Gold- or Indium-Catalyzed Cross-Coupling of Bromoalkynes with Allylsilanes through a Concealed Rearrangement

Article abstract of DOI:10.1021/acscatal.9b02314

The gold(I)-catalyzed reaction of bromoalkynes with allylsilanes gives 1,4-enynes in a formal cross-coupling reaction. Mechanistic studies revealed the involvement of gold(I) vinylidenes or vinylidenephenonium gold(I) cations depending on the substituent on the bromoalkyne. In the case of bromo arylalkynes, the vinylidenephenonium gold(I) cations lead to 1,4-enynes via a 1,2-aryl rearrangement. The same reactivity has been observed in the presence of InBr₃

Full text of DOI:10.1021/acscatal.9b02314

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Article
Gold- or Indium-Catalyzed Cross-Coupling of Bromoalkynes
with Allylsilanes through a Concealed Rearrangement
M. Elena de Orbe, Margherita Zanini, Ophelie Quinonero, and Antonio M. Echavarren
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02314 • Publication Date (Web): 15 Jul 2019
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ACS Catalysis
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Gold- or Indium-Catalyzed Cross-Coupling of Bromoalkynes with
Allylsilanes through a Concealed Rearrangement
M. Elena de Orbe,†‡ Margherita Zanini,†‡ Ophélie Quinonero,† and Antonio M. Echavarren†‡
† Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute of Science and Technology, Av. Països
Catalans 16, 43007 Tarragona, Spain
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‡ Departament de Química Analítica i Química Orgànica, Universitat Rovira i Virgili, C/Marcel·li Domingo s/n,
43007 Tarragona, Spain
ABSTRACT: The gold(I)-catalyzed reaction of bromoalkynes with allylsilanes gives 1,4-enynes in a formal cross-coupling reaction.
Mechanistic studies revealed the involvement of gold(I) vinylidenes or vinylidenephenonium gold(I) cations depending on the
substituent on the bromoalkyne. In the case of bromo arylalkynes, the vinylidenephenonium gold(I) cations lead to 1,4-enynes via
a 1,2-aryl rearrangement. The same reactivity has been observed in the presence of InBr3.
KEYWORDS: bromoalkynes, allylsilanes, 1,4-enynes, metal vinylidene, gold catalysis, indium catalysis
INTRODUCTION
bromoalkynes
a
more favorable hydroarylation/1,2-H
shift/1,2-halide shift sequence was proposed for the formation
of hydroarylation products.7 Apart from the widely studied
hydroarylation,8 haloalkynes9 are scarcely involved in gold(I)-
catalyzed reactions, especially with alkenes. Only few examples
of 1-bromo-1,5-enynes partaking in cycloisomerization
reactions have been reported,10 whereas chloroalkynes
undergo intermolecular [2+2] cycloadditions with alkenes to
form cyclobutenes11 and react with electron-rich arenes to give
(Z)-alkenyl chlorides in a hydroarylation reaction.12
The gold(I) catalyzed intermolecular reaction of alkenes with
alkynes can lead to the formation of cyclobutenes by a [2+2]
cycloaddition or to 1,3 dienes via a rearrangement reaction.1
Both reactions start with the anti-attack of the alkene on (2-
alkynes)gold(I) complexes to form cyclopropyl gold(I)
carbenes I or II (Scheme 1A). The regioselectivity in the
generation of these intermediates mainly depends on the
substitution pattern of the substrates and influences the
evolution of the reaction either towards the cyclobutene
formation or the rearrangement in 1,3-dienes. As a general
trend, for terminal alkynes the gold(I) carbene is preferentially
formed at the alkyne carbon in β-position to electron-donating
groups and in α-position to electron-withdrawing groups (I
and II, respectively).
We have now discovered a new mode of reactivity of
bromoalkynes in the presence of gold(I). Bromoalkynes react
with allyl silanes as electron-rich alkenes (R’ = CH2SiMe3)
forming the gold(I) carbenes V where the carbene is located in
-position to the more electron-withdrawing bromide
substituent (Scheme 2). Intermediates
V then undergo
intramolecular attack of the bromine to form unprecedented
cyclic bromonium intermediates VI13. Depending on the nature
of the R substituent, ring opening of VI can generate gold(I)
vinylidenes VII (R = alkyl) or vinylidenephenonium gold(I)
cations (R = aryl). Interestingly, the same reactivity can be
triggered by InBr3 instead of gold(I).
