
17
18
1r
1s
A
A
–
–
–
–
–
–
2s
11
19
20
1t
A
B
–
–
–
–
2t
23
32
1u
2u
21
22
1v
A
A
–
–
–
–
2v
65
85
1w
2w
[a] A=Ph3PAuNTf2, B=Mes3PAuNTf2; [b] All reactions were conducted at room temperature with 5 mol% of the catalyst in dichloromethane.
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Au-Catalyzed Alkyne Insertion
COMMUNICATION
spectrum showed intense signals for liberated benzaldehyde.
The phenyl-substituted substrate 1d, with a methyl group on
the furan 3-C, was tested next. The reaction was finished
within 4 min and the product 3d was isolated with a much
better yield of 44% (Table 3, entry 3). The formation of
para-anisaldehyde as a side product was observed in this
case. The more electron-donating para-anisyl-substituted 1e
gave the product 3e in 43% yield (Table 3, entry 4).
oacetyl group as the protecting group on nitrogen in sub-
strate 1t resulted in no formation of the insertion product
(Table 3, entry 19); however, phenol 2t was isolated in 23%
yield.
The structure of insertion product 3 was confirmed by X-
ray crystal-structure analysis for 3k (Figure 3).[11] Two
carbon atoms of the substrate triple bond were formally in-
serted into a carbon–carbon single bond. Formation of
phenol as the expected product was also confirmed by X-ray
crystal structure analysis of compounds 2 f and 2t (Figures 4
and 5).[11]
Having found that the oxy-tethered systems deliver the in-
sertion products only in moderate yields with partial frag-
mentation of the substrate, which corresponds to our previ-
ous observation of a slow reaction in the case of a bridging
oxygen,[12] we returned to nitrogen-tethered substrates. Thus
the substrate 1m with a furyl moiety on the tether was used,
and the five-membered-ring product 3m was isolated in
42% yield (Table 3, entry 12). The substrate 1n, with
a para-anisyl substituent on the tether and a methyl group
on the furan 3-C, was quite reactive and highly selective,
and the insertion product 3n was isolated in a very good
yield of 78% (Table 3, entry 13). The reaction of NSO2tBu-
tethered 1l, which contains a cyclopropyl substituent, was
also impressive, and the product 3l was isolated in 75%
yield (Table 3, entry 11). The substrate 1o followed suit and
furnished 3o with an impressive yield of 85% (Table 3,
entry 14). Most remarkably, none of these substrates showed
Figure 3. Solid-state molecular structure of insertion product 3k.
1
any trace of the phenol products in the crude H NMR spec-
tra. The same is true for the reactions of 1p and 1q
(Table 3, entries 15 and 16, respectively), which also provide
evidence that for 3-methylfurans with aryl substituents in
the tether, this reaction can be regarded as a viable synthetic
method.
However, an electron-withdrawing substituent on the
furan ring was not tolerated; the bromofuran compound 1r
did not react, even after a prolonged reaction time (4 days;
Table 3, entry 17). The interesting substrate 1v, which has
a longer tether consisting of two carbon atoms, did not de-
liver the six-membered insertion product, but reacted in the
classical fashion to form the phenol 2v in 65% isolated
yield (Table 3, entry 21). The substrates 1s and 1w with
ethyl substitution also gave the phenols 2s and 2w, respec-
tively (Table 3, entries 18 and 22). The substrate 1u with an
allyl substituent provided a complex product mixture, and
the phenol product 2u was isolated in only 32% (Table 3,
entry 20).
Figure 4. Solid-state molecular structure of phenol 2 f.
Figure 5. Solid-state molecular structure of phenol 2t.
As the positive charge in the cationic intermediate A is
stabilized by the group R in the tether, the nitrogen also
plays an important role in stabilizing the intermediate.
Hence, the protecting group on the nitrogen atom influences
its ability to stabilize a positive charge in the a position.
