Gold(I)-assisted α-allylation of enals and enones with alcohols

Article abstract of DOI:10.1002/anie.201507218

The intermolecular α-allylation of enals and enones occurs by the condensation of variously substituted allenamides with allylic alcohols. Cooperative catalysis by [Au(ItBu)NTf₂] and AgNTf₂ enables the synthesis of a range of densely functionalized α-allylated enals, enones, and acyl silanes in good yield under mild reaction conditions. DFT calculations support the role of an α-gold(I) enal/enone as the active nucleophilic species. A golden ally in allylation: In a gold(I)-assisted formal α-allylation of acrylaldehyde, enones, and acyl silanes with alcohols, allenamides were used as precursors to intermediate α-gold-substituted unsaturated carbonyl compounds. The transformation enabled the synthesis of a diverse range of products under mild conditions (see scheme; ItBu=1,3-di(tert-butyl)imidazol-2-ylidene).

Full text of DOI:10.1002/anie.201507218

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201507218
German Edition: DOI: 10.1002/ange.201507218
Homogeneous Catalysis
Gold(I)-Assisted a-Allylation of Enals and Enones with Alcohols
Marco Michele Mastandrea, Niall Mellonie, Pietro Giacinto, Alba Collado, Steven P. Nolan,
Gian Pietro Miscione, Andrea Bottoni, and Marco Bandini*
+
[5,8]
Abstract: The intermolecular a-allylation of enals and enones
occurs by the condensation of variously substituted allen-
amides with allylic alcohols. Cooperative catalysis by [Au-
and [H ]-assisted manipulation of allenamides,
we envi-
sioned the possibility of exploiting the intrinsic nucleophilic
character of B’-type adducts to develop the first gold-
mediated a-allylation of unsaturated carbonyl moieties.
[9]
(
ItBu)NTf ] and AgNTf enables the synthesis of a range of
2
2
densely functionalized a-allylated enals, enones, and acyl
silanes in good yield under mild reaction conditions. DFT
calculations support the role of an a-gold(I) enal/enone as the
active nucleophilic species.
Moreover, to validate the chemical sustainability of this
method, we selected environmentally desirable allylic alco-
[
10]
hols
as potential alkylating agents (Scheme 2). Allena-
mides have already been used in numerous elegant applica-
G
old-containing oxocarbenium derivatives A
have been utilized extensively in homogeneous
gold catalysis for the synthesis of new carbon–
[
1]
carbon and carbon–heteroatom bonds.
This
2
family of activated [Au]ÀC(sp ) species is com-
monly accessible through initial gold-promoted
[
3,3] rearrangement of the corresponding propar-
gylic carboxylates, followed by inter- as well as
[
2]
intramolecular electrophilic interception. Alter-
natively, hydrolysis of the oxocarbenium adducts
has been postulated to deliver the corresponding
I
a-gold(I) enals/enones B during oxidative cross- Scheme 1. a) Classical approach to the in situ generation of a-[Au ]-substituted enals
[3]
coupling reactions (Scheme 1a).
and enones. b) Our approach to the nucleophilic organogold intermediate
L=P(2,4-tBu C H O) ). TFA=trifluoroacetate, Ts =p-toluenesulfonyl.
(
Faza and López have investigated the mecha-
2 6 3 3
I
nism of the [Au ]-catalyzed oxidative cross-cou-
pling in silico. Their study revealed the presence
I
III
and role of a-gold(I) enone species in the [Au /Au ]-based
[4]
redox transformation. In this context, we recently reported
the spectroscopic identification of an analogous a-gold(I)
enal adduct B’ upon treatment of the complex [Au(P(2,4-
[
5]
tBu C H O) )(tfa)] (tfa = trifluoroacetate) with the allen-
2
6
3
3
[
6]
[7]
amide C in wet CDCl or CD Cl (Scheme 1b).
3
2
2
To the best of our knowledge, this alternative approach to
I
a-[Au ] enals is unprecedented. On the basis of these recent
findings, and in conjunction with our interest in the gold(I)-
Scheme 2. Working hypothesis for the gold(I)-assisted a-allylation of
a,b-unsaturated carbonyl compounds. EWG=electron-withdrawing
group.
