Gold-catalyzed tandem hydroamination/formal Aza-Diels-Alder reaction of homopropargyl amino esters: A combined computational and experimental mechanistic study

Article abstract of DOI:10.1002/chem.201406224

A tandem gold-catalyzed hydroamination/formal aza-Diels-Alder reaction is described. This process, which employs quaternary homopropargyl amino ester substrates, leads to the formation of an intrincate tetracyclic framework and involves the generation of four bonds and five stereocenters in a highly diastereoselective manner. Theoretical calculations have allowed us to propose a suitable mechanistic rationalization for the tandem protocol. Additionally, by studying the influence of the ligands on the rate of the gold-catalyzed reactions, it was possible to establish optimum conditions in which to perform the process with a variety of substituents on the amino ester substrates. Notably, the asymmetric version of the tandem reaction was also evaluated.

Full text of DOI:10.1002/chem.201406224

DOI: 10.1002/chem.201406224
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&
Gold Catalysis |Hot Paper|
Gold-Catalyzed Tandem Hydroamination/Formal Aza-Diels–Alder
Reaction of Homopropargyl Amino Esters: A Combined
Computational and Experimental Mechanistic Study
Javier Miró,[a] María Sµnchez-Roselló,[a, b] Javier Gonzµlez,[c] Carlos del Pozo,*[a] and
Santos Fustero*[a, b]
Abstract: A tandem gold-catalyzed hydroamination/formal
aza-Diels–Alder reaction is described. This process, which
employs quaternary homopropargyl amino ester substrates,
leads to the formation of an intrincate tetracyclic framework
and involves the generation of four bonds and five stereo-
centers in a highly diastereoselective manner. Theoretical
calculations have allowed us to propose a suitable mecha-
nistic rationalization for the tandem protocol. Additionally,
by studying the influence of the ligands on the rate of the
gold-catalyzed reactions, it was possible to establish opti-
mum conditions in which to perform the process with a vari-
ety of substituents on the amino ester substrates. Notably,
the asymmetric version of the tandem reaction was also
evaluated.
Introduction
cade transformations, which enables the formation of complex
molecules in a one-pot fashion.
The hydroamination reaction is a pivotal transformation in or-
ganic chemistry. It enables the direct formation of a new CÀN
bond by the addition of a nucleophilic nitrogen source to an
unsaturated CÀC bond in an atom-economical manner, from
readily available alkenes and alkynes substrates.[1] The intramo-
lecular version of this process gives direct access to nitrogen-
containing heterocycles, which are present as recurrent scaf-
folds in naturally occurring molecules and biologically active
compounds.[2] Despite its simplicity, this reaction suffers from
a high activation barrier due to electrostatic repulsions be-
tween the electron density of the multiple bond and the nitro-
gen lone pair. One of the most common approaches to over-
come this activation energy is the use of catalytic methods
based on transition metal complexes.
In the last decade, the development of gold catalysis has
witnessed extraordinary growth. The unique features of gold
salts, including exceptional alkynophilicity and low oxophilicity,
make gold complexes well suited catalysts for the activation of
alkenes, alkynes, and allenes. Hence, the activation of alkynes
by gold salts provides a useful method for facilitating the addi-
tion of nitrogen nucleophiles, both inter- and intramolecularly,
with high efficiency and under mild conditions.[3] Likewise,
gold salts have shown exceptional properties for promoting
tandem reactions, and there are numerous examples in the lit-
erature that combine a hydroamination step with further trans-
formations.[4]
It is accepted that gold-catalyzed reactions of alkynes start
with the electronic activation of the alkyne to generate a vinyl
gold intermediate.[5] After evolution of this gold species, the
last step of the reaction is protodeauration, which releases the
product and regenerates the active catalytic species.[6] A recent
study demonstrated how the nature of the ligands influences
each stage of the catalytic cycle.[7] Actually, it is well known
that ligands play a major role in tuning the reactivity and se-
lectivity of gold complexes. The nature of the ancillary ligand
directly influences the properties of the chemical bond be-
tween the gold and an unsaturated substrate. Therefore, the
correct choice of ligand is crucial for the success of a gold-cat-
alyzed transformation.[8]
In this context, the hydroamination of alkynes is especially
important. They are more prone to undergo this type of trans-
formation than their olefinic counterparts, and the in situ gen-
erated imines/enamines are suitable substrates for further cas-
[a] J. Miró, Dr. M. Sµnchez-Roselló, Dr. C. del Pozo, Prof. S. Fustero
Departamento de Química Orgµnica, Universidad de Valencia
46100 Burjassot (Spain)
E-mail: carlos.pozo@uv.es
santos.fustero@uv.es
[b] Dr. M. Sµnchez-Roselló, Prof. S. Fustero
Laboratorio de MolØculas Orgµnicas
Centro de Investigación Principe Felipe
46012 Valencia (Spain)
Homopropargyl amines are common substrates in gold-cata-
lyzed reactions. A wide variety of transformations have been
devised that employ these substrates, which give access to
several nitrogen-containing heterocycles.[9] However, to date,
substrates bearing a quaternary stereocenter have not yet
been tested. In the context of an ongoing project in our labo-
[c] Dr. J. Gonzµlez
Departamento de Química Orgµnica e Inorgµnica
Universidad de Oviedo, 33006 Oviedo (Spain)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406224.