With a methylsulfonyl group in substrate 1 f, insertion prod-
uct 3 f and phenol 2 f were obtained in yields of 22% and
29%, respectively (Table 3, entry 5). Furanyne 1g delivered
a similar result for the insertion product 3g (23%, Table 3,
entry 6), whereas more sterically demanding protecting
groups increased the formation of the insertion product up
to 75% isolated yield (Table 3, entries 7–11). In accordance
with this observation, the use of an electronegative trifluor-
Benzofuran substrate 1x delivered neither phenol nor the
insertion product, in accordance with our previous observa-
tions in the context of gold-catalyzed phenol synthesis.[13] In-
stead, hydroarylation product 4x was isolated from reaction
under the optimized conditions in 83% yield (Scheme 4).
The structure of 4x was also confirmed by X-ray crystal-
structure analysis (Figure 6).[11]
For confirmation of the proposed mechanism shown in
Scheme 3, which involves the cationic achiral intermedia-
te A, the enantiomerically enriched compound 1y and enan-
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A. S. K. Hashmi et al.
Scheme 4. Formation of the hydroarylation product 4x (A=
Ph3PAuNTf2).
Figure 6. Solid-state molecular structure of the hydroarylation product
4x.
tiomerically and diastereomerically pure compounds 1za
and 1zb were synthesized. The chiral centers in these com-
pounds were installed by a stereocontrolled Grignard reac-
tion. Since the ee of 1y was only 15%, we also prepared 1k
with an ee of 65%. If the proposed mechanism is correct,
a racemization of the stereocenter at the furfurylic position
of the starting material was expected to occur. Indeed, inser-
tion product 3y showed complete racemization and com-
pound 3z was isolated as a 1:1 mixture of two diastereo-
meres from the reactions of either 1za or 1zb (Scheme 5).
These results are in complete accordance with the proposed
Scheme 5. Experiments supporting the formation of the proposed cation-
ic intermediate B (A=Ph3PAuNTf2).
Acknowledgements
We thank Umicore AG & Co. KG for the generous donation of gold
salts.
À
new mechanism for this gold-catalyzed formal C C insertion
reaction. These observations also rule out the possibility of
a direct symmetry-allowed suprafacial/antarafacial 1,3-shift
from intermediate A to C because a clean inversion of con-
figuration would be expected: the allylic part of the inter-
mediate can only react as the suprafacial component, and
therefore an inversion of configuration at the stereogenic
center at the migrating asymmetric center would be necessa-
ry.
To broaden the scope of the new reaction pathway for
gold-catalyzed phenol synthesis, the furan ring in the fura-
nynes was substituted with aryl, pyrrole, and thiophene
rings. Unfortunately, gold catalysis of these compounds
showed decomposition of the starting material or unselec-
tive reactions.
In conclusion, this study not only provides a new reaction
pathway for furanyne cycloisomerization, but also allows
easy access to new structures, especially in the case of sub-
stituents that strongly stabilize a positive charge. The mech-
anistic investigation also demonstrates the involvement of
open-chained cationic intermediates in furanyne reactions
for the first time. This finding will be of importance for new
developments in other areas of homogeneous gold catalysis.
Keywords: alkynes
heterocycles · reaction mechanisms
·
carbocations
·
furans
·
gold
·
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122, 11553–11554; for recent results on furan synthesis, see: b) J.
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Au-Catalyzed Alkyne Insertion
COMMUNICATION
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5882–5885; Angew. Chem. Int. Ed. 2011, 50, 5762–5765.
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6576–6580.
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Received: January 18, 2012
Published online: && &&, 0000
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A. S. K. Hashmi et al.
Alkyne Insertion
A. S. K. Hashmi,* T. Hꢀffner, W. Yang,
S. Pankajakshan, S. Schꢀfer,
L. Schultes, F. Rominger,
It takes al-kynes: The formation of
furyl-substituted heterocycles from
furanynes with donor groups on the
furan–alkyne tether and mechanistic
control experiments indicate the
involvement of open-chained carbe-
nium ions in the overall insertion of an
W. Frey ......................... &&&& — &&&&
À
alkyne into a C C bond, rather than
the usual spirocyclic intermediates (see
scheme).
Gold Catalysis: Non-Spirocyclic Inter-
mediates in the Conversion of Fura-
nynes by the Formal Insertion of an
À
Alkyne into an Aryl–AlkylC C Single
Bond
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