Gold catalyzed stereoselective tandem hydroamination-formal aza-Diels-Alder reaction of propargylic amino esters

Article abstract of DOI:10.1039/c2cc37796a

A gold-catalyzed tandem intramolecular hydroamination-formal aza-Diels-Alder reaction of propargylic amino esters is described. The overall process leads to the formation of a tetracyclic framework as a single diastereoisomer, with the creation of four bonds and five stereocenters.

Full text of DOI:10.1039/c2cc37796a

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Gold catalyzed stereoselective tandem
hydroamination–formal aza-Diels–Alder reaction of
Cite this: DOI: 10.1039/c2cc37796a
propargylic amino esters†
Received 27th October 2012,
Accepted 21st December 2012
a
a
ab
Santos Fustero,*ab Paula Bello, Javier Miro, Marıa Sanchez-Rosello,
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´
´
´
c
d
a
´
Miguel A. Maestro, Javier Gonzalez and Carlos del Pozo*
DOI: 10.1039/c2cc37796a
www.rsc.org/chemcomm
A gold-catalyzed tandem intramolecular hydroamination–formal fluorinated heterocycles8 by means of an intramolecular hydro-
aza-Diels–Alder reaction of propargylic amino esters is described. amination reaction.9 In the pursuit of this goal, a gold-catalyzed
The overall process leads to the formation of a tetracyclic frame- process was envisioned to effect the desired transformation.
work as a single diastereoisomer, with the creation of four bonds However, during the evaluation of this methodology, we
and five stereocenters.
found that these propargylic amino esters undergo a novel
tandem hydroamination-formal aza-Diels–Alder reaction, giving
Cationic gold(I) and gold(III) complexes display unique behaviour rise to the formation of a tetracyclic intrincated framework.
towards unactivated multiple bonds such as alkenes, alkynes, The scope of this process and its extension to non-fluorinated
allenes, 1,3-dienes or enynes, promoting the nucleophilic amino esters as well as a plausible mechanistic proposal are
addition of a variety of functional groups both inter- and intra- disclosed herein.
molecularly.1 These complexes have shown an extraordinary
Our starting materials for the gold-catalyzed hydroamina-
ability to catalyze hydroamination reactions of alkynes.2 The tion reaction, i.e. amino esters 2, were assembled by reacting
intramolecular version of this reaction is noteworthy since propargyl bromide with imino esters 1 in the presence of zinc
nitrogen heterocycles such as indoles, pyrroles, quinolines, metal under Barbier-type conditions and DMF as solvent
pyridines or isoquinolines are formed in a very simple manner.3 (see ESI†).10 With substrates 2 in hand, we proceeded to study
On the other hand, one of the most effective ways of the behaviour of these propargylic amino esters in the presence
achieving synthetic efficiency is to implement a cascade reaction, of gold salts.
thus enabling several bond-forming events to occur in a single
Compound 2a was used as a model substrate on which
synthetic operation. Gold complexes exhibit exceptional properties different conditions were evaluated in order to perform the
for promoting cascade or tandem reactions, thanks to their ability desired hydroamination reaction that would render fluorinated
to activate alkyne, alkene or allene functionalities under mild pyrrolines in a straightforward manner. An initial attempt was
conditions at low catalyst loadings.4 Therefore, different types of made in dichloromethane with gold(I) chloride; however, a
gold-catalyzed tandem reactions have been successfully employed complex reaction mixture was obtained (Table 1, entry 1). The
for the synthesis of densely functionalized polycyclic5 and hetero- use of gold(III) chloride or Ph3PAuOTf (in situ generated from
cyclic6 structures. Many of these tandem processes involve a Ph3PAuCl and AgOTf) led to similar results (Table 1, entries 2
hydroamination reaction step.7
and 3). At this point, we found that the correct choice of the
In the context of an ongoing project in our laboratory, we devised solvent was crucial in these reactions; while more polar solvents
fluorinated a-substituted propargylic a-amino esters as suitable such as acetonitrile or methanol also afforded complex reaction
building blocks for the synthesis of several nitrogen-containing mixtures (Table 1, entries 4 and 5), the use of toluene changed
the situation dramatically since clean formation of two pro-
ducts was observed. The minor one, obtained in 13% yield, was
a
´
´
Dept. de Quımica Organica, Universidad de Valencia, E-46100, Burjassot, Spain.
identified as the intramolecular hydroamination product 4a,
while the structure of major product 3a, isolated in 76% yield,
had to be unambiguously determined by means of an X-ray
experiment (Table 1, entry 6).11 Besides Ph3PAuOTf, gold(I)
complexes II–IV were tested and comparable results were
achieved (Table 1, entries 7–9). Additionally, other silver salts
such as AgNTf2, AgSbF6 or AgBF4 also gave comparable results
to the ones obtained with AgOTf (Table 1, entries 10–12).