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ratory, we evaluated the reactivity of protected quaternary
homopropargylic amino esters under gold catalysis. We antici-
pated that, depending on the nature of the N-protecting
group, we could expect differential reactivity with these sub-
strates. Accordingly, when the amino ester substrates contain
a carbamate or an amide functionality, we would expect a nu-
cleophilic carbonyl addition across the triple bond to occur
(Scheme 1, via A).[10] However, when they contain an aryl sub-
Scheme 2. Gold(I)-mediated tandem process with homopropargyl amino
esters 1.
curred, which gave rise to the final products as single diaste-
reoisomers. Several fluorinated and non-fluorinated amino
ester substrates 1 were compatible with this tandem protocol.
Blocking the NH bond in the substrates (Scheme 1, R3, R4 ¼ H)
prevented the hydroamination step, and instead, a tandem hy-
droarylation/isomerization process occured in the presence of
gold salts to afford a new family of dihydroquinolines.[15]
The initial results of the tandem process (via B) showed that
this reaction is very efficient when the aryl substituent is
a PMP (p-methoxyphenyl) group; whereas, the use of other ar-
omatic groups with different electronic properties led to a dra-
matic decrease in the product yields.[14] Herein, a careful inves-
tigation of the tandem process, mainly based on studying the
effects of ligands on the gold catalyst, has allowed us to identi-
fy suitable conditions to extend the scope of this transforma-
tion to substrates with other types of aromatic substituents on
the nitrogen atom. Theoretical studies have also been per-
formed to shed light on the mechanism and the stereochemi-
cal outcome of the reaction. Additionally, the use of chiral sub-
strates in this process is also discussed.
Scheme 1. Differential reactivity of quaternary homopropargyl amines under
AuI catalysis.
stituent, they would react in the presence of gold salts
through a hydroamination protocol (via B).[11] Finally, with sub-
strates that bear a tertiary nitrogen group, the hydroamination
reaction is blocked and a hydroarylation-type reactivity would
be expected (via C).[12]
In fact, preliminary evaluation of the reactivity of homopro-
pargyl amino esters 1 showed that substrates that bear an
amide functionality (Scheme 1, R3 =CO(O)ÀR) underwent
a tandem carbonyl addition/nucleophilic addition/Petasis–Ferri-
er rearrangement in the presence of gold(I) salts to give 2,3-di-
hydropyridin-4-(1H)-ones in an efficient manner.[13] On the
other hand, substrates that contain aromatic groups (R3 =aryl)
followed a tandem hydroamination/formal aza-Diels–Alder re-
action sequence, which generated tetracyclic frameworks 2 in
a single step (Scheme 2).[14] In the overall process, the simulta-
neous generation of four bonds and five stereocenters oc-
Results and discussion
Initially, we sought to evaluate the differential reactivity of
homopropargyl amines in the presence of gold salts based on
the nature of the nitrogen protecting group. When fluorinated
propargylic amino ester 1a was treated with [AuCl(PPh3)] and
AgOTf in toluene at room temperature, we observed the unex-
pected formation of tetracyclic compound 2a in 76% yield to-
gether with a small amount (13% yield) of the hydroamination
product 3a (Scheme 3). Whilst studying the scope of this pro-
cess, our attempts to extend the tandem protocol to include
substrates that contained other N-aromatic substitution dis-
tinct from PMP were ineffective. With substrate 1b, which bore
a p-tolyl group, an equimolecular amount of 2b and the hy-
droamination product 3b were obtained; whereas, with sub-
Abstract in Spanish: En el presente trabajo se describe una
reacción tµndem hidroaminación/aza-Diels–Alder formal catali-
zada por sales de oro. El proceso, que emplea amino Østeres
propargílicos cuaternarios como sustratos de partida, conduce
