Gold(I)-Catalyzed Intramolecular Hydroamination and Hydroalkoxylation of Alkynes: Access to Original Heterospirocycles

Article abstract of DOI:10.1021/acs.orglett.0c02070

We report here a simple and robust gold-catalyzed annulation reaction, giving N- and O-spirocycles in good to excellent yields. We have prepared a library of protected amines and tertiary alcohols that give, upon cyclization with alkynes, a representative set of heterospirocycles and illustrate reaction compatibility with diverse functional groups. A change in catalytic activity is possible by modifying the solvent, and two original tricyclic spirocycles were synthesized in a tandem reaction.

Full text of DOI:10.1021/acs.orglett.0c02070

pubs.acs.org/OrgLett
Letter
Gold(I)-Catalyzed Intramolecular Hydroamination and
Hydroalkoxylation of Alkynes: Access to Original Heterospirocycles
Kossi Efouako Soklou,∥ Hamid Marzag,∥ Jean-Philippe Bouillon, Mathieu Marchivie, Sylvain Routier,*
́
and Karen Ple*
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ABSTRACT: We report here a simple and robust gold-catalyzed annulation reaction,
giving N- and O-spirocycles in good to excellent yields. We have prepared a library of
protected amines and tertiary alcohols that give, upon cyclization with alkynes, a
representative set of heterospirocycles and illustrate reaction compatibility with diverse
functional groups. A change in catalytic activity is possible by modifying the solvent, and
two original tricyclic spirocycles were synthesized in a tandem reaction.
been effectively used for spiroacetal formation,23 reports of
pirocycles are characterized by the presence of a fully
3
Ssubstituted sp carbon that defines a well-organized 3D intramolecular gold-catalyzed ring formation with amines or
alcohols attached to a fully substituted carbon center remain
scarce when compared with their less hindered counter-
parts.24−28 Literature examples are, in most cases, reserved to
specific substrates with no further exploration.
orthogonal structure. They are attractive targets in the search
for chemical diversity and as an escape from “flatland” in
medicinal chemistry.1−5 Different synthetic methodologies
have been developed to generate these scaffolds, but their
preparation remains challenging.6−11 There are several
common strategies available to construct the spirocyclic
core,12 and metal catalysis is one important option. The use
of organometallic reagents generally avoids aggressive reaction
conditions, reduces the risk of side reactions, and can remove
certain reaction barriers while maintaining compatibility with
most organic functions.
Gold catalysis has been widely used for the construction of
carbon−carbon or carbon−heteroatom bonds over the past 15
years.13−17 The gold-catalyzed activation of alkynes followed
by inter- or intramolecular nucleophilic attack leads to a
multitude of different chemical structures.18,19 In particular,
gold(I)-catalyzed hydroamination and hydroalkoxylation are
both powerful methods for building new heterocycles.20−22
Gold catalysis has changed the way chemists view reactivity
and bond formation, giving access to a greater number of
available nucleophilic partners, even those that are traditionally
seen as non-nucleophilic.
In general, when a heteroatom is attached to a fully
substituted carbon center, its reactivity is limited because of
the hindered steric environment. Harsh conditions are often
necessary for the heteroatom to engage in further reactions, in
particular during ring formation to create a new spirocyclic
center. To overcome this problem, we sought to develop a
mild and efficient process that would both boost reactivity and
promote intramolecular cyclization to form new functionalized
heterospirocycles starting from tertiary alcohols and the
corresponding protected amines. Although gold catalysis has
As illustrated in Scheme 1 a−c, formal hydroxyalkoxylation
or hydroamination reactions with alkynes have been described
with both gold(I) and (III) catalysts, but hydration or further
oxidation is always observed, either by the capture of the
reactive intermediate or as a desired part of the reaction
process.29−31 In our work, the addition of various tertiary
alcohols or protected amines to alkynes has been achieved
without affecting the oxidation state of the newly formed
spirocycle (Scheme 1 d).
We wish to report here the gold-catalyzed intramolecular
hydroamination and hydroalkoxylation of alkynes with tertiary
alcohols or protected amines to form new spirocycles. Starting
from the general structure I containing a piperidine, a
tetrahydro(thio)pyran ring, or a simple carbocyle, access to
dihydro-pyrazinone and -oxazinone spirocycles with the
general structure II was achieved (Scheme 1 d).
