Gold(I)-catalyzed bis-alkynylation reaction of aromatic aldehydes with alkynylsilanes

Article abstract of DOI:10.1002/adsc.201300578

The first successful gold(I)-catalyzed reaction of aryl aldehydes with trimethyl(arylethynyl)silanes to furnish bis-alkynylated derivatives is reported. Key C-C bond-forming events involved in the catalytic cycle are analyzed. Copyright

Full text of DOI:10.1002/adsc.201300578

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DOI: 10.1002/adsc.201300578
Gold(I)-Catalyzed Bis-Alkynylation Reaction of Aromatic
Aldehydes with Alkynylsilanes
Belꢀn Rubial,a Alfredo Ballesteros,a and Josꢀ M. Gonzꢁleza,*
a
Departamento de Quꢂmica Orgꢁnica e Inorgꢁnica and Instituto Universitario de Quꢂmica Organometꢁlica “Enrique
Moles”, Universidad de Oviedo, C/ Juliꢁn Claverꢂa 8, 33006 Oviedo, Spain
Fax : (+34)-985-103-446; phone: (+34)-985-102-980; e-mail: jmgd@uniovi.es
Received: June 28, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300578.
Abstract: The first successful gold(I)-catalyzed re-
action of aryl aldehydes with trimethyl(arylethyn-
required. This claim is solidly supported by pertinent
experimental work. Also, concerning the second C C
bond-forming event, which eventually furnishes the
products through an intermediate propargyl cation,
the central role that the rhenium catalyst plays was
proven,[5,6] and gold chloride was shown to be ineffi-
cient to assist this task.
À
yl)silanes to furnish bis-alkynylated derivatives is
À
reported. Key C C bond-forming events involved
in the catalytic cycle are analyzed.
Keywords: aldehydes; alkynes; coupling; gold; sili-
con
On the basis of our ongoing research program in
gold catalysis[7] and the acquired experience in iodoni-
À
um-mediated activation of C C unsaturations for re-
action discovery,[8] we were intrigued about the possi-
bility of timely developing an entirely gold-based ap-
Nowadays gold catalysis offers a valuable tool in proach to achieve this demanding aldehyde bi-func-
searching for new chemical transformations[1] and ap- tionalization process, which ultimately relies on the
À
proaching a swift increase of molecular complexity catalytic and consecutive creation of two C C bonds
from carbon-carbon unsaturations.[2] The selective ac- in one synthetic operation.[9] Considering the concep-
tivation of an alkyne by a proper carbophilic gold tual frame graphically outlined in Scheme 2, we rea-
centre is often at the onset of these reactions.[3,4]
soned that tuning the nature of the electrophilic
A significant bis-alkynylation reaction of aromatic metal would allow execution of this tandem process
aldehydes and alkynylsilanes was recently disclosed. on the exclusive basis of gold catalysis.[10]
Cooperation of two metals, a rhenium(I) complex and
First, as a consequence of the activation of the
gold(I) chloride, is required to provide catalytic alkyne by the carbophilic gold catalyst, and likely as-
access to the depicted 1,4-diyne scaffolds sisted by the presence of the added carbonyl group,
(Scheme 1).[5] The synergic action of the two catalysts the reaction could give rise to the formation of the
to accomplish the overall bis-alkynylation process is corresponding gold acetylide. In turn, this would pro-
Scheme 1. Seminal work on the synthesis of diethynylmethane frames by the rhenium/gold-catalyzed direct coupling between
aldehydes and alkynylsilanes.
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Several ligands were found to be useful to produce
gold(I) complexes that behave as active catalysts for
the target transformation. The best result in the direct
assembly of 3a was accomplished using di-tert-butyl-
(o-biphenyl)-phosphine (JohnPhos) as the ancillary
ligand. Besides, bis(trifluoromethanesulfonyl)imidate
(NTf2) was selected as counteranion, on a routine
basis. Compared with halides, its use avoids the need
for adding silver salts to generate gold catalysts en-
dowed of high electrophilicity, as early documented
by Gagosz.[14] For the reaction of 1a with 2a, heating
allows us to shorten the reaction time. Furthermore,
more demanding substrates required this option to
react efficiently. In this scenario, the gold(I) complex
with JohnPhos (Scheme 3, ligand L3) was found to be
superior to the other ligands tested.[15]
Scheme 2. Working hypothesis to obtain 1,4-diynes from al-
dehydes and alkynylsilanes under sole gold(I)-catalysis.