Scheme 2. Proposed evolution of cyclopropyl gold(I)
carbenes into gold(I) vinylidenes.
RESULTS AND DISCUSSION
Synthesis
of
1,4-Enynes.
The
reaction
of
Scheme 1. Generation of cyclopropyl gold(I) carbenes and
gold(I) vinylidenes.
(bromoethynyl)benzene (1a) with allyltrimethylsilane (2a) in
presence of cationic gold(I) catalysts A-C led to skipped enyne
3a in a formal cross-coupling reaction with loss of TMSBr in
low to moderate yield (Table 1, entries 1-3).14 Whereas more
electrophilic phosphite-based catalyst D, AuCl, and AuCl3 salts
failed to catalyze this transformation (Table 1, entries 4-6),
doubling the amount of 2a using gold complex B led to 3a in
77% yield. Among the variety of other tested Lewis acids (Table
1, entries 8-11), InBr3 provided enyne 3a in yields comparable
to those obtained with cationic gold(I) catalyst B.
Gold(I) vinylidenes III-IV2 are a second fundamental group of
intermediates in gold(I) catalysis, which can be generated by
attack of a gold(I) acetylide to electrophiles (III, Scheme 1B)3
or by an alkyne-vinylidene isomerization with 1,2-migration of
a functional group (IV, Scheme 1B).4,5
The alkyne-vinylidene isomerization via 1,2-halogen migration
was invoked for the intramolecular gold(I)-catalyzed
hydroarylation of haloalkynes,6 although in the case of
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Table 1. Reaction of bromoalkyne 1a with allylsilane 2a to
form 1,4-enyne 3a.
1
2
3
4
5
6
7
8
9
As expected,1 reaction between phenylacetylene 1e and
allylsilane 2a gave cyclobutene 4 (Table 2, entry 10).
Entry
Catalyst (mol%)
1a:2a
1:1
1:1
1:1
1:1
1:1
1:1
1:2
1:1
1:1
1:1
1:2
Yield (%)a
13 (7)
50
14
traces
0
0
(77)
traces
28-45b
50-55b
(81)
1
2
3
4
5
6
7
8
A (5)
B (3)
C (5)
D (5)
AuCl (5)
AuCl3(5)
B (3)
PtCl2 (3)
GaCl3 (3)
InBr3 (3)
InBr3 (3)
Table 3. Scope of the gold- or indium-catalyzed synthesis
of skipped enynes 3a-y.a
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10
11
Yields determined by 1H NMR using mesitylene as internal standard.
a
Isolated yields in parentheses. b Range of yields obtained in different runs.
(Chloroethynyl)benzene also reacted with allyltrimethylsilane
(2a) to give 3a in 68% yield (Table 2, entry 2), while
(iodoethynyl)benzene provided 3a in poor yield15 (Table 2,
entry 3). Regarding the allylic partner (Table 2, entries 4-8),
allyltriphenylsilyane also reacted satisfactorily with 1a to give
3a in 66% yield (Table 2, entry 6). Nonetheless, in the interest
of the atom economy, we continued our study using
allyltrimethylsilanes as substrates. The reversed reaction of
alkynylsilane 1d with allylbromide 2f did not occur under
these conditions (Table 2, entry 9).
Table 2. Optimization of the substitution pattern of the
substrates to form 3a.a
Yield
Entry
1a-e R1
2a-g R2
(%)b
(77)
68c
9
1
2
3
4
5
6
7
8
1a
1b
1c
1a
1a
1a
1a
1a
1d
1e
Br
Cl
I
Br
Br
Br
Br
Br
SiMe3
H
2a
2a
2a
2b
2c
2d
2e
2f
SiMe3
SiMe3
SiMe3
a
b
c
Isolated yields. Reaction at 50 °C. Yields determined by 1H NMR using
mesitylene as internal standard. d Product 5g was also formed. e Product 5h
was also formed.
