Gold(i) catalysed regio- and stereoselective intermolecular hydroamination of internal alkynes: towards functionalised azoles

Article abstract of DOI:10.1039/C9OB00587K

Gold(i) catalysed regio- and stereoselective intermolecular hydroamination of internal alkynes was developed for the effective synthesis of a series of (Z)-functionalised vinylazoles under solvent free conditions. The catalytic hydrogenation of the resulting enamines leads to substituted saturated azoles in good yields.

Full text of DOI:10.1039/C9OB00587K

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DOI: 10.1039/C9OB00587K.
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Gold(I) catalysed regio- and stereoselective intermolecular
hydroamination of internal alkynes: towards functionalised azoles
Christophe Michon,*a,b Joachim Gilbert,a,b Xavier Trivelli,c Fady Nahra,d Catherine S. J. Cazin,d
Francine Agbossou-Niedercorn,a,b and Steven P. Nolan*d,e
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract: Gold(I) catalysed regio- and stereoselective intermolecular hydroamination of internal alkynes was developed for
the effective synthesis of a series of (Z)-functionalised vinylazoles under solvent free conditions. The catalytic
hydrogenation of the resulting enamines leads to substituted saturated azoles in good yields.
N-functionalised azoles are important molecular scaffolds selective anti-Markovnikov hydroamination of terminal and
for pharmaceuticals, bioactive compounds and natural internal alkynes with N-silylamines to afford N-silylenamines.9
products. They are useful in the treatment of various diseases The latter either led to primary amines, after desilylation, or to
as they exhibit antifungal (I),1 antibacteria (II),2 anxiolytic (III),3 various pyridines through reactions with α,β-unsaturated
analgesic (IV),4 antidepressant (IV)4 and anticancer (V)5 carbonyls followed by oxidation.9 The versatility of rhodium(I)
activities (Figure 1). If various methodologies including catalyst was also concomitantly highlighted by several
cycloaddition and multicomponent reactions focused on contributions.10 Dong et al. and Sunoj et al. reported on the
building these heterocycles,6 direct functionalisation of azoles hydroamination of internal alkynes via tandem rhodium
has been much less explored. Considering that the catalysis to yield branched N-allylic amines and more
hydroamination of alkenes and alkynes is the shortest specifically N-allyl indolines with high regio- and
synthetic route to secondary and tertiary amines, this reaction enantioselectivities.10a,e In parallel, Breit et al. have developed
should be of practical interest for the preparation of azole a rhodium catalyst allowing for the chemo ‑ , regio ‑ , and
derivatives. In this context, if the intermolecular enantioselective allylation of pyrrazoles and triazoles with
hydroamination of alkenes remains a challenge, the inter- and internal alkynes.10b,d Interestingly, Zhao et al. combined
intramolecular hydroamination of terminal alkynes has been rhodium-catalysed hydroamination and C–H activation in a
broadly studied.7 The resulting substituted enamines, imines highly selective [4+2] imine/alkyne annulation to form multi-
or functionalised heterocycles are obtained as Markovnikov or substituted 3,4-dihydroisoquinolines10c. Regarding Group 11-
anti-Markovnikov products and are useful intermediates in based catalysts, Zhu et al. (Ag(I)) and later Kawatsura et al.
organic
synthesis.