The scope of the reaction was further investigated
vide an activated form of the carbonyl group as the using thermal conditions, in search for both a fast re-
result of its interaction with the in situ generated action and wide aldehyde compatibility. After some
source of an oxophilic silicon reagent.[11] This set-up initial exploratory studies, it was found that simply
À
would favour the formation of the first C C bond, conducting the reaction at 708C, in 1,2-dichloroethane
which affords an O-silylated propargyl alcohol. Next, as solvent, provides convenient experimental condi-
the inherent basic character of the ether would facili- tions for various aldehydes. The results for the John-
tate its activation, again as a consequence of its com- PhosAuNTf2-catalyzed reaction of the trimethylsilyl
petent role to capture an additionally released silicon- derivative of phenylacetylene towards a variety of car-
based electrophile. In the end, the eventually resulting bonyl derivatives are now summarized and depicted
propargyl cation would trap another molecule of the in Table 1.
gold acetylide and deliver the noticed 1,4-diyne scaf-
The reaction allows us to prepare a representative
set of 3-aryl-substituted 1,4-diynes in fair to good
fold.[12]
We decided to explore the validation of this hy- yield. Interestingly and for the first time, this transfor-
pothesis making use of the already well recognized al- mation is shown to take place under the sole influ-
teration in the reactivity trend for gold(I) catalysts as ence of gold(I) catalysis. Aryl- and naphthyl-substitut-
function of the nature of the ancillary ligand. This ed aldehydes (entries 4 and 5) react satisfactorily
notion provides a key designing feature in attempting under these conditions. For the former the substituent
to meet the goal of accessing the target catalytic bis- at the 4-position was modified and the process was
alkynylation reaction on the ground of a single gold found to be compatible with both electron-donating
catalyst.[13] In the screening of gold catalysts, the room groups (see, for instance, entries 7 and 9) and elec-
temperature reaction of benzaldehyde 1a with trime- tron-withdrawing groups (entries 1, 6 and 8). The re-
thyl(phenylethynyl)silane 2a for a period of 90 min action outcome is also of practical utility for sub-
was investigated as model (Scheme 3).
strates in which the substituent switches from the
para- to the ortho-position (entries 2 and 3). Even
a more densely functionalized molecule was efficient-
ly transformed (see entry 10).
Hexanal, a simple aliphatic aldehyde, failed to react
using the same experimental protocol. Nevertheless,
simply changing the solvent, using acetonitrile rather
than 1,2-dicholoroethane, allows the first addition
step to take place (Scheme 4); thus, matching the
early noticed scope for the reaction of aliphatic alde-
hydes catalyzed by the bimetallic system, but relying
only on a proper gold catalyst.[5]
Next, a microwave-assisted heating protocol was
developed and found to be useful for reducing the re-
action time and the catalyst loading at once. For in-
stance, diyne 3h was prepared from 4-methoxybenzal-
dehyde and phenylacetylene in parallel yield to the
one accomplished under the standard thermal condi-
Scheme 3. Gold catalysts for aldehyde bis-alkynylation.
2
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Gold(I)-Catalyzed Bis-Alkynylation Reaction of Aromatic Aldehydes with Alkynylsilanes
Table 1. Gold-catalyzed bis-alkynylation of aryl aldehydes.
Table 1. (Continued)
Entry Product
T
t
Yield
[8C] [min] [%][a]
9
3j 70
20
15
77
73
Entry
Product
T
t
Yield
[8C] [min] [%][a]
10
3k 70
1
3b 70
3c 70
3d 70
180
30
72
65
77
[a]
Isolated yield after chromatography.
[b]
Yield measured from the crude reaction by NMR, using
acetanilide as internal standard. Mono-alkynylated 4g
also present in 12% yield.
2
3
30
Scheme 4. Catalytic mono alkynylation of hexanal.
4
5
3e 70
15
30
60
58
3f 70
Scheme 5. 1,4-Diynes: microwave-assisted gold catalysis.