a la formación de una compleja estructura tetracíclica, con gen-
eración simultµnea de cuatro enlaces y cinco estereocentros de
manera altamente diastereoselectiva. Se han llevado a cabo
cµlculos teóricos que nos han permitido proponer un mecanismo
que permite racionalizar el proceso tµndem. Adicionalmente, me-
diante el estudio de la influencia de los ligandos en la reactividad
de las reacciones catalizadas por oro, se han encontrado condi-
ciones de reacción que permiten extender el proceso a amino Øs-
teres de partida con una gran variedad de patrones de sustitu-
ción. Finalmente, la versión asimØtrica del proceso tµndem fue
tambiØn objeto de estudio.
Scheme 3. Gold(I)-mediated tandem protocol with amines 1a–c.
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strate 1c, which contained a phenyl N-substituent, the hydro-
amination product 3c was the major product.
leads to intermediate A, which is a five-membered ring ammo-
nium salt (Figure 1a).
To gain some insight into the mechanistic details of this
transformation,[16] we carried out a theoretical study by using
the density functional theory (DFT). In the gold(I)-mediated re-
actions described in this paper, [AuOTf(PPh3)] was assumed to
be the catalytically active species and the complex [AuPMe3]+
was used as a model in the theoretical study.[17] Full methodo-
logical details of this theoretical study are shown in the Sup-
porting Information.
Transition state TS1 shows one imaginary vibrational fre-
quency with a normal mode that corresponds to the formation
of the NÀC bond, as expected for a hydroamination reaction.
The distance between the two carbon atoms, which initially
corresponds to a triple bond, increases from 1.208 Š in 1a to
2.264 Š in TS1. Transition state TS2, involved in the deprotona-
tion of intermediate A, shows an imaginary normal mode that
corresponds to the proton transfer from the nitrogen atom of
A to the oxygen atom of the triflate anion, which is a process
that leads to the formation of intermediate B. As can be seen
from the values of the NÀH (1.420 Š) and OÀH (1.129 Š) bond
lengths in the transition state, the proton has already been
transferred from the nitrogen atom of A to the oxygen atom
of the triflate. The activation Gibbs free energy for each of
these reactions was calculated to be 11.5 and 0.2 kcalmolÀ1, re-
spectively (Figure 1a).
Based on the results of these calculations, we have proposed
a plausible mechanistic explanation for the formation of the
tetracyclic structures 2; the proposed mechanism involves an
initial hydroamination reaction of 1, followed by an asymmet-
ric dimerization pathway. The full process, which can be
viewed as a formal aza-Diels–Alder reaction, is depicted in
Scheme 4.
The initial step is the activation of the alkyne moiety of sub-
strate 1a through the coordination of the gold catalyst, which
acts as a p-Lewis acid, with the triple bond. This step has a neg-
ligible energy barrier and proceeds to give complex I, which is
16.6 kcalmolÀ1 more stable than the reactants. Cyclic inter-
mediate A is then formed by the attack of the amine nitrogen
atom on the triple bond in a favored 5-endo-dig cyclization.[18]
Then, intermediate A releases a proton, which leads to the for-
mation of triflic acid and intermediate B, which in turn reacts
with triflic acid at the b-enaminic position to give two diaste-
reoisomeric iminium salts Csyn and Canti. The reaction of inter-
mediates C with the triflate anion leads to the enaminic deriva-
tive 3a and the catalyst [Au(L)OTf] is regenerated.[19]
The reaction at the b-position of the enaminic intermediate
B with triflic acid, which gives rise to the diastereoisomeric imi-
nium intermediates Csyn and Canti, was shown to take place
through two possible transition states, TS3 or TS4, depending
on the stereochemistry of the proton addition (Figure 1a). The
imaginary normal mode in these transition states involves
both the proton transfer and the shortening of the NÀC bond.