Although
the
intermolecular (Cu(II))
reported
the
regioselective
intermolecular
hydroamination of internal alkynes with primary amines has hydroamination of internal alkynes functionalized with
been effectively performed using Group 4-based catalysts,8 the electron-withdrawing groups in the presence of various
use of other nucleophiles such as dialkylamines or amines.11
heterocycles remains more challenging due to a lack of general
synthetic method. Recently, Schaffer et al. have reported on
the use of bis(amidate)bis(amido)titanium(IV) to catalyse the
R4
*
N
N
R1
R2
N
N
N
N
N
N
NHAc
F
R3
O
N
I
II
O
(antifungal)
(antibacterial)
a. Univ. Lille, CNRS, Centrale Lille, ENSCL, Univ. Artois, UMR 8181 - UCCS - Unité de
Catalyse et Chimie du Solide, F-59000 Lille, France
N
N
E-mail: christophe.michon@univ-lille.fr
N
N
b. ENSCL, UCCS-CCM-MOCAH UMR 8181, (Chimie-C7) CS 90108, 59652 Villeneuve
d’Ascq Cedex, France
R1
*
*
N
NR3R4
N
MeO
IV
c. UGSF CNRS, UMR 8576, Univ. Lille, 59655 Villeneuve d'Ascq Cedex France
d. Department of Chemistry, Ghent University, Building S3, Krijgslaan 281, 9000
Gent, Belgium
N
(analgesic,
antidepressant)
R2
N
N
N
E-mail: steven.nolan@ugent.be
N
e. Department of Chemistry, College of Science, King Saud University, P.O. Box 2455,
Riyadh 11451, Saudi Arabia
*
HN
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: Figures S1 and S2, Table S1,
synthetic and catalytic details, NMR spectra of all products. See
DOI: 10.1039/x0xx00000x
V
(anticancer)
N
Figure 1. Azoles found in the pharmaceutical industry
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In parallel, gold-catalysed additions to CC multiple bonded
substrates proved to be effective in intramolecular reactions Table 1 Development of the catalytic reaction
though intermolecular versions have remained more
catalyst
(0.5 mol%)
NBu4X
challenging.12 Interestingly, Bertrand et al. have developed
N
N
N
gold(I) catalysts based on cyclic(alkyl)(amino)carbenes (CAACs)
for the intermolecular hydroamination of alkynes with
ammonia, hydrazine and amines.13a,d This methodology was
later applied to the one-pot three-component synthesis of 1,2-
dihydroquinolines.13b,c Thereafter, Stradiotto et al. reported
P,N-ligand based gold(I) catalysts for the stereo- and
regioselective hydroamination of internal alkynes using various
dialkylamines.14 In parallel, triazole-gold(I) complexes
developed by Shi et al. proved to be also valuable catalysts for
the intermolecular hydroamination of internal alkynes with
primary amines,15a the reaction yields being improved by the
use of an acid co-catalyst. Interestingly, this methodology was
further extended to the synthesis of several vinyl-substituted
triazoles.15b Some related pyrazoles were later prepared by
Chen et al. through a 1,4-conjugate addition to propiolates
using gold(I) chloride as a catalyst.16 Following our interests in
gold(I)-catalysed hydrophenoxylation, hydroalkoxylation and
hydrocarboxylation of alkynes17 as well as in gold(I)-catalysed
hydroamination of alkenes,18 we report here gold(I)-catalysed
regio- and stereoselective intermolecular hydroamination of
internal alkynes for the effective synthesis of a broad range of
functionalised vinylazoles under solvent-free conditions.
Interestingly, the subsequent catalytic hydrogenation of the
resulting (Z)-enamines leads to the related saturated azoles in
good yields.
Initially, diphenylacetylene 2a and benzotriazole 3a were
selected as model substrates to test the three selected pre-
catalysts, e.g. [Au(IPr)(OH)] 1a,19a [Au(IPr)][NTf2] 1b19b and
[{Au(IPr)}2(-OH)][BF4] 1c19c and establish the best catalytic
conditions (Table 1). Reactions were performed with 0.5 mol%
catalyst loading, in closed vials containing 0.22 mmol of alkyne
2a without any solvent. The mixtures were heated at 100°C for
72 hours using a sand bath (method A) or by using microwave
heating at 150°C for 0.75 hour (method B). At first, none of the
catalysts were active when the reaction was performed using
method A (entries 1-3). However, we found the use of a
catalytic amount (5 mol%) of NBu4OTf as an additive allowed
the reactions to proceed. Other ammonium salts bearing
anions like BF4 or OTos led also to hydroamination product 4aa
but yields were lower and some by-products were formed. The
critical effect of NBu4OTf (and of the OTf anion) can be
explained by its role in the proto-deauration step (see Scheme
2 and the mechanism discussion below).20,21 Indeed, the
hydroamination product 4aa was obtained in a 22% yield while
using catalyst 1a (entry 4).