[
*] M. M. Mastandrea, N. Mellonie, P. Giacinto, Dr. G. P. Miscione,
Prof. A. Bottoni, Prof. M. Bandini
Department of Chemistry “G. Ciamician”
Alma Mater Studiorum—University of Bologna
via Selmi 2, 40126, Bologna (Italy)
tions in gold catalysis; however, most often the condensation
E-mail: marco.bandini@unibo.it
of nucleophilic species with the metal-activated allenyl unit is
Dr. A. Collado, Prof. Dr. S. P. Nolan
EaStCHEM School of Chemistry, University of St. Andrews
St. Andrews, KY16 9ST (UK)
[11]
the dominant chemical event in these transformations. In
contrast, the proposed methodology would involve the
electrophilic trapping of the organogold intermediate derived
Prof. Dr. S. P. Nolan
Chemistry Department, College of Science
King Saud University, Riyadh 11451 (Saudi Arabia)
[12]
from the hydrolysis of a gold–allenamide adduct.
Allenamide 1a and the secondary alcohol 2a (model
substrates) were initially subjected to various reaction
conditions (Table 1). First attempts with [Au(P(2,4-
tBu C H O) )(tfa)] (2.5 mol%) led to the formation of the
Dr. G. P. Miscione
Department of Chemistry, Universidad de los Andes
Carrera 1 N8 18A 10, Bogotµ (Colombia)
2
6
3
3
desired product 3aa in modest yield (28%) and also to the
concomitant formation of by-products II and III in varying
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507218.
Angew. Chem. Int. Ed. 2015, 54, 14885 –14889
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14885

.
Angewandte
Communications
Table 1: Optimization of the reaction conditions for the formal
a-allylation of “acrylaldehyde”.
(Au(IPr)Cl with AgNTf ), a marked improvement in chem-
2
[
a]
ical yield was observed (96%; Table 1, entry 7). We reasoned
that this improved performance might be due to the presence
of excess AgNTf2 with respect to the gold source and
therefore carefully investigated the impact of the [Au]/[Ag]
ratio on the reaction outcome (Table 1, entries 8–11). Opti-
mal chemoselectivity was reached by the use of a 1:3
[
Au]/[Ag] ratio (2.5:7.5 mol%), which provided a nearly
quantitative amount of 3aa (97% yield; Table 1, entry 10).
This optimization classifies the present gold catalysis as
[15,16]
Entry [Au]/[Ag] (x [mol%])
T [8C]/ Yield of
Yield of
I/II/III [%]
a “silver-assisted” transformation (see below).
A pecu-
[
b]
[c]
t [h]
3aa [%]
liarity distinguishing carbene-based from other phosphorus-
based gold species is the complete suppression of the
formation of by-product III, which was not detected in the
crude product mixture. This outcome stresses the higher
selectivity of NHC-based catalysts in promoting the cross-
condensation over “homocoupling” processes. Notably, the
use of AgNTf2 alone led to the formation of a complex
product mixture (Table 1, entry 17), and no reaction was
observed in the absence of catalytic species (entry 18).
We then examined the scope of the reaction by conducting
the cross-condensation of a range of allylic alcohols 2 with
allenamide 1a (Table 2). A tolerance towards both electron-
withdrawing and electron-donating substituents on the aryl
moiety (at the ortho, meta, and para position) provided the
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
[Au(P(OtBu Ph) )(tfa)]/–
110/4 28
110/4 60
–/40/50
35/–/25
32/–/–
30/–/18
53/–/–
44/–/–
36/–/–
55/–/–
41/–/–
35/–/–
40/–/–
–/–/–
34/–/–
37/–/–
57/–/–
53/–/–
26/–/9
–/–/–
2
3
[Au(PPh )Cl]/AgNTf (2.5)
3
2
[Au(JohnPhos)Cl]/AgNTf (2.5) 110/4 61
2
[Au(XPhos)(NTf )]/–
110/4 61
110/4 70
110/2 84
110/4 96
110/4 68
110/4 89
110/4 97
110/4 35
110/4 96
25/24 99
110/4 94
110/4 65
110/4 71
110/4 68
110/4 NR
2
[Au(IPr)(NTf )]/–
2
[Au(ItBu)(NTf )]/–
[Au(IPr)Cl]/AgNTf2
2
[
d]
[
[
[
[
e]
f]
[Au(IPr)Cl]/AgNTf (2.5)
2
[Au(IPr)Cl]/AgNTf (5)
2
g]
h]
1
1
1
1
1
1
1
1
1
[Au(IPr)Cl]/AgNTf (7.5)
2
[Au(IPr)Cl]/AgNTf (10)
2
[Au(IPr)(NTf )]/AgNTf (5)
2
2
[Au(ItBu)Cl]/AgNTf (7.5)
2
[
g]
[Au(ItBu)Cl]/AgNTf (7.5)
2
[Au(IAd)Cl]/AgNTf (7.5)
2
[Au(IPr*)Cl]/AgNTf (7.5)
2
–/AgNTf (7.5)
2
[a]
Table 2: Scope of the formal a-allylation of acrylaldehyde.
–
[
a] Reactions were carried out under anhydrous conditions (1a/2a/
catalyst 1:1.5 :0.025). [b] Yield of the isolated product after flash
chromatography. [c] Yield after flash chromatography. The yields of I and
III are given with respect to the initial amount of alcohol 2a. By-product II
was always isolated as a 1:1 diastereomeric mixture. [d] An unweighed
[b]
Entry
R (1)
Ar/R’ (2)
Yield [%] (3)
amount of AgNTf was used. [e] [Au]/[Ag] 1:1. [f] [Au]/[Ag] 1:2. [g] [Au]/
2
1
2
3
4
5
6
7
8
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
Ar/R’=p-MeC H (2b)
95 (3ab)/(71)
94 (3ac)
55 (3ad)
94 (3ae)
94 (3af)
86 (3ag)/(trace)
84 (3ah)/(52)
84 (3ai)/(trace)
6
4
[
Ag] 1:3. [h] [Au]/[Ag] 1:4. IAd=1,3-di(adamantyl)imidazol-2-ylidene,
Ar/R’=o-MeC H (2c)
6
4
ItBu=1,3-di(tert-butyl)imidazol-2-ylidene, IPr=1,3-di(isopropylphenyl)-
imidazol-2-ylidene, IPr*=1,3-bis(2,6-bis(diphenylmethyl)-4-methylphe-
nyl)imidazo-2-ylidene, NR=no reaction, Tf =trifluoromethanesulfonyl.
Ar/R’=m-MeOC H (2d)
6
4
Ar/R’=p-FC H (2e)
6
4
Ar/R’=p-ClC H (2 f)
6
4
Ar/R’=o-ClC H (2g)
6
4
Ar/R’=p-BrC H (2h)
6
6
4
4
amounts (Table 1, entry 1). Among them, the condensation
product derived from the oxazolidinone and 2a (compound
II), was present in high enough amounts to be isolated. We
were encouraged by these early results, and the presence of II
supports our working hypothesis of the initial electrophilic
activation of the allenyl group by the metal.
We reasoned that the isolation of II could be attributable
to the use of a highly electrophilic gold species, and that more
s donating ligands could result in the formation of a more
nucleophilic organogold(I) intermediate, thereby, hopefully,
enabling 3aa to be obtained in higher yields. Gratifyingly, 3aa
was obtained in higher yield by moving from phosphite- to
Ar/R’=o-BrC
H
(2i)
[c]
9
H (1a)
88 (3aj)
[d]
1
0
H (1a)
Ar=Ph/R’=p-ClC H (2k)
45 (3ak)
6
4
[a] Reactions were carried out under anhydrous conditions with
.1 mmol of 1 (1a/2 1:2.5). [b] Yield of the isolated product after flash
chromatography. Values in brackets are the yields observed with AgNTf2
7.5 mol%) as the catalyst. [c] Product 3aj was isolated as a 4:1 mixture
of regioisomers; the major isomer featured an exocyclic C=C bond. [d] A
:1 mixture of products was obtained.
0
(
1
phosphine-based gold catalysts. In this context, [Au(PPh )-
corresponding a-allylated acrylaldehydes in good to excellent
3
[13]
[17]
(
NTf )]
and [Au(JohnPhos)(NTf )] formed in situ, and
yield (55–95%; Table 2, entries 1–8).
Furthermore, the
2
2
preformed [Au(XPhos)(NTf )], provided 3aa in comparable
amounts (Table 1, entries 2–4).
asymmetrically substituted allylic alcohols 2j and 2k were
converted into the desired products 3aj and 3ak in moderate
to good yield (45–88%) as mixtures of regioisomers (up to
2
Next, the gold–N-heterocyclic-carbene (NHC) complexes
[
Au(IPr)(NTf )] and [Au(ItBu)(NTf )] were tested, with very
4:1). These results point to a possible S 1-type mechanism of
2
2
N
[
14]
promising results (Table 1, entries 5 and 6). Intriguingly,
when we carried out the reaction by in situ cation formation
CÀC bond formation (see below for a mechanistic discus-
[18]
sion).
1
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The scope of the methodology was further
assessed by applying the optimal reaction con-
ditions to a-substituted allenamides 1b–f
(
Table 3). Chemical manipulation at the C1
position of the starting allene would also allow
[19]
direct access to a-allylated keto derivatives.
Gratifyingly, a range of a-allylated enones 4
were isolated in moderate to good yield (40–
6
5%), regardless of the nature of the a substitu-
ent or the electronic properties of the allylic
alcohol (Table 3, entries 1–9). The introduction of
a substituent at the a carbon atom of the allenyl
unit of 1 significantly enhanced the overall
reactivity of the p system towards the allylation 2a and ether III.
Scheme 3. Experiments in support of the proposed role of AgNTf in the activation of
2
Experiments toward the elucidation of the role of AgNTf2
[
a]
Table 3: Formal a-allylation of enones and acyl silanes.
were next carried out (Scheme 3). We had observed that
AgNTf alone (7.5 mol%) does promote the reaction, but
2
with lower chemoselectivity (Table 1, entry 17). This trend
was more evident when a selection of secondary allylic
alcohols was treated under similar conditions for comparison
[22]
1
[b]
(see Table 2, entries 1 and 6–8).
We reasoned that the
Entry
R/R (1)
Ar (2)
Yield [%] (4/5)
presence of an excess amount of the Lewis acid could
promote the activation of the allylic alcohol (i.e. formation of
the allylic carbocation) and/or convert the ether III into
a chemically active alkylating form. To test this hypothesis, 2a
was heated at reflux in the presence of a catalytic amount of
1
2
3
4
5
6
7
8
9
0
1
2
3
Bn/H (1b)
Bn/H (1b)
Bn/H (1b)
Bn/H (1b)
C H (2a)
p-MeC H (2b)
6 4
p-FC H (2e)
6 4
p-ClC H (2 f)
6 4
p-BrC H (2h)
6 4
C H (2a)
6 5
p-MeC H (2b)
6 4
52 (4ba)
57 (4bb)
65 (4be)
48 (4bf)
50 (4bh)
63 (4ca)
40 (4cb)
46 (4ce)
50 (4da)
36 (4ea)
77 (5a)
6
5
Bn/H (1b)
p-FC H CH /H (1c)
6
4
2
AgNTf in toluene for 2 h. The corresponding ether III was
2
p-FC H CH /H (1c)
6
4
2
isolated in high yield (88%) along with the disproportiona-
p-FC H CH /H (1c)
p-FC H (2e)
[23,24]
6
4
2
6
4
tion products 6a and 7a in 9% combined yield.
More-
Me/H (1d)
H/Me (1e)
C H (2a)
6 5
C H (2a)
6 5
[
[
[
[
c]
c]
c]
c]
over, when III was used as the starting material in combina-
1
1
1
1
tion with water (1 equiv) and AgNTf , a mixture of 6a and 7a
SiMe /H (1 f)
C H (2a)
2
3
6
5
SiMe /H (1 f)
p-ClC H (2b)
70 (5b)
57 (5e)
was obtained with high conversion (90%), and when III was
used as the starting material in combination with 1a (2 equiv)
3
6
4
SiMe /H (1 f)
p-FC H (2e)
3
6
4
and [Au(ItBu)(NTf )]/AgNTf , the desired product 3aa was
[
a] Reactions were carried out with 0.1 mmol of 1 under nitrogen in dry
2
2
toluene (1/2 1:1.5). [b] Yield after flash chromatography. [c] The reaction
was carried out under reflux for 2 h. Bn=benzyl.
isolated in 40% yield. These experimental results support the
key role of the silver salt in activating 2a and “recycling” III
[25,26]
towards nucleophilic trapping.
We fully examined the reaction profile by DFT calcula-
tions (see the Supporting Information for an exhaustive
discussion), which accounted for the initial formation of the
postulated organogold intermediate of type B through
reaction, so that the temperature could be lowered and the
[20]
reaction time shortened to just a few minutes!
Importantly, the method could also be extended to the a-
allylation of a,b-unsaturated acyl silanes (Table 3,
[26]
5
hydrolysis of the gold-activated allenyl unit, and its site-
entries 11–13), which are a well-known class of synthetically
versatile building blocks. The products of these reactions were
obtained in 57–77% yield (reflux, 2 h). Additionally, the g,g-
disubstituted allenamide 1e was treated with 2a under the
optimized conditions. The corresponding enal 4ea, featuring
a tetrasubstituted C=C double bond, was isolated in moderate
selective S 1 addition to the allylic carbocation formed in situ
(see Figures S1–S3 in the Supporting Information). Analo-
N
gous calculations with AgNTf as the catalytic agent led to
2
significantly higher energy barriers (see the Supporting
Information for more details).