TS3 presents an activation barrier of 2.3 kcalmolÀ1 and gives
rise to intermediate Csyn; whereas, TS4 is predicted to be
1.3 kcalmolÀ1 less stable than TS3. Both intermediates, Csyn and
C
anti, show similar levels of stability; Canti is slightly energetically
favored by 0.3 kcalmolÀ1.
The most relevant geometrical and energetic features of the
stationary points that were found for the transformation of
compound 1a into intermediates C and 3a are shown in
Figure 1. Complex I shows an asymmetric coordination of the
AuPMe3 moiety to the triple bond, and the CÀC bond length is
slightly increased (1.230 Š vs.1.208 Š in 1a). In this step, the
alkyne moiety of substrate 1a is activated by the gold catalyst;
thus, the 5-endo-dig cyclization of complex I is favored. This
The stationary points for the deauration reaction of inter-
mediates Csyn and Canti are shown in Figure 1b. In these reac-
tions, the hydroamination product 3a is formed and the cata-
lytically active species [AuOTf(PPh3)] is regenerated. The prod-
uct 3a can be formed from either Csyn or Canti via the transition
state structures TS5 or TS6, respectively. The imaginary normal
mode in these transition states corresponds to the formation
of the bond between the gold and the oxygen atoms and the
Scheme 4. Mechanistic proposal for the gold-catalyzed transformation of amine 1a into the tetracyclic structure 2a (only the intermediates with the relative
configuration that lead to the experimentally observed product 2a are shown).
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Figure 1. a) Stationary points located for the cyclization reaction of 1a, which leads to intermediates Csyn and Canti. b) Stationary points for the deauration re-
action that leads to intermediate 3a and the active catalytic species [AuOTf(PPh3)] (bond lengths are in Š and Gibbs free energies in kcalmolÀ1).
breaking of the carbon–gold bond, as might be expected from
nucleophilic attack of the triflate anion on the AuPMe3 moiety.
The deaurations of both Csyn and Canti are slightly endothermic
and they have activation barriers of 14.5 and 13.2 kcalmolÀ1,
respectively.
tion could lead to the formation of eight diastereoisomers of
intermediate D.
An intramolecular imine–iminium addition reaction via inter-
mediates D leads to tetracyclic intermediates E. The TfO-pro-
moted aromatization of E gives rise to intermediate F and trifl-
ic acid, which in turn will participate in the protodeauration of
F to form the final product 2 (Scheme 4). According to the ex-
perimental evidence, the tetracyclic structures 2 are obtained
in most cases as single diastereoisomers. This fact implies
a high level of facial stereoselectivity in the addition of 3a to
iminium intermediate C.
As shown in Scheme 4, an asymmetric dimerization pathway
that involves 3a and either Csyn or Canti accounts for the forma-
tion of the tetracyclic skeleton of derivatives 2. As both the nu-
cleophilic carbon atom of 3a and the electrophilic iminium
carbon atom of C are prochiral (Figure 2), their addition reac-
The 32 stationary points located for each step of the trans-
formation of 3a into tetracyclic intermediate E are shown in
the Supporting Information. The four reaction pathways with
the lowest Gibbs free energies are presented in Figure 3. In the
case of the reaction of 3a with Canti or Csyn, the lowest Gibbs
free energies (DG#) for the first step of the reaction are 27.6
(TS17), 28.2 (TS7), 29.6 (TS9), and 31.9 kcalmolÀ1 (TS13). In the
case of TS17, intermediate D6 is not very stable and can easily
revert back towards the reactants. The situation is even worse
in the case of D2, which is only 0.4 kcalmolÀ1 more stable than
TS9. On the other hand, intermediate D1 is 3.2 kcalmolÀ1 more
stable than TS7; however, the DG# for the cyclization step via
TS8 is very high. In the case of the reaction of 3a with Canti
,
which possesses the relative si/si stereochemistry, intermediate
D4 is 6.8 kcalmolÀ1 more stable than both TS13 and TS14. In
Figure 2. Relative stereochemistry of the addition reactions of 3a with Csyn
or Canti
.