N
N
NH
Ph
(0 or 5 mol%)
Ph
Ph
+
Ph
H
T(°C), t (h)
neat
2a
1.3 eq.
4aa
(Z)-
3a
1 eq.
iPr
iPr
iPr
iPr
N
N
N
N
Au
Au
iPr
iPr
N
iPr
iPr
iPr
H
iPr
OH
O
1a
1b
[Au(IPr)(OH)]
iPr
BF4
iPr
Au
N
N
N
Au
iPr
iPr
iPr
iPr
NTf2
1c
[Au(IPr)][NTf2]
[{Au(IPr)}2(µ-OH)][BF4]
Entry
Cat.
(mol%
NBu4X
(mol%)
T (°C)
time
(h)
72
72
72
72
72
72
72
0.75
0.75
Yield
(%)b
-
-
(method)a
1
2
3
4
5
6
7
8
9
1a
1b
1c
1a
1b
1c
1c
1c
1c
0
0
0
100 (A)
100 (A)
100 (A)
100 (A)
100 (A)
100 (A)
100 (A)
150 (B)
150 (B)
-
X = OTf (5)
X = OTf (5)
X = OTf (5)
X = OTf (5)
X = OTf (5)
X = OTf (5)
22
61
66
44c
66
96c
a) Method A using a sand bath at 100°C for 72 h, method B using
microwave heating at 150°C for 0.75 h. b) 0.22 mmol of 3a used ,
isolated yields. c) 1.10 mmol of 3a used, isolated yields.
3
N
N
N
3
2
N
2
N
O
N
1
N
N
1
N
N
H
N
H
H
H
3ca
3a
3d
3b
N
N
N
N
N
N
H
N
H
N
H
N
H
3e
3g
3f
3h
Figure 2 Azole nucleophiles used in this study. 3c is the N2
a
tautomer of 3b in solution22
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[{Au(IPr)}2(OH)][BF4] (0.5 mol%)
R1
Nu
R2
H
R1
Nu
R1
H
Nu
R2
H
Bu4NOTf (5 mol%)
R2
+
R1
+
NuH
+
method A or Ba
R2
3a-h
1 eq.
2a-g
1.3 eq.
4
(E)-
4
5
(Z)-
(Z)-
N
N
N
N
N
N
N
N
O
N
N
N
O
N
+
N
Ph
Ph
Ph
Ph
+
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
Ph
4aa
4ab
4ac
(Z)-
4ad
(Z)-
4ad
(Z)-
(Z)-
(E)-
A: 83%
4ad 4ad
A: 66%, B: 96% A: 31%, B: 57% A: 15%, B: 21%
b
Ratio (Z)-
/ (E)-
(68/32)
N
N
N
N
N
N
N
N
N
N
CO2Me
+
CO2Me
+
CO2Me
MeO2C
MeO2C
MeO2C
MeO2C
2b
MeO2C
CO2Me
CO2Me
4ba
(Z)-
4ba
4be
(Z)-
4be
(E)-
(E)-
c
b
b
4ba
4ba
A: 69%, Ratio (Z)-
/ (E)-
(1/1 )
4be
4be
/ (E)- (1/9)
A: 56%, B: 65%, Ratio (Z)-
N
N
N
N
N
N
N
N
N
N
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Ph
Ph
Ph
Ph
2c
Ph
4ca
(Z)-
4cb
(Z)-
4ce
(Z)-
4cf
(Z)-
A: 88%, B: 50%
A: 70%, B: 70%
A: 62%, B: 74%
A: 65%
N
N
N
N
N
N
N
N
N
N
Me
CN
Ph
Me
+
CN
Ph
+
Ph
NC
2e
Me
2d
4de
(Z)-
5de
(Z)-
4ea
(Z)-
5ea
(Z)-
A: 91%, B: 67% A: 10%, B: 14%
b
4ea 5ea
A: 75%, Ratio
/
(23/77)
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me
+
Ph
Me
Ph
Me
Ph
Me
+
Ph
+
Ph
Me
Ph
Me
Ph
(Z)-
Me
(Z)-
2f
4fe
(Z)-
5fe
(Z)-
4fb
5fb
(Z)-
(Z)-
4fa
5fa
A: 76%,
A: 83%,
A: 88%,
4fa 5fa
: (3/7)
Ratio
/
: (23/77)
Ratio
nPr
/
(2/8)b
b
b
4fb 5fb
4fe 5fe
Ratio
N
/
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
nPr
nPr
nPr
nPr
nPr
+
nPr
nPr
nPr
nPr
nPr
nPr
nPr
2g
nPr
4gb
(Z)-
4gc
4gg
(Z)-
4gh
(Z)-
(Z)-
4ga
4ge
(Z)-
NuH pKad 19.8
(Z)-
NuH pKad 13.9 NuH pKad 13.9
NuH pKad 10.3 NuH pKad 14.4
NuH pKad 11.9
A: 56%, B: 45% A: 10%, B: 24%
A: 74%, B: 63% A: 21%, B: 47%
A: 70%, B: 80%
A: 62%, B: 75%
Scheme 1 Scope of the reaction. a Method A using a sand bath at 100°C for 72h, method B using microwave heating at 150°C for
45 min., isolated yields; b determined by 1H NMR; c 6 h reaction; d pKa in reference to DMSO
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A change to catalysts 1b and 1c led to a significant increase in acetylenedicarboxylate (DMAD) 2b with benzotriazole 3a
yields of 4aa to 61% and 66%, respectively (entries 5 and 6). afforded a 1/1 mixture of (Z) and (E) 4ba isomers in a good
Finally, the reaction was performed on a larger scale starting yield. By comparison, the use of pyrazole 3e led to a more
with 1.1 mmol of 2a. While a decrease in product 4aa yield selective reaction with a mixture of (Z)/(E) 4be isomers in a 1/9
was noticed using a sand bath for 72 hours (method A) (entry ratio. Unsymmetrical phenylpropiolate 2c underwent
7), we observed a nearly quantitative yield, e.g. 96%, of hydroamination with azoles 3a-b and 3e-f with complete
enamine 4aa by employing microwave heating for 0.75 hour regio- and stereoselectivity and good isolated yields. In
(method B) (entry 9). It is noteworthy that similar yields of 4aa contrast, the hydroamination of 3-phenylpropiolonitrile 2d
were obtained starting from 0.22 mmol of 2a and applying with pyrazole 3e led to isolated (Z)-regioisomers 4de and 5de
method A or B (entries 6, 8).
in a 9/1 ratio and high yields. The reactions of unsymmetrical
The scope of the gold(I)-catalysed hydroamination was 5-methylhex-2-yne 2e and phenylpropyne 2f with azoles 3a,b
studied for a series of alkynes and azole nucleophiles by using and 3e gave mixtures of the corresponding (Z)-regioisomers 4
method A and B (Scheme 1 and Figure 2). The (Z)/(E) (cis/trans) and 5 in high yields with ratios from 3/7 to 2/8. The
isomerism of pure or mixed isomers was established based on hydroaminations of 4-octyne 2g with azoles 3a-c, 3e and 3g-h
the observed and non-observed NOEs profiles after full afforded the related enamines
4 with complete (Z)-
assignment of 1H/13C/15N chemical shifts (see the SI for stereoselectivity in average to good yields independently of
details). By studying all hydroamination products 4, we noticed the pKa of the azole nucleophile. It is worth noting that the
3
the J(1H-15N) coupling constants were larger than or equal to reaction of 4-octyne 2g with triazole 3b led to a mixture of the
4.8 Hz for all (Z)-enamines and less than 2 Hz for the (E)- preferred N1 addition product 4gb and the minor N2 tautomer
enamines in agreement with previous analyses23 (see SI, product 4gc. By comparison to the previous work of Shi et al.