6
7
8
3g 80
3h 70
3i 70
120
30
53[b]
tions developed earlier (Table 1, entry 7), but now
using only 1 mol% of JohnPhosAuNTf2, 3 min reac-
tion time and lower excess of alkyne (Scheme 5).
This protocol was further tested over additional
model compounds. The results are reported in
Table 2.
The catalyst loading was diminished in all cases.
For most of alkynylsilanes the reaction time was re-
duced without much affecting the yield, which even
was slightly improved for some specific products, such
as for 3c. Besides, under these alternative experimen-
tal conditions, silyl-substituted aliphatic terminal al-
kynes (entries 9–11) were found to be useful partners
in processes taking place at 1208C, under microwave
irradiation. Although still in modest yield, and requir-
66
30
77
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Table 2. Microwave-assisted aldehyde bis-alkynylation.
ing further optimization, this finding
expands the scope for the known
metal-catalyzed direct bis-alkynACHTUNGTRENNUNGylation
reaction of aldehydes and alkynylsi-
lanes.[5,16] Moreover, the reactivity of
a two-ends silicon-caped and chemical-
ly differentiated surrogate for acety-
lene is challenging. Thus, starting from
À ꢀ À
readily available TMS C C TBDMS,
Entry
Product
t [min] Yield [%][a]
the attractive diyne 3s (Table 2,
entry 12) was directly assembled from
benzaldehyde.
1
2
3
4
3a (R=H)
35
105
15
70
42
73
74
This experimental protocol is
robust. Typically, reactions were con-
ducted on a 0.4-mmol scale of alde-
hyde 1. Remarkably, using the proto-
col defined in Scheme 5, 3c was pre-
pared after chromatography (silica gel,
hexane-CH2Cl2, 20:1) on a gram scale
(1.2 g, 65%) from the reaction of 1c
(6 mmol) and 2a (2.5 equiv.) catalyzed
by JohnPhosAuNTf2 (1 mol%), in 1,2-
dichloroetane (12 mL) heating under
microwave irradiation at 1508C for
15 min.
3b (R=4-Br)
3c (R=4-Me)
3d (R=2-Me)
15
5
3e
5
50
6
7
8
3m (Ar=4-Me-C6H4)
3n (Ar=4-Br-C6H4)
3o (Ar=4-MeO-C6H4) 20
5
100
40[b]
37[c]
50
The content reported in Table 1 and
Table 2 agrees with the assumption
outlined in Scheme 1 and reveals that
gold, in its own right, is a proper metal
to catalyze the desired bis-alkynylation
process, simply on adjusting the elec-
trophilic nature and stability of the in-
tended catalyst. Further experimental
work was conducted to scrutinize this
claim and to offer a rationale for some
of the noticed findings. Relevant data
are given in the following paragraphs.
At the onset, the possibility of alde-
hydes directly reacting with gold ace-
tylides was ruled out on an experimen-
tal basis. A mixture of 1a and the gold
acetylide 6a (1:2.5 molar ratio) was
stirred at room temperature, in 1,2-di-
chloroethane, for one hour and a half
without noticeable change. Subse-
quently, the mixture was heated at
708C for an identical period of time.
NMR inspection of the crude reaction
9
3p
3q
15[d]
30
31
10
11
90[d]
3r
3s
5[d]
25
39
12
1
À
shows a lack of C C bond-forming
processes taking place.
The
proposal
formulated
in
[a]
Scheme 1 invokes the addition of
gold(I) acetylide[17] to the aldehyde ac-
tivated by the in situ generated active
silicon.[18] Additional support to vali-
date this arrangement comes from the
experiment depicted in Scheme 6.
Isolated yield after chromatography.
57% yield for 3m using the conditions depicted in Table 1 (708C, 4 h,
5 mol% of catalyst).
65% yield for 3n under the conditions depicted in Table 1 (4 h at 708C,
5 mol% of added catalyst).
At 1208C (MW), 5 mol% catalyst loading.
[b]
[c]
[d]
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Gold(I)-Catalyzed Bis-Alkynylation Reaction of Aromatic Aldehydes with Alkynylsilanes
reaction of JohnPhosAuNTf2 (0.05 mmol) with excess
(1 mmol) of 2a, in dry CDCl3. Almost instantaneously,
a representative peak is evident from the 31P NMR
spectrum. This new signal at d=62.7 ppm is indicative
of the desilylation[21c] and accounts well for the forma-
tion of 7a under the reaction conditions.