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stable intermediates (Figure 4,
D1 and D4), the trifluoromethyl
groups are in an anti relation-
ship, relative to each other,
which minimizes the steric in-
teractions. This also ensures
that the two aromatic rings are
spatially close, such that two
hydrogen atoms of the aromatic
ring that corresponds to the 3a
moiety point towards the PMP
ring. In addition, the steric
effect of the trifluoromethyl
group appears to strongly de-
stabilise the transition state
structure TS18 relative to TS14,
as shown in Figure 5 (see the
Supporting Information). The
combination of both of these
steric interactions explains the
selective formation of inter-
mediate E4 and the observed
diastereoisomer of tetracyclic
derivative 2a.
Considering this reaction
pathway, the key step for the
success of the tandem process
is the addition of the enaminic
moiety of pyrroline 3 to the imi-
nium functionality of Canti. As
the hydroamination product 3a
arises from the deauration of
Figure 3. Stationary points located for the addition reaction of 3a with intermediates Csyn and Canti, with the speci-
fication of the reaction stereochemistry (bond lengths are in Š and Gibbs free energies in kcalmolÀ1).
C
anti, a low rate of reaction is re-
quired in this step to increase
the presence of intermediate
this situation, the tetracyclic intermediate E4 is expected to be
formed preferentially and after the aromatization and deaura-
tion reactions it will give rise to final product 2a.
C
anti and enable its reaction with 3a.
As mentioned above, a recent study demonstrated that it is
possible to categorize and tune-up most gold-catalyzed reac-
tions through the careful choice of the ligand.[7] This study in-
dicated that, when basic substrates were involved in the pro-
cess, the protodeauration is the rate-determining step. The
presence of strong acids in the reaction media that would in-
crease the rate of protodeauration, such as triflic acid, is mini-
mised by neutralisation with the basic substrate. In the present
As expected, the imaginary normal mode of TS13 corre-
sponds to the bond formation reaction between the iminium
carbon atom of Canti and the enaminic b-carbon atom of 3a,
which leads to intermediate D4. This intermediate contains
two reactive centers: an electrophilic iminium carbon atom
and an enamine-like fragment that is incorporated in the aro-
matic ring of the PMP group. Thus, TS14, as its imaginary
normal mode shows, corresponds to the CÀC bond formation
that takes place between the aromatic ortho-carbon atom, rela-
tive to the nitrogen, and the iminium carbon atom. Overall,
these last two steps may be considered together as a formal,
stepwise aza-Diels–Alder reaction.
Owing to the high degree of functionalization of the reac-
tants, it is not easy to single out just one factor that is respon-
sible for the facial selectivity observed in this reaction. Howev-
er, examination of the geometry of the transition state struc-
tures (TS7, TS9, TS13, and TS17) and the corresponding inter-
mediates (D1, D2, D4, and D6) has shed some light on the
origin of the observed stereochemical outcome. In the most
Figure 4. Geometry of intermediates D1 and D4, showing the relative anti
relationship of the CF3 groups and the spatial proximity of the PMP rings.
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Table 1. Optimisation of the ligands in the tandem protocol.
Figure 5. Geometry of transition state structures TS18 and TS14, showing
the relative position of the CF3 group.
case, the triflic acid, which is formed during the generation of
the catalytic gold species, will be partially neutralised by the
amine. This will decrease the rate of the deauration step and
allow pyrroline 3a to react with the iminium intermediate C.
With these considerations and on the basis of the proposed
mechanism, it is possible to rationalise the different behavior
of substrates 1a–c (Scheme 3) in the tandem process. When
the aromatic substituent at the nitrogen atom is the PMP
group (1a), the electron-donating properties of the methoxy
group increase the basicity of the nitrogen, which lowers the
protodeauration rate, and this subsequently translated into an
improved ability for the tandem reaction to proceed. With the
p-tolyl and phenyl groups (1b,c), the basicity of the amine de-
creases, respectively, which increases the rate of deauration
and in turn diminishes the formation of the tandem products.