Although the coexistence of a background reaction
involving the spontaneous condensation of the unactivated
allenamide 1a with allylic cationic species cannot be com-
pletely excluded, this reaction pathway seems noncompetitive
with the gold-assisted pathway in terms of chemoselectivity
(see also Table 2, entries 1 and 6–8 for comparison with gold
catalysis). Indeed, when a “naked” allylic carbocation gen-
yield (36%; Table 3, entry 10).
Mechanistically, this transformation poses several ques-
tions, for example: What is the role of the excess silver? What
is the reaction profile of the CÀC bond-forming event? What
is the nature of the nucleophilic species? Insight into the CÀC
bond-forming step comes from the isolation of products 3aj
and 3ak as mixtures of regioisomers (Table 2, entries 9 and
[27]
erated in situ was directly treated with 1a, the correspond-
ing enal 3aa was obtained in only 40% yield along with
a large amount of unknown by-products.
1
0). Accordingly, a S 1-type mechanism involving stabilized
N
[21]
allylic carbocations could be invoked.
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Finally, the further transformation of model allylated
products 3 and 5 highlights their synthetic utility (Scheme 4).
Acyl silane 5a was conveniently converted into the corre-
sponding a,b-unsaturated carboxylic acid 8a in 99% yield by
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[
6] For general reviews on allenamides in organic synthesis, see:
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treatment with an aqueous mixture of H O2 and NaOH
2
7
73 – 782; b) T. Lu, Z. Lu, Z.-X. Ma, Y. Zhang, R. P. Hsung,
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[
[
7] L. Rocchigiani, M. Jia, M. Bandini, A. Macchioni, ACS Catal.
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b) Y. Tamaru, Eur. J. Org. Chem. 2005, 2647 – 2656; c) J. Muzart,
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Scheme 4. Synthetic manipulation of the allylated compounds 3 and 5:
a) 99% yield; b) i) room temperature, 15 min, 77%; ii) CH Cl , room
2
2
temperature, 4 h, 41%. TEA=triethylamine.
[
28]
(
Scheme 4a). Additionally, aldehyde 3ad was converted in
two steps into the densely functionalized exo-methylene
[
29]
dihydroindene structure 10ad (Scheme 4b).
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In conclusion, we have disclosed a gold(I)/silver(I)-
cocatalyzed a-allylation of unsaturated carbonyl compounds
with allylic alcohols that provides rapid access to substituted
enals, enones, and acyl silanes. The cooperative action of gold
and silver salts was elucidated by experimental as well as
computational studies. The present methodology represents
a valuable synthetic alternative to the well-known Baylis–
Hillman reaction for the a-functionalization of a,b-unsa-
turated carbonyl compounds, which has found sporadic
application for allylic alkylation. We are currently developing
an enantioselective variant of the present protocol.
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Keywords: alcohols · allylation · gold catalysis ·
reaction mechanisms · unsaturated carbonyl compounds
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[17] Differently substituted allylic alcohols, such as cyclohexen-2-ol
and (E)-pent-3-en-2-ol were also tested, but unfortunately they
were found to be unreactive under the optimized conditions.
Decomposition the allylic alcohol 2a was observed, with the
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Angew. Chem. Int. Ed. 2015, 54, 14885 –14889

Angewandte
Chemie
formation of the corresponding compound of type III as the
main side product.
18] The allenamide C and the aryloxyallene D were also tested as
allylating agents; however, 3aa was isolated in lower yield: 52
and 33% yield, respectively.
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[24] [Au(ItBu)(NTf )] also enabled the formation of III (55% yield,
[
[
2
toluene, reflux), in agreement with the efficiency of silver-free
catalytic systems.
[
25] In the absence of AgNTf , only trace amounts of ether III were
2
detected when 2a was heated at reflux in toluene for 4 h.
26] The water for the hydrolysis of the immonium intermediate
could be derived from the silver-assisted dehydrative dimeriza-
tion of 2a to give III. The addition of activated molecular sieves
seriously eroded the performance of the catalytic system (yield
of 3a: 41%).
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[
20] The temperature profile for the reaction of the a-alkylated
allenamide 1b was investigated (see the Supporting Information
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Received: August 4, 2015
[
22] When AgNTf (7.5 mol%) was tested with alcohol 2a at room
Revised: September 18, 2015
Published online: October 16, 2015
2
temperature for 24 h, 3a was isolated in 70% yield.
Angew. Chem. Int. Ed. 2015, 54, 14885 –14889
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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