Figures S1,S2). At first, diphenylacetylene 2a was reacted with who reported the synthesis of several vinyl-substituted
benzotriazole 3a and triazoles 3b-c to lead to the triazoles from terminal and internal alkynes using PPh3AuOTf
corresponding (Z)-products 4aa, 4ab and 4ac in good yields. catalyst in toluene,15b our synthetic methodology operates in
The reaction with triazole 3b afforded preferentially the N1 solvent free conditions and therefore allows practical, simple,
addition product 4ab, the N2 tautomer product 4ac being and scalable reactions using standard thermal heating or more
minor. In spite of a high yield, the hydroamination of alkyne 2a convenient microwave heating. Moreover, the scope of our
with 1-methylimidazolidin-2-one 3d was not entirely (Z)- reactions is broader and allows the hydroamination of seven
selective, a (Z)/(E) ratio of 68/32 was observed for 4ad. As internal alkynes with eight heterocycles including triazoles,
noticed during the development of the catalytic reaction, the pyrazoles, imidazole and a cyclic urea to form (Z)-enamines
use of microwave heating (method B) led to higher yields for with very minor exceptions.
[Au(IPr)][BF ] [Au(IPr)(OH)]
+
4
products 4aa, 4ab and 4ac. The hydroamination of dimethyl
Lewis acid
Brønsted base
H
O
proton transfer
H
2a-g
R1
R2
O
(IPr)Au
Au(IPr)
BF4
1c
R1
Nu
[Au]
+
H
NuH 3a-h
- H2O
O
Tf
R2
R2
H2O +
NBu4OTf
Nu
R1
(Z)-4,
(E)-4
or (Z)-5
NBu4
E
[Au]
H
Nu
D
R2
A
+ NBu4OTf
R1
R2
BF4
R1
[Au]
[Au] = [Au(IPr)]
+ [Au(IPr)Nu] B
C
+ [Au][BF4]
BF4
Nu
R1
R2
[Au]
- [Au][BF4]
[Au]
Scheme 2 Proposed reaction mechanism
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8n,28
Finally, along our study, we observed triazole 3b reacted selectivities as well as narrow substratDeOsI:c1o0p.1e0s3.9/C9OAB00ra58p7idK
preferentially to form the N1 addition product, the N2 screening of the reaction conditions determined EtOAc to be
tautomer product being minor or not formed.
Regarding the reaction mechanism, some of us have 3 and SI, Table S1). The Pd/C catalyst (5% Pd) loading was set
demonstrated that [{Au(IPr)}2(μ-OH)][BF4] 1c is highly at 1 mol% and other parameters, e.g. temperature, time and
the best solvent in order to reach high isolated yields (Scheme
a
efficient bifunctional catalyst for the hydrophenoxylation, pressure, needed to be adjusted as a function of the substrate.
hydroalkoxylation and hydrocarboxylation of internal Hydrogenation of enamines 4aa, 4ad and 4ce proceeded
alkynes.17 This complex can be regarded as a catalyst able to smoothly within 15 hours at room temperature and 1 bar of
activate substrates in a dual-mode providing Lewis acid H2. Under the same reaction conditions except heating at 60°C,
[Au(IPr)][BF4] and Brønsted base [Au(IPr)(OH)] (Scheme 2). On triazole and pyrazole derivatives 4be and 4cb were reduced
the basis of previous mechanistic studies,17 we propose the effectively in 15 and 30 hours, respectively. The hydrogenation
Lewis acid [Au(IPr)][BF4] would coordinate to the alkyne to of enamines 4ab and 4ca required 10 bar pressure of H2 and
form species A24 and the Brønsted base [Au(IPr)(OH)] would 60°C heating to proceed in 15 and 72 hours. As previously
deprotonate the azole nucleophile to generate the observed by Pfaltz et al. and Hou et al. on other similar
corresponding gold-azole complex B and release a water derivatives,29 the hydrogenation of conjugated nitrile 4de into
molecule (Scheme 2). Afterwards, the subsequent nucleophilic saturated pyrazole 6de required stronger reaction conditions,
attack of gold-azole B15a toward -complex A in an anti-fashion i.e. 80°C and 50 bar of H2, to reach a very good 85% yield. The
would lead to the formation of gem-diaurated species C25 or σ- vinyltriazole 4gb was hydrogenated in a similar manner but
monoaurated species D26 (most likely in equilibrium), C acting required a longer reaction time, 72 hours.
as an off-cycle species. Finally, protodeauration with H2O and
the assistance of OTf anion20,21 through intermediate E would intermolecular hydroamination of internal alkynes for the
deliver the vinylazole product 4 or 5 and catalyst 1c. This effective synthesis of broad range of functionalised
To summarise, we have developed a gold(I)-catalysed
a
assisted proton-transfer/protodeauration step underlines the vinylazoles with fair to high yields and high regio-, chemo-, and
prominent role of counterions during gold catalysed stereoselectivity. The use of solvent-free conditions allows a
practical, simple, and scalable synthetic methodology using
Pd/C (1 mol%)
Nu
Nu
R1
R2
H
standard thermal heating or more convenient microwave
heating. In addition, the catalytic hydrogenation of the
resulting (Z)-enamines led to various substituted saturated
azoles in good yields without the formation of significant by-
products. The present process represents a practical and
atom-economical alternative to existing synthetic methods to
assemble a variety of functionalised azoles.
H2 (x bar)
R2
R1
EtOAc
4
T (°C), t (h)
6
N
N
N
N
N
N
N
6ad
6aa
6ab
N
O
Ph
Ph
Ph
Ph
Ph
Ph
(25°C, 15 h, 1 bar)
73 % yield
(25°C, 15 h, 1 bar)
44 %
(60°C, 15 h, 10 bar)
95 %
Conflicts of interest
There are no conflicts to declare
N
N
6cb
6ca
6be
N
N
N
N
N
N
CO2Me
CO2Et
CO2Et
MeO2C
Ph
Ph
Acknowledgements
(60°C, 15 h, 1 bar)
67 %
(60°C, 30 h, 1 bar)
63 %
(60°C, 72 h, 10 bar)
53 %
The CNRS, the Chevreul Institute (FR 2638), the Ministère de
l’Enseignement Supérieur et de la Recherche et de
l’innovation, the Région Hauts-de-France and the FEDER are
acknowledged for supporting and funding partially this work.
The University of Lille is acknowledged for funding partially this
work (AO 2016-2017 Lille-Gent-Louvain, G11Flow project). The
Bruker 300 AVANCE III spectrometer is co-funded by the
European Union with the European Regional Development
Fund (ERDF), by the Hauts de France Regional Council
(contract n°17003781), Métropole Européenne de Lille
(contract n°2016_ESR_05), French State (contract n°2017-R3-
CTRL-Phase 1), the Pasteur Institute of Lille, the Lille University
and the French CNRS. Umicore AG is thanked for generous
donations of auric acid. Dr M. Kouach (Univ. Lille) is thanked
for HRMS analyses. Mrs C. Delabre (UCCS) is thanked for GC-
MS and elemental analyses. For work carried out in Ghent,
N
6gb
6ce
6de
N
N
N
N
N
N
CO2Et
CN
nPr
Ph
Ph
nPr
(25°C, 15 h, 1 bar)
53 %
(80°C, 15 h, 50 bar)
85 %
(80°C, 72 h, 50 bar)
84 %
reactions.20,21
Scheme
3
Hydrogenation
of
enamines
4
The catalytic hydrogenation of a series of vinylazoles 4 into
saturated azoles 6 was then investigated (Scheme 3 and SI,
Table S1). Although the hydrogenation of enamines has been
well-studied,8b,n,16,27,28 it is also clear that it suffers from
important limitations regarding the reaction activities and
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