According to the aforementioned studies of ligand effects
on the kinetics of the deauration step,[7] an electron-rich ligand
should accelerate this process. Conversely, electron-withdraw-
ing ligands would decelerate the deauration step and, both in
our case and based on the previous mechanistic discussion,
they would favor the tandem transformation. To test this hy-
pothesis, substrate 1c was subjected to the tandem reaction
conditions in the presence of gold salts that bore electronically
deficient ligands relative to PPh3 (Table 1, entry 1).
Entry
Ligand
Solvent
T [8C]
Time [h]
3c [%]
2c [%][a]
1
2
3
4
5
6
7
8
9
PPh3
L1
L1
L2
L2
L3
L3
L3
L4
L4
toluene
toluene
CH2Cl2
toluene
CH2Cl2
toluene
CH2Cl2
toluene
toluene
CH2Cl2
25
25
0
25
0
25
0
0
5
24
1
12
2
1
2
2
24
15
64
–
14
47[b]
72
51
55
48
51
58
55
53
3
3
3
3
1
3
3
3
25
0
10
[a] Yield of the isolated major diastereoisomer. [b] 60% conversion.
(entry 5). When ligand L3, which contains the phosphite unit
with the most electron-deficient substituents, was used in the
tandem reaction, either in toluene or in CH2Cl2, the reaction
was complete in 2 h; however, these conditions did not im-
prove the reaction yield (entries 6–8). Finally, the use of Jackie-
Phos L4 afforded results that were comparable to the reaction
with L2 in terms of reaction time and yield of compound 2c,
in either toluene or CH2Cl2 (entries 9 and 10).
With these results in hand, we concluded that the optimum
conditions to carry out the tandem process involve the use of
ligand L1 in CH2Cl2 at 08C, when the amino ester substrates
contain electron-poor aromatic N-substituents. These condi-
tions were applied to other amine substrates 1 and the results
that were obtained are summarised in Table 2.
The first attempt was performed with ligand L1, which con-
tained three phenyl rings each with a 4-trifluoromethyl sub-
stituent. Initially, the reaction was performed in toluene at
room temperature, with the gold salt generated in situ; we ob-
served that, after 24 h, only 60% conversion was achieved.
Nevertheless, the exclusive formation of tetracycles was detect-
ed, albeit as a mixture of diastereoisomers, in which the major
compound was 2c, which was isolated in 47% yield (entry 2).
The use of CH2Cl2 as the solvent led to an unexpected increase
in the rate, with the reaction being completed in 1 h even at
08C. In this case, the major isomer 2c was isolated in 72%
yield together with 3% yield of the hydroamination product
3c (entry 3). Therefore, according to our hypothesis, ligand L1
decreases the protodeauration rate, which favors the tandem
process, albeit with some erosion of the selectivity, and mini-
mizes the formation of the hydroamination product. Following
the same reaction trend, the use of ligand L2 in the tandem re-
action provided tetracycle 2c in 51% yield after 12 h in tolu-
ene, with complete conversion being observed in this case
(entry 4). When CH2Cl2 was used as the solvent and the reac-
tion was performed at 08C, 2c was isolated in 55% yield
Substrates 1b–f, which bear a variety of electron-donating
and electron-withdrawing substituents on the aromatic ring
(other than PMP), underwent the tandem protocol very effi-
ciently to afford tetracycles 2b–f in good yields (Table 2, en-
tries 2–6). Substrates with fluorinated (entries 1, 7–9) and non-
fluorinated (aliphatic: entry 10, aromatic: entries 11 and 12)
substituents at the alpha position relative to the nitrogen
atom were also compatible with the process, when PPh3 was
used as the ligand (when R2 =OMe).
In summary, the results from the experimental ligand study
and the theoretical calculations led us to identify suitable con-
ditions to broaden the scope of our tandem protocol, just by
changing the ligand of the gold(I) salt and the solvent. Nota-
bly, all of the final products contain two alpha amino acid
units.
Additional experiments were performed to provide further
evidence for the mechanistic pathway that was proposed
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proposal, substrate 3a was independently treated
with [AuOTf(PPh3)] (Scheme 5, conditions A), triflic
acid (conditions B), and the silver salt (conditions C).