E-mail: santos.fustero@uv.es, carlos.pozo@uv.es
b
´
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Laboratorio de Moleculas Organicas, Centro de Investigacion Prıncipe Felipe,
E-46012, Valencia, Spain
c
´
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Dept. Quımica Fundamental, Universidad da Coruna, E-15071, A Coruna, Spain
d
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Dept. Quımica Organica e Inorganica, Universidad de Oviedo, E-33006, Oviedo,
Spain
† Electronic supplementary information (ESI) available. CCDC 894411. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c2cc37796a
c
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Table 1 Optimization of the reaction conditions
undergo a [4+2] formal cycloaddition, acting both as diene and
dienophile. In the formation of this product four new bonds
were created (two C–C and two C–N bonds), giving rise to a fused
tetracyclic structure containing five stereocenters. It is note-
worthy that compound 3a was obtained as a single diastereo-
isomer. With these optimized conditions in hand (Table 1,
entry 6), the scope of this new transformation was explored with
substrates 2a–n affording the results shown in Table 2.
As expected, substitution at the ester group (R3 position) had
no influence on the process since ethyl, benzyl and trimethyl-
silyl esters afforded the final tetracyclic products 3a,b,e respec-
tively (Table 2, entries 1, 2 and 5). Likewise, several fluorinated
substitutions (Table 2, entries 1–5) were allowed at the R1
position. In all these cases, the tandem reaction took place in
moderate to good yields. However, the nitrogen substitution
(R2 position) was crucial for the success of the tandem protocol.
Propargyl amino esters 2 bearing a PMP group underwent the
process efficiently, yielding the corresponding tetracyclic
compounds 3a–e (Table 2, entries 1–5). In contrast, when
amino esters 2 containing less activated aromatic rings at the
nitrogen atom were subjected to gold(I) catalysis, the hydro-
amination pathway leading to fluorinated pyrrolines 4 became
more important. With a p-tolyl substituent, equimolecular
amounts of tetracycle 3f and hydroamination product 4f were
formed (Table 2, entry 6). Other substituents such as the phenyl
group at the nitrogen atom produced a noticeable increase of
the secondary product 4g (Table 2, entry 7). The starting sub-
strate bearing two aromatic methoxy groups (2h) failed in the
tandem reaction and only gave the hydroamination adduct in
low yield, which could be explained on the basis of steric
Entry
Catalyst
Additive
Solvent
3aa (%)
4aa (%)
b
1
2
3
4
5
6
7
8
AuCl
AuCl3
I
I
I
I
II
III
IV
I
—
—
DCM
DCM
DCM
—
—
—
—
—
—
13
10
12
20
15
16
18
b
—
b
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgNTf2
AgSbF6
AgBF4
—
b
MeOH
CH3CN
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
—
b
—
76
70
78
68
73
70
72
9
10
11
12
I
I
a
b
Isolated yields after column chromatography. A complex mixture
was formed. PMP = 4-Methoxyphenyl.
The formation of 3a would involve a tandem process consisting requirements (Table 2, entry 8). Amino ester 2n with two fluorine
of a hydroamination followed by a formal aza-Diels–Alder atoms at the propargylic position produced the corresponding
reaction. In this manner, the hydroamination product would tetracycle 3n in excellent yield (90%) although as a 7 : 1 mixture
Table 2 Scope of the gold-catalyzed tandem reaction on a-amino esters 2
Entry
2
R1
R2
R3
R4
R
3 (yield %)a
4 (yield %)a
1
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
CF3
CF3
ClCF2
CF3CF2
AllylCF2
CF3
CF3
CF3
Ph
Me
4-Cl-C6H4
PMP
2-Naphthyl
Allyl
PMP
PMP
PMP
PMP
PMP
4-MeC6H4
Ph
3,5-(MeO)2C6H3
PMP
PMP
PMP
PMP
PMP
PMP
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
F
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-Me
3a (76)
3b (52)
3c (60)
3d (51)
3e (62)
3f (34)
3g (14)
—
3i (60)
3j (74)
3k (70)
3l (72)
3m (75)
3n (90)c
4a (13)
—
—
—
—
4f (34)
4g (64)
4h (34)
—
—
—
2
(CH2)2TMS
3b
4b
5
Et
Et
Bn
Et
Et
Et
Et
Me
Et
Et
Et
Bn
6b
7b
8
H
3,5-(OMe)2
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
9
10
11
12
13
14
—
—
—
a
b
c
Isolated yields after column chromatography. In these cases, the reaction mixture was stirred for 12 h at rt. Compound 3n was obtained as a
7 : 1 mixture of diastereoisomers as determined by 19F-NMR.
c
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five stereocenters. Theoretical calculations are currently underway in
order to elucidate the reaction mechanism.