Si(OMe)3 21
Si(iPr)3
SiPh3
Bpin
Sn(nBu)3 14
Br
23
66
16
We then examined the scope of the reaction between
bromoalkynes 1 and allylsilanes 2 using either gold complex B
or InBr3 and, in general, comparable yields were obtained with
both catalysts (Table 3). Allylsilane 2a reacts with
bromoalkynes bearing differently substituted aryl groups to
give the corresponding skipped enynes 3a-n in yields ranging
from 40 to 96%. The reaction of 1-(bromoethynyl)-1-
cyclohexene with 2a gave rise to 1,6-dien-3-yne 3o, albeit in
low yields. Furyl substituted 1,4-enynes 3q,r were also
obtained in low yields, whereas thiophenyl and indolyl
substituted 1,4-enynes 3p,s were prepared in 48% and 87%
yield, respectively. Diverse substituents at the 2 and 3 position
of the allylsilane are tolerated, leading to skipped enynes 3t-x.
d
9
10
2g
2a
-
-
e,f
SiMe3
Substrates 1:2 in a 1:2 ratio. Yields determined by 1H NMR using
a
b
mesitylene as internal standard. Isolated yields in parentheses. c Reaction
time was 48 h. d No reaction. e Product 4 was formed instead. f Reaction at
50 °C.
2
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The formation of 3-substituted 1,4-enynes 3w,x starting from
heated at 75 °C with gold(I) complexes E or F as catalysts, in
presence of 2,3-dihydro-1H-
BHT,16
cyclopenta[b]naphthalenes 12a-c were obtained in
1
2
3
4
3-substituted allylsilanes indicates that the reaction proceeds
by -attack on the allylsilane, commonly observed in reactions
with electrophiles. Moreover, 1,3-bis(bromoethynyl)benzene
underwent a twofold reaction with allylsilane 2a to afford
bisallylated product 3y.
satisfactory yields as a result of a formal [4+2] cycloaddition.
5
Interestingly, in the gold(I)-catalyzed reaction of o-methyl- or
o-ethyl(bromoethynyl)benzene with 2a, the 3-allylindenes 5g
and 5h were formed together with the 1,4-enynes 3g,h. Control
experiments showed that 3g cannot be converted into 5g
under the reaction conditions.14 These two results suggested
the involvement of gold(I) vinylidenes as reactive
intermediates that undergo C−H insertion on the o-methyl or o-
ethyl groups to form indenes 5g and 5h.
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Hydroarylation Cascade. Intrigued by the hint on the
involvement of gold(I) vinylidenes in the formation of 5g and
5h, we tested aryl substituted bromoalkynes in the reaction
Scheme
4.
Synthesis
of
2,3-dihydro-1H-
cyclopenta[b]naphthalenes 12a-c from 11a-c.
with allylsilanes to trigger
a
gold(I) vinylidene
formation/hydroarylation cascade. Initially, we evaluated the
reaction of allylsilane 2a with o-alkynylbiaryls 6a-c at 75 °C
(Scheme 3A). Using 6a in presence of catalyst B, 1,4-enyne 7a
and allylphenantrene 8a were obtained in 53% and 23% yields,
respectively. With InBr3 as catalyst, both products were
generated in similar ratios, although in lower yield. In the case
of methyl substituted derivative 6b, gold(I) catalyst led to the
formation of 7b and 8b in 2:1 ratio. Importantly, the formation
of phenanthrene 8b, with differently substituted A and C rings,
demonstrates that the cyclization proceeds by a process in
which a formal 1,2-migration of the allyl chain takes place. No
hydroarylation was observed with 6c, which gave the skipped
enyne 7c in excellent yield with both gold and indium catalysts.
In this last example, the bis(trifluoromethyl)aryl moiety in 6c
is not electron-rich enough to undergo the hydroarylation
Insights into the reaction mechanism. To prove our initial
hypothesis of the formation of the gold(I) vinylidene
intermediate, we performed
a
series of mechanistic
experiments and computational DFT calculations. Firstly, we
investigated the possible intermediacy of gold acetylide and/or
,-digold(I) alkyne complexes, which has been proposed in
other reactions of haloalkynes and in the formation of gold(I)
vinylidenes.17 Thus, we subjected complexes G and H to the
reaction conditions, in absence or presence of the gold catalyst
B or different bromide sources, although no reaction was
detected in any case (Scheme 5).14 Hence, we discarded
possible mechanisms involving those intermediates.
reaction. On the other hand, substrate
9 reacts with
allyltrimethylsilane in the presence of catalyst B to give 1,2-
dehydronapthalene 10 (64% yield) (Scheme 3B).
Scheme 5. Reactions with gold(I) acetylides.
To demonstrate the bromine migration, we conducted the
reaction of 1a with simple alkenes 13a-c (Scheme 6A). In these
reactions, homopropargyl bromides 14a-c were obtained as
major products as a result of a 1,2-bromoalkynylation of the
alkenes. The high diasteroselectivity observed in the formation
of 14b,c suggests that the reaction occurs through a cyclic
intermediate.18 Finally, 13C-labeled bromoalkyne 13C-1a was
prepared and subjected to the reaction with allylsilane 2a or
alkene 13b (Scheme 6B). Remarkably, in both 13C-3a and 13C-
14b products, the 13C carbon had migrated from the - to the
-position with respect to the phenyl group.
Scheme 3. Intramolecular hydroarylation reactions.
The intramolecular reaction of 1-bromo-1,6-enynes 11a-c was
also examined to test if the corresponding gold(I) vinylidenes
would undergo an intramolecular hydroarylation with the aryl
substituent of the alkene (Scheme 4). Thus, when 11a-c were
3
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by means of DFT calculations (Scheme 7).19 The most favored
1
pathway involves the generation of cyclopropyl gold(I)
carbenes Int2a,b (a: R = Ph; b: R = (CH2)2Ph), in which the
gold(I) carbene is formed in β-position to the electron-
donating R group and in α-position to electron-withdrawing
bromine, in agreement with the previously observed tendency
(Scheme 1A). In these intermediates, the partially cationic
center at C4 is stabilized by the -silyl group and can
experience nucleophilic attack by the bromine to form cyclic
bromonium intermediates Int3a,b. Depending on the nature of
the R group, Int3a,b undergo ring opening to form different
intermediates. The opening of Int3a (R = Ph) is assisted by the
phenyl group to form Int4a, a vinylidenephenonium-gold(I)
cation,20 instead of a gold(I) vinylidene. Then, Int4a leads to
Int5a in a highly exothermic step reminiscent of the Fritsch-
Buttenberg-Wiechell rearrangement.21 Int5a corresponds to
the product of formal 1,2-bromoalkynylation of the alkene, as
observed in products 14a-c (Scheme 6A). Gold-promoted
elimination of the bromide in Int5a via Int6a leads to bromide
gold(I) complex Int7 and skipped enyne Int8a, in which the
trimethylsilyl group is still bound to the alkene.14 Finally, the
activation of the gold complex Int7 with the trimethylsilyl
derivative Int8a releases TMSBr along with (η2-alkene)gold(I)
complex Int9a,14 which can turn over the catalytic cycle by
ligand exchange to form Int1a. Thus, this reaction would afford
1,4-enyne 3a, which is in agreement with the experimental
results.
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Scheme 6. Experimental mechanistic investigations.
Considering all these experimental results, we examined the
mechanism of the reactions of bromoalkynes 1a and 9 with 2a
2a
+
10
3a
1a
9
∆Gº = -15.8
AuL+
C1 C2
Me3SiBr
AuL+
R
Br
Ph
LAuBr
C2 C1
C1
C2
Int1a,b
Int9a
∆Gº = -16.6
∆G‡ = 14.2
∆Gº = -14.2
∆G‡ = 15.9
∆Gº = -11.3
AuL+
+SiMe3
Me3SiBr
LAuBr
+SiMe3
Int14
AuL
Ph
Int13
R
Br
∆G‡ = 3.0
∆Gº = -10.2
Int8a
+
SiMe3
LAuBr
C3
∆G‡ = 8.8
∆Gº = -3.2
C4H
Int2a,b
∆G‡ = 8.6
∆Gº = 6.9
AuL
LAuBr
Int7
AuL
∆G‡ = 6.2
∆Gº = 5.0
+Br
Ph
SiMe3
LAu Br+ SiMe3
Int12
∆Gº = 6.8
Br
R
C2
C1 Br+
Int6a
Int4b
C3
C4
∆Gº = 1.3
SiMe3
+
Int3a,b
AuL
Int4a
SiMe3
AuL+
∆G‡ = 0.8a, ∆Gº = 0.6
∆G‡ = 3.1
∆Gº = 2.7
C3
C4
Int11
∆G‡ = 8.6
∆Gº = -50.9
Ph
AuL+
C1 C2
AuL
+
H
C1
AuL
Br
Br
Int5a
SiMe3
Br
Br
C1
C2
C3
SiMe3
SiMe3
SiMe3
C4
C4
C2
∆G‡ = 3.3
∆Gº = -22.6
∆G‡ = 0.6
∆Gº = -3.8
C3
Int4a
Path a: R = Ph
Int10
Int4b
Path b: R = (CH2)2Ph
d(C2-CAr) = 1.61 Å
d(C1-CAr) = 1.61 Å
Int4c
4
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Scheme 7. Mechanism for the formation of 1,4-enyne 3a and cyclized product 10 based on DFT calculations. Free energies
in kcal/mol. L = PMe3. a The energy of TS3b-4b was calculated by freezing the d(C1−Br). The value of this distance was taken from
the previously optimized geometry of the corresponding TS with R = o-MeC6H4
1
2
3
4
5
6
7
8
9
[AuLL’]+
Ph
SiMe3
The opening of Int3b (R = (CH2)2Ph) originates gold(I)
vinylidene Int4b, which undergoes an intramolecular
hydroarylation, via Wheland-type intermediate Int10, to form
Int11 (Scheme 7). Final gold(I)-promoted elimination of
TMSBr via Int12 gives Int13, and then Int14, which
corresponds to the observed product 10 (Scheme 3B).
+
Br
Ph
CH2Cl2
23 ºC
AuL
Br+
AuL
AuL
Br
+
Ph
Ph
Br
SiMe3
+
According to 13C-labeling experiments, the indium-catalyzed
transformations follow analogous mechanisms to that of the
gold(I)-catalyzed reactions.22 Indeed, DFT calculations with
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SiMe3
via vinylidenephenonium-gold(I)
H
SiMe3
+
InBr2 as the catalytic species show that the minimized
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equidistant from C1 and C2 in
intermediate.
a cyclopropene-like
CONCLUSIONS
We have found that the gold(I)-catalyzed reaction of
bromoalkynes with allylsilanes gives rise to 1,4-enynes by an
unprecedented mechanism initiated by the formation of five-
membered ring bromonium intermediates. Although this cyclic
intermediate can give rise to gold(I) vinylidenes, in the case of
aryl alkynes, vinylidenephenonium cations are formed and
undergo a 1,2-aryl migration, bypassing the formation of
gold(I) vinylidenes. These new reaction pathways could be the
basis of the discovery of new transformations in electrophilic
metal-catalyzed reactions of haloalkynes.
AUTHOR INFORMATION
Corresponding Author
aechavarren@iciq.es
ORCID
M. Elena de Orbe: 0000-0001-9603-3699
Margherita Zanini: 0000-0002-7469-3183
Ophélie Quinonero: 0000-0003-4561-8763
Antonio M. Echavarren: 0000-0001-6808-3007
Notes
No competing financial interests have been declared.
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website.
Experimental procedures, characterization data, experimental
and theoretical mechanistic studies (PDF).
ACKNOWLEDGMENTS
We thank the Agencia Estatal de Investigación
(AEI)/FEDER, UE (CTQ2016-75960-P), Severo Ochoa
Excellence Acreditation 2014-2018 (SEV-2013-0319, Severo
Ochoa predoctoral fellowship to M.E.d.O. and Caixa-Severo
Ochoa predoctoral fellowship to M.Z.), Juan de la Cierva
postdoctoral fellowship (O.Q.), AGAUR (2017 SGR 1257) and
CERCA Program/Generalitat de Catalunya for financial
support.
TOC graphic
(5) See also: Jaroschik, F.; Simonneau, A.; Lemière, G.; Cariou, K.;
Agenet, N.; Amouri, H.; Aubert, C.; Goddard, J.-P.; Lesage, D.;
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reaction conditions. For this purpose, 2-methylbut-2-ene could
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