The capability of JohnPhosAuNTf2 to catalytically
promote the second alkynylation step was also docu-
mented (Scheme 7).
This time, 2a was allowed to react with pure 4a in
the presence of the catalyst, at room temperature, to
afford the target bis-alkynylated derivative 3a in 60%
isolated yield. The observed outcome for this reaction
offers clear proof of the competence of the title modi-
fication of gold(I) to effect catalytic access to the
Scheme 6. Activating aldehydes towards gold acetylides.
[22]
À
The examples in Scheme 6 endorse the intended second key C C bond-forming event.
active involvement of a gold acetylide as a reactive in-
Besides, ongoing activity on dinuclear gold s,p-
termediate. Interestingly, this experimental protocol alkyne complexes and their impact on various pro-
stands for the labile heterocyclic indole scaffold.[19]
cesses involving dual catalysis[23] prompted us to
The activation of alkynylsilanes 2 by gold(I) was broach the reactivity of 7a in this new synthetic sce-
also tested. Exposing 2a to JohnPhosAuNTf2 in the nario.[24] In this regard, reaction of 1h with 2a under
absence of 1 proves that alkyne desilylation smoothly the catalytic influence of the s,p-digold catalyst 7a
occurs. In this regard, addition of 2a to a solution of (2.5 mol%) was totally inefficient to produce the de-
the above mentioned gold source (2.5ꢄ10À3 M in dry sired 3h, either at room temperature or heating in
CDCl3, at room temperature, 1.0:1.5 molar ratio for 1,2-dichloroetane at 708C. Remarkably, carrying out
gold and the alkyne, respectively) furnishes the s,p- the reaction at 1508C, under microwave irradiation,
digold phenylacetylene adduct 7a.[20,21]
affords 3h in 72% isolated yield, in 30 min
(Scheme 8).
Eventually, altogether those experiments nicely
provide compelling evidence that firmly support the
invoked hypothesis behind the aim for this study.[25]
Overall, and for the first time, gold(I) catalysis has
been found to be efficient to accomplish a direct alde-
hyde bis-alkynylation synthetic operation. The out-
Alternatively, a fast formation of 7a was also evi- come of the herein reported protocol, based on the
dent upon NMR monitoring of the evolution of the sole use of JohnPhosAuNTf2 as catalyst parallels, and
slightly enlarges, the scope noticed for the bimetallic
catalytic systems based on Re(I) and Au(I) used in
the pioneering work by Kuninobu and Takai. Rea-
search is in progress in our laboratory to further in-
vestigate the impact of this transformation. Main ef-
forts will be devoted to unveil new catalytic processes
where the unique combination of gold and silicon
might acts as a trigger as the result of the in situ
switching from carbophilic to oxophilic control.
Scheme 7. Gold(I) catalysis: alkynylation of propargyl silyl
ether.
Scheme 8. s,p-Digold species in the catalytic aldehyde bis-alkynylation reaction.
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Wright II, F. S. Tham, S. Quinlivan, Angew. Chem.
2013, 125, 3255–3258; Angew. Chem. Int. Ed. 2013, 52,
3172–3176; i) H. Ito, A. Harada, H. Ohmiya, M. Sawa-
mura, Adv. Synth. Catal. 2013, 355, 647–652; j) Y.
Wang, L. Liu, L. Zhang, Chem. Sci. 2013, 4, 739–746;
k) S. Ghorpade, M.-D. Su, R.-S. Liu, Angew. Chem.
2013, 125, 4323–4328; Angew. Chem. Int. Ed. 2013, 52,
4229–4234; l) T. Iwai, H. Okochi, H. Ito, M. Sawamura,
Angew. Chem. 2013, 125, 4333–4336; Angew. Chem.
Int. Ed. 2013, 52, 4239–4242.
Experimental Section
General Procedure
A
mixture of aldehyde 1 (1 equiv.), alkynylsilane 2
(3.75 equiv.) and JohnPhosAuNTf2 (5 mol%) was dissolved
in 1,2-dichloroethane (0.5M) and heated at 708C to afford
bis-alkynylation product 3, which was purified by flash chro-
matography (silica gel, hexane).