This work was supported by the Ministerio de Ciencia e
´
Innovacion of Spain (CTQ2010-19774-C02) and Generalitat
Valenciana (GV/PROMETEO/2010/061). P.B. thanks the University
of Valencia for a predoctoral fellowship.
Notes and references
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G. Fabrizi, A. Goggiamani, R. S. Ramon, S. P. Nolan and M. Bandini,
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Scheme 1 Proposed mechanistic explanation.
of diastereoisomers (Table 2, entry 14). This result indicates that
the triple bond in this substrate would be more activated than in
the rest of the amino esters 2 towards the gold-catalyzed reaction,
probably due to the increased electrophilicity produced by the two
fluorine atoms at the a-position. This transformation was further
extended to non-fluorinated amino esters 2i–m. Either aliphatic
substituents at the R1 position or aromatic ones (bearing electron-
donating or electron withdrawing groups) were tolerated in this
gold catalyzed tandem process, affording the desired tetracycles
3i–m in good yields (Table 2, entries 9–13).
´
˜
4 (a) A. Fu¨rstner, Chem. Soc. Rev., 2009, 38, 3208; (b) E. Jimenez-Nunez
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2008, 64, 3885.
7 For recent examples of gold-catalyzed tandem processes that involve
a hydroamination step, see: (a) N. A. Romero, B. M. Klepser and
C. E. Anderson, Org. Lett., 2012, 14, 874; (b) H. Wu, Y.-P. He and
L.-Z. Gong, Adv. Synth. Catal., 2012, 354, 975; (c) G. Liu, Y. Zhou,
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It is important to note that compounds 3a–m were obtained
as single diastereoisomers and, according to the X-ray analysis
of 3a,11 the same stereochemical outcome was assumed for all
the tetracycles synthesized.
A mechanistic proposal, shown in Scheme 1, for this unpre-
cedented tandem reaction involves the intramolecular addition
of amine 2a to the triple bond, activated by the gold catalyst,
to render intermediate A, which is in equilibrium with its
tautomer B. Subsequent protodeauration would afford the hydro-
amination product, namely pyrroline 4a. A key step of the process
is the formation of the cyclic intermediate B, bearing the gold
catalyst. This intermediate is trapped for pyrroline 4a by means
of an enamine attack to render intermediate C.12 This iminium
intermediate is now prone to undergo the nucleophilic attack by
the ortho position of the N-PMP group giving rise to the tetracyclic
intermediate D, the overall sequence from A to D, resembling a
stepwise aza-Diels–Alder reaction. The aromatization and proto-
deauration of the tetracyclic intermediate E would yield product
3a and regenerate the catalytic species.
´
´
A. Ballesteros, A. L. Suarez-Sobrino and J. M. Gonzalez, Chem.–Eur.
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8 For the importance of fluorine in medicinal chemistry, see:
(a) W. K. Hagmann, J. Med. Chem., 2008, 51, 5359; (b) S. Purser,
P. R. Moore, S. Swallow and V. Gouverneur, Chem. Soc. Rev., 2008,
37, 320 and references cited therein.
9 For an account of the preparation of fluorinated heterocycles, see:
S. Fustero, J. F. Sanz-Cervera, J. L. Acena and M. Sanchez-Rosello,
Synlett, 2009, 525.
˜
´
´
10 This protocol was previously reported for the propargylation of fluori-
´
nated aldimines: G. Magueur, J. Legros, F. Meyer, M. Ourevitch,
B. Crousse and D. Bonnet-Delpon, Eur. J. Org. Chem., 2005, 1258.
11 For the X-ray structure of compound 3a, see ESI† (CCDC 894411).
12 When compound 4a was treated again with the gold catalyst or with
a catalytic amount of triflic acid, no reaction was observed. Addi-
tionally, reaction of 2a with the gold catalyst in the presence of
BEMP (a non-poisoning base) resulted in no reaction with 10% and
retarded rate with 1%. These results suggest that an alternative
pathway where gold species provide Brønsted acidity for the cata-
lysis of the second step cannot be overruled. See, for example:
T. Yang, L. Campbell and D. J. Dixon, J. Am. Chem. Soc., 2007,
129, 12070 and references cited therein.
In conclusion, a new gold(I)-catalyzed tandem process has been
described. It involves propargylic a-amino esters as starting materials
and consists of an intramolecular hydroamination followed
by a formal aza-Diels–Alder reaction. The overall sequence leads to
nitrogen-containing tetracycles, as single diastereoisomers in most
cases, through the creation of two C–C bonds, two C–N bonds and
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.