Initial tests were carried out using the commercially available
4-N-Boc-amino-1-Cbz-piperidine-4-carboxylic acid function-
alized with propargylamine. JohnPhosAu(MeCN)SbF6 was
chosen as the catalyst because acetonitrile is a relatively weak
coordinating ligand and is easily displaced, thus avoiding the
Received: June 23, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02070
© XXXX American Chemical Society
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time, with spectacular results. Only 10 min at 120 °C was
necessary to obtain 78% of the desired spirocycle (entry 3).
Decreasing the reaction temperature, but for a longer period of
time, gave the desired product in 88% yield (entry 4).
Decreasing the catalyst loading to 2.5 mol % was possible, with
no effect on the reaction efficiency (entry 5). Finally, the best
results were obtained with a 2.5 mol % catalyst loading at 120
°C for only 5 min under microwave irradiation (entry 6).
Different gold chloride catalysts were then tested, but the
substrate conversion was poor in all cases (entries 7−9). In
comparison, the presence of the weakly coordinating bis-
(trifluoromethanesulfonyl)amide ligand (entry 10) gave the
desired product in excellent yield, confirming our results in
which highly coordinating anions are poorly reactive (entry 9
vs 10). The nature of the phosphine ligand was then modified
(entries 11−13), with no significant difference in reactivity. We
thus chose JohnPhosAu(MeCN)SbF6 as the best catalyst with
regard to both cost and availability. The potentially
deactivating tert-butyloxycarbonyl (Boc) amino protecting
group had no effect on the cyclization, and the presence of
intermediate 4 was never observed in any of the reactions.
We then applied the optimized conditions to the
corresponding oxygenated substrate 7, made in four steps,
and a 58% yield from the commercially available 1-
(benzyloxycarbonyl)-4-piperidinone. (See the SI for the
detailed synthesis of 7.)
Scheme 1. (a−c) Gold-Catalyzed Heterospirocyclization in
the Literature and (d) Our Proposed Methodology
In this case, the formation of two alkene regioisomers was
observed in 94% overall yield as a clean mixture (Scheme 3).
Scheme 3. Spirocyclization with a Tertiary Hydroxyl Group
use of silver salts to activate the catalytic species. To our
disappointment, heating the secondary amide 1 in the presence
of the gold complex gave the oxazoline derivative 2 in good
yield (Scheme 2).32 Using different gold catalysts such as
(Ph3P)AuCl or JohnPhosAuCl gave the same results.
Scheme 2. Oxazoline Formation
We were surprised to find that the major reaction product was
1
the exomethylene derivative 8, as determined by H NMR.
The separation of the isomers by column chromatography gave
a 74% isolated yield of 8, with the remaining amount being a
mixture of the two compounds. A shorter reaction time (1 or 2
min) was ineffective in suppressing the small amount of
isomerized product 9 formed. Moreover, we also found that
compound 8 was easily transformed into 9 when treated with
p-toluenesulfonic acid (PTSA·H2O) (10.0 mol %) at rt (total
conversion after 5 min). This led us to perform the reaction in
the presence of PTSA to provoke double-bond migration in
situ, giving the endo isomer 9 as the unique product in 87%
isolated yield.
To evaluate the observed microwave effect, we subjected
compound 7 to our optimized conditions in a sealed tube at
120 °C in a preheated heating block. Conventional heating was
less efficient, with only a 78% conversion and a 55% isolated
yield.
To avoid oxazoline formation due to tautomerization of the
secondary amide, the corresponding N-methyl amide 3 was
prepared. Conventional heating (80 °C) in the presence of 5.0
mol % of JohnPhosAu(MeCN)SbF6 gave an 81% yield of the
endocyclic product 5. The presence of the exocyclic compound
4 was undetected (Table 1, entry 1). Even though our first
reaction was successful, we felt that there was room for
improvement, so we set out to optimize various reaction
conditions such as the reaction length, catalyst, and loading.
(See the SI for catalyst structures.)
A slight increase in yield was obtained by decreasing the
reaction temperature to 40 °C (entry 2), but 24 h was
necessary for the full conversion of the starting material.
Microwave irradiation was then tested to shorten the reaction
The crystallization of regioisomer 9 gave us the opportunity
to prove its structure by X-ray analysis. The ORTEP
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Table 1. Optimization of Au-Catalyzed Cyclization and Catalyst Screening
a
b
c
entry
temp (°C)
time
cat. (mol %)
conv. (%)
yield (%)
1
2
3
4
5
6
7
8
Δ, 80
Δ, 40
120
80
16 h
24 h
10
20
20
5
5
5
5
5
JohnPhosAu (MeCN)SbF6 (5)
JohnPhosAu (MeCN)SbF6 (5)
JohnPhosAu (MeCN)SbF6 (5)
JohnPhosAu (MeCN)SbF6 (5)
JohnPhosAu (MeCN)SbF6 (2.5)
JohnPhosAu (MeCN)SbF6 (2.5)
AuCl3 (2.5)
PPh3AuCl (2.5)
JohnPhosAuCl (2.5)
JohnPhosAuNTf2 (2.5)
SPhosAu (MeCN)SbF6 (2.5)
t-BuXPhosAu (MeCN)SbF6 (2.5)
100
100
100
100
100
100
21
5
64
100
100
100
100
81
90
78
88
90
92
n.d.
n.d.
n.d.
92
80
120
120
120
120
120
120
120
120
d
9
10
11
12
13
5
5
5
90
89
90
t-BuBrettPhos Au(MeCN)SbF6 (2.5)
a
b
c
d
μW irradiation unless otherwise indicated. Time in minutes unless otherwise indicated. Determined by 1H NMR analysis. n.d., not determined.
representation (Figure 1) clearly shows an oxazinone moiety
linked by a fully substituted carbon to a piperidine moiety in
Figure 1. ORTEP representation of compound 9.
chair conformation with the oxygen atom in the axial position.
The oxazinone ring is not planar due to a significant deviation
from the mean plane of the C4 and O3 atoms.
With these results in hand, we wished to generalize this
quick and efficient gold-catalyzed spirocyclization to other
nitrogen- and oxygen-containing substrates of type I. (See the
SI for the preparation of the starting amides 10−22.) A
catalytic amount of PTSA·H2O was systematically added in the
oxygen series to favor double-bond migration and give only
one product.
The desired N-spirocycles were obtained in good to
excellent yields (Figure 2). The use of N-Boc protected
substrates gave the corresponding endocyclic double bonds in
all cases, whereas protection with a p-toluenesulfonyl group led
to the exclusive formation of an exocyclic double bond (29).
For this substrate, a reduced reactivity was also observed, as
microwave irradiation for 2 h was necessary for a complete
conversion with a total of 5% mol JohnPhosAu(MeCN)SbF6.
This lack of reactivity can most likely be explained by the
electron-withdrawing nature of the amino protecting group
(Tosyl vs Boc). Heterospirocyclization was compatible with
the presence of sulfur atoms, although with a substantially
longer reaction time of 2.5 h, to give the desired product 25 in
Figure 2. Substrate scope of the heterospirocyclization reaction.
79% yield. A slight decrease in yield was also observed when
the starting substrates contained multiple bonds (final
compounds 26 and 27).
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We performed the cyclization with amide 3 on a 1.0 mmol
scale using our optimized conditions. For practical purposes,
linked to the use of microwave irradiation and the limit
imposed by the size of the microreactors, it was carried out at a
concentration of 0.08 M. To our satisfaction, the spirocycle 5
was obtained in an excellent 98% yield. In a second larger scale
reaction (2.6 mmol), increasing the reaction concentration to
0.26 M was successfully achieved while simultaneously
decreasing the catalyst loading to only 1.0 mol %. Once
again, we observed no changes in outcome or yield (96%).
One real advantage of our process is that microwave irradiation
is only 5 min on whatever scale performed for the majority of
our substrates. Cyclization is also independent of the reaction
concentration, and no intermolecular side reactions occur.
Extending the scope of the reaction in the oxygen series gave
the N-allyl derivative (31) in moderate yield (Figure 2). The
use of a dipropargyl-substituted amide led to a unique tricyclic
structure, which was obtained in good yield through a double
in situ cyclization process (32). The corresponding endo
product (33) could be prepared by performing the reaction in
DMF, which presumably reduces the catalytic efficiency by
complexation of the gold catalyst. One limitation that we found
in both series was the absence of cyclization when an ester was
present in the starting material (30 and 34). Surprisingly, the
unreacted esters were fully recovered in both cases. This
constraint was lifted with the removal of the carbonyl group
and the use of a simple ether, which gave compound 35
quantitatively.
We then decided to apply the spirocyclization reaction to a
more complex chiral substrate. Several amide derivatives were
prepared from a protected quinic acid derivative in good yields.
(See the SI for the preparation of starting compounds.)
Cyclization was performed in the presence of a catalytic
amount of PTSA·H2O in all cases to give the corresponding
spirocycles 36−39. No racemization of the chiral quaternary
stereocenter was observed (1H NMR), and the tricyclic
product 39 was obtained as a separable mixture of
diastereomers.
Our next steps were devoted to further transforming our
molecules through the selective deprotection of the amino
groups or double-bond reduction. The hydrogenation of
compound 5 in the presence of palladium chloride allowed
the removal of the benzyl carbamate in 70% yield, with no
observed reduction of the double bond (Scheme 4).
Conventional alkene reduction methods (H2, Pd/C, or Pt)
were unsuccessful, with the recovery of the unreacted starting
material. Ionic conditions were then tried, and whereas the use
of triethylsilane/trifluoroacetic acid failed with compound 5, it
proved to be successful starting from spirocycle 9.33 The
desired spiromorpholinone 41 was isolated in 84% yield.
In conclusion, we have developed a spirocyclization reaction
based on the intramolecular gold-catalyzed hydroamination
and hydroalkoxylation of alkynes. Both tertiary alcohols and
protected amines react to form new heterospirocycles in good
to excellent yields under microwave irradiation in only a few
minutes with low catalyst loading. We have prepared a small
library of spirocycles containing dihydro-pyrazinone and
-oxazinone cores, with no further oxidation of the final
product. Gram quantities were also prepared in a practical and
robust manner with an even lower catalyst loading. We have
likewise proven the compatibility of the method toward
asymmetric centers as well as common protective groups. As
an added bonus, a tandem reaction to give unique tricyclic
spirocycles (32 and 39) was observed, and the catalyst
reactivity could be altered using DMF as a coordinating
solvent. Further reactions such as isomerization, reduction, and
selective deprotection increase the significance of the present
work and offer possibilities for the use of these spirocyles as
candidates to increase molecular diversity in medicinal
chemistry.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02070.
1
Experimental procedures and H NMR and 13C NMR
for all compounds (PDF)
Accession Codes
CCDC 2009173 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
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AUTHOR INFORMATION
Corresponding Authors
■
́
Karen Ple − Institut de Chimie Organique et Analytique,
́
́
Universite d’Orleans, CNRS UMR 7311, 45067 Cedex 2
́
Orleans, France; orcid.org/0000-0003-3749-1723;
Email: karen.ple@univ-orleans.fr
Sylvain Routier − Institut de Chimie Organique et Analytique,
Scheme 4. Protecting Group Removal and Double-Bond
Reduction
́
́
Universite d’Orleans, CNRS UMR 7311, 45067 Cedex 2
́
Orleans, France; orcid.org/0000-0002-2823-0591;
Email: sylvain.routier@univ-orleans.fr
Authors
Kossi Efouako Soklou − Institut de Chimie Organique et
́
́
Analytique, Universite d’Orleans, CNRS UMR 7311, 45067
́
Cedex 2 Orleans, France
Hamid Marzag − Institut de Chimie Organique et Analytique,
Universite d’Orleans, CNRS UMR 7311, 45067 Cedex 2
Orleans, France
Jean-Philippe Bouillon − Normandie Universite, COBRA,
CNRS UMR 6014, Universite de Rouen, 76000 Rouen, France
Mathieu Marchivie − Universite de Bordeaux, ICMCB CNRS-
UMR 5026, 33608 Pessac, France
́
́
́
́
́
́
D
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(16) Friend, C. M.; Hashmi, A. S. K. Gold Catalysis (Special
thematic edition on gold catalysis). Acc. Chem. Res. 2014, 47, 729−
730.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02070
(17) Rudolph, M.; Hashmi, A. S. K. Heterocycles from gold catalysis.
Author Contributions
∥K.E.S. and H.M. contributed equally.
Chem. Commun. 2011, 47, 6536−6544.
(18) Dorel, R.; Echavarren, A. M. Gold(I)-Catalyzed Activation of
Alkynes for the Construction of Molecular Complexity. Chem. Rev.
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Notes
(19) Alyabyev, S. B.; Beletskaya, I. P. Gold as a catalyst. Part I.
Nucleophilic addition to the triple bond. Russ. Chem. Rev. 2017, 86,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank the Region Centre Val de Loire (Ph.D. funding
SKE), the Labex programs SYNORG (ANR-11-LABX-0029)
and IRON (ANR-11-LABX-0018-01), the Ligue contre le
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