[5] Y. Kuninobu, E. Ishii, K. Takai, Angew. Chem. 2007,
119, 3360–3363; Angew. Chem. Int. Ed. 2007, 46, 3296–
3299.
Acknowledgements
[6] For rhenium-catalyzed coupling reactions of propargyl
alcohols with allyl silanes, see: M. R. Luzung, F. D.
Toste, J. Am. Chem. Soc. 2003, 125, 15760–15761.
[7] a) S. Suꢁrez-Pantiga, C. Hernꢁndez-Dꢂaz, E. Rubio,
J. M. Gonzꢁlez, Angew. Chem. 2012, 124, 11720–11723;
Angew. Chem. Int. Ed. 2012, 51, 11552–11555; b) S.
Suꢁrez-Pantiga, C. Hernꢁndez-Dꢂaz, M. Piedrafita, E.
Rubio, J. M. Gonzꢁlez, Adv. Synth. Catal. 2012, 354,
1651–1657; c) S. Suꢁrez-Pantiga, E. Rubio, C. ꢈlvarez-
Rffla, J. M. Gonzꢁlez, Org. Lett. 2009, 11, 13–16.
Generous financial support by the Spanish MINECO and the
Principality of Asturias (Grant CTQ2010-20517-C02-01 and
FC-11CO11-17) are acknowledged. B. R. is grateful to the
Spanish Government for an FPU predoctoral fellowship.
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Gold(I)-Catalyzed Bis-Alkynylation Reaction of Aromatic Aldehydes with Alkynylsilanes
[15] For instance, the reaction of 4-bromobenzaldehyde 1b
with 2a requires additional heating to take place satis-
factorily. When the mixture was heated at 808C, for
105 min, in 1,2-dichloroethane, 1b was fully consumed
and the bis-alkynylated derivative 3b was obtained.
The yield was dependent on the ligand on gold, with
the JohnPhos (L3) catalyst giving rise to best isolated
yield for 3b (75%). Under these conditions, the gold
catalyst with the phosphite ligand (L1) affords a less
clean reaction and furnishes 3b in the range of 60%,
whereas the IPr-containing catalyst gives 65% yield.
[16] Under the heating process conditions reported in
Table 1, these aldehydes fail to produce the corre-
sponding compounds 3. Only mono-addition products
were detected, except for the case of 2p that gave rise
to trace amounts of 3p.
[17] For recent reports involving gold(I) acetylides, see:
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F. Jaroschik, D. Lesage, M. Karanik, R. Guillot, M.
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À
[22] For gold-catalyzed C C bond forming reactions from
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[23] For a highlight on this topic, see: a) A. Gꢇmez-Suꢁrez,
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[18] a) A. Schulz, A. Villinger, Angew. Chem. 2012, 124,
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ˇ
ˇ
ˇ
´
b) H. Cicak, H. Vancik, Z. Mihalic, J. Org. Chem. 2010,
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[24] 7a is easily prepared from 6a and JohnPhosAuNTf2, see
the Supporting Information. Alternatively, the desired
transformation can be accomplished in comparable
yield from a reaction relying on in situ performing the
catalyst, just mixing JohnPhosAuNTf2 and 6a in 1:1
molar ratio.
[19] Previously, 3t was prepared in 45% from the catalytic
reaction of 1t and 2a using the conditions outlined in
Scheme 2 and Table 1, except for running the reaction
at room temperature for 2 h.
[20] For experimental details and characterization data, see
the Supporting Information.
[25] A. S. K. Hashmi, Angew. Chem. 2010, 122, 5360–5369;
Angew. Chem. Int. Ed. 2010, 49, 5232–5241.
[21] For recent work on digold-acetylide complexes, see:
a) A. S. K. Hashmi, T. Lauterbach, P. Nçsel, M. H. Vil-
Adv. Synth. Catal. 0000, 000, 0 – 0
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COMMUNICATIONS
8 Gold(I)-Catalyzed Bis-Alkynylation Reaction of Aromatic
Aldehydes with Alkynylsilanes
Adv. Synth. Catal. 2013, 355, 1 – 8
Belꢀn Rubial, Alfredo Ballesteros, Josꢀ M. Gonzꢁlez*
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