In all cases, the starting material remained unaltered,
even when the reaction was heated at 808C for sev-
eral hours. Alternatively, hydroamination reactions
can also be promoted by Brønsted acids;[22] therefore,
triflic acid could be the catalyst of the tandem proto-
col. However, no reaction was observed when com-
pound 1a was treated with triflic acid in toluene
after 24 h at RT (Scheme 5); therefore, triflic acid is
not the catalyst of the process. These observations
are also in agreement with the relevance of inter-
mediate C (Scheme 4) in our tandem process and
they corroborate the fact that the hydroamination
product, by itself, does not undergo the tandem pro-
tocol.
Table 2. Broadening the scope of the tandem protocol.
In addition, compound 1a was subjected to the
gold-catalyzed reaction conditions in the presence of
BEMP (2-tert-butylimino-2-diethylamino-1,3-dimethyl-
perhydro-1,3,2-diazaphosphorine),
a non-poisoning
base. In the presence of 10 mol% BEMP and 5 mol%
of the gold catalyst, the reaction did not proceed
and the starting material was recovered unaltered
(Scheme 6). With 1 mol% BEMP and 5 mol% of the
gold catalyst, the rate of reaction was slowed, and
after 20 h at RT only 22% conversion was reached
(Scheme 6). The former experiment, with 10 mol%
BEMP, indicates that all the triflic acid that is necessa-
ry to close the gold catalytic cycle is captured by the
base, which inhibits the tandem process. However,
with 1 mol% BEMP the tandem process is diminished
but not eliminated. Therefore, the gold species can
act as a Brønsted acid to catalyze the formal aza-
Diels–Alder reaction; consequently, this alternative
mechanism for the tetracycle formation cannot be
overruled.[23]
The last step of our study was the development of
an asymmetric version of the tandem protocol. Accordingly,
substrate 1a was subjected to chiral HPLC and, once condi-
tions to separate the enantiomers in a semi-preparative
manner were identified, we isolated both enantiomers sepa-
rately.[24] Each enantiomer was independently treated with
[Au(OTf)PPh3] in toluene at room temperature, and clean for-
mation of the corresponding tetracycles 2a as single enantio-
mers was observed by analytical chiral HPLC (Scheme 7).
above. It is important to mention that the cyclization step
would be further promoted by either the triflic acid or the
gold salt. Accordingly, several authors have suggested that hy-
droamination products analogous to 3a–c could be protonat-
ed by triflic acid, which would give rise to iminium intermedi-
ates of type C, thus initiating a dimerization protocol.[20] It is
also known that gold salts can activate enamines and enol
ethers for the nucleophilic attack.[21] To prove our mechanistic
Scheme 5. Reactivity evaluation of 1a and 3a.
Scheme 6. Gold-catalyzed process in the presence of BEMP.
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Scheme 7. The asymmetric tandem protocol.
Conclusion
A tandem hydroamination/formal aza-Diels–Alder reaction of
homopropargyl amino esters 1 is described, which gives rise to
tetracyclic structures 2 in good yields and steroselectivities.
Theoretical calculations led us to propose all the intermediates
of the process and to rationalise the formation of the final
products as well as the stereochemical outcome of the reac-
tion. In combination with a ligand screening, these studies per-
mitted us to broaden the reaction scope to include substrates
that contained substituted aromatic rings with diverse elec-
tronic properties. Notably, the use of enantiomerically pure
starting materials indicated that the process is stereospecific.
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Acknowledgements
We would like to thank the Spanish Ministerio de Economía y
Competitividad (CTQ-2013-43310-P) and Generalitat Valenciana
(GV/PrometeoII/2014/073) for their financial support. J.M.
would like to thank University of Valencia for a predoctoral fel-
lowship.
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Keywords: aza-Diels–Alder · density functional calculations ·
gold · hydroamination · tandem reaction
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[24] For the determination of the absolute configuration of enantiomerically
pure substrates 1a, see the Supporting Information.
Received: November 25, 2014
Published online on February 20, 2015
Chem. Eur. J. 2015, 21, 5459 – 5466
www.chemeurj.org
5466
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim