Gold-catalyzed mannich addition reactions of 1,3-dicarbonyl compounds with n-protected imines

Article abstract of DOI:10.1002/ejoc.201201252

The first (N-heterocyclic carbene)Au^I-catalyzed Mannich addition reactions of N-protected imines with different 1,3-dicarbonyl compounds are described. IPrAuNTf₂ was proven to be an efficient catalyst for the reactions of β-keto este

Full text of DOI:10.1002/ejoc.201201252

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201252
Gold-Catalyzed Mannich Addition Reactions of 1,3-Dicarbonyl Compounds
with N-Protected Imines
Manuela Delgado-Rebollo,[a] Rocio Moreno,[a] Manuel R. Fructos,*[a] and
Auxiliadora Prieto*[b]
Keywords: Gold / Mannich bases / Carbene ligands / Homogeneous catalysis
The first (N-heterocyclic carbene)AuI-catalyzed Mannich ad-
dition reactions of N-protected imines with different 1,3-di-
carbonyl compounds are described. IPrAuNTf2 was proven
to be an efficient catalyst for the reactions of β-keto esters
and 1,3-diketones with N-sulfonylimines to afford the de-
sired β-amino carbonyl compounds in good yields under very
mild conditions.
Introduction
In the last decade, gold complexes have emerged as ef-
ficient catalysts for C–C bond-forming reactions.[1] In this
context, nucleophilic additions to the C–C multiple bonds
of alkynes, allenes, and alkenes, as well as to the C=O bond
of carbonyl groups, are definitely the most common reactiv-
ity pattern in gold-catalyzed organic reactions.[1,2] In con-
trast, only a few examples of gold-catalyzed nucleophilic
additions to C=N bonds have been published.[3] Addition-
ally, although gold catalysts have been shown to promote
the addition of 1,3-dicarbonyl compounds to C–C multiple
bonds,[1a] the addition to imine C=N bonds (Scheme 1) re-
mains, to the best of our knowledge, unknown with this
metal. The intermolecular Mannich reaction is the tradi-
tional method used to prepare β-amino carbonyl com-
pounds that usually serve as versatile intermediates and im-
portant building blocks in the synthesis of products with
biological activities.[4] Given the importance of Mannich
bases, a wide variety of organocatalysts[5] and metal com-
plexes[6] have been studied as catalysts in direct Mannich
addition reactions of 1,3-dicarbonyl compounds to imines.
Scheme 1. Mannich addition of 1,3-dicarbonyl compounds to
imines.
Taking into account the catalytic capabilities of gold(III)
chloride in three-component Mannich reactions of alde-
hydes, alkynes, and carbamates,[7] we wondered if we could
use gold(I) N-heterocyclic carbene (NHC) complexes as
catalysts in the Mannich addition of 1,3-dicarbonyl com-
pounds to imines. Such (NHC)Au units have been described
in a number of cases to promote interesting catalytic trans-
formations.[8]
Results and Discussion
Initially, the reaction of β-keto ester 1a with N-tosyl-α-
imino ester 2a in CH2Cl2 was chosen as the model reaction
(Table 1). If 5 mol-% of the neutral complex IPrAuCl[9] [IPr
= 1,3-bis(diisopropylphenyl)imidazol-2-ylidene] was em-
ployed as the catalyst precursor, no reaction was observed
at room temperature after 24 h (Table 1, entry 1). In view
of this result, we decided to check the catalytic activity of
different cationic gold complexes, either well defined or
in situ generated. Thus, the use of an equimolar mixture of
IPrAuCl and NaBArЈ4 as a halide scavenger [ArЈ = 3,5-
bis(trifluoromethyl)phenyl] induced the targeted reaction
and provided 3aa in 50% yield with 58:42dr (24 h, r.t.;
[a] Laboratorio de Catálisis Homogénea, Departamento de
Química y Ciencia de los Materiales, Unidad Asociada al CSIC,
Centro de Investigación en Química Sostenible, Universidad de
Huelva,
Campus de El Carmen, 21071 Huelva, Spain
Fax: +34-959219942
E-mail: manuel.romero@dqcm.uhu.es
Homepage: http://www.uhu.es/ciqso/
[b] Departamento de Ingeniería Química, Química Física y
Química Orgánica, Universidad de Huelva,
Campus de El Carmen, 21071 Huelva, Spain
Fax: +34-959219983
E-mail: maria.prieto@diq.uhu.es
Homepage: http://www.uhu.es/ciqso/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201252.
Table 1, entry 2). Additionally, the reaction carried out with
[8d]
[IPrAu(NCMe)]BF4
afforded the two diastereoisomers
(56:44dr) in 52% yield after 12 h (Table 1, entry 3).
Eur. J. Org. Chem. 2013, 31–34
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
31

M. Delgado-Rebollo, R. Moreno, M. R. Fructos, A. Prieto
SHORT COMMUNICATION
Table 1. Mannich addition of β-keto ester 1a to N-tosyl-α-imino
ester 2a with IPrAuI complexes.[a]
Table 2. Mannich addition of β-keto ester 1 with imines 2b–f cata-
lyzed by IPrAuNTf2.
Entry Catalyst
t [h]
Yield[b] [%]
dr[c]
Entry Imine
PG
R
Product,
dr[b]
yield[a] [%]
1
2
3
4
5
6
IPrAuCl
48
0
–
IPrAuCl + NaBArЈ4 24
50
52
95
40
51
58:42
56:44
56:44
66:34
56:44
1
2
3
4
5
2b
2c
2d
2e
2f
Ts
Ts
Ts
Boc
PMP
p-NO2C6H4
C6H5
p-MeOC6H4 3ad, 31
C6H5
3ab, 84
3ac, 45
58:42
58:42
51:49
–
IPrAu(NCMe)+BF4 12
–
IPrAuNTf2
AuCl(SCH3)2
IPrAuBr3 + AgNTf2 12
12
12
3ae, trace
3af, trace
CO2Et
–
[a] Reaction conditions: gold complex (0.0125 mmol), imine
(0.3 mmol), β-keto ester (0.25 mmol), CH2Cl2 (2 mL). [b] Isolated
yield. [c] Diastereomeric ratio (major/minor); determined by analy-
[a] Isolated yield. [b] Diastereomeric ratio (major/minor); deter-
mined by analysis of the crude reaction mixture by 1H NMR spec-
troscopy. PG = N-Boc (tert-butoxicarbonyl); N-PMP (p-meth-
oxyphenyl).
1
sis of the crude reaction mixture by H NMR spectroscopy.
Once the catalytic capabilities of the IPAuNTf2 complex
Fortunately, complex IPrAuNTf2,[10] with a weakly coor- had been demonstrated for this transformation, we ex-
dinating counteranion, showed higher catalytic activity, and tended the scope to other nucleophiles (Table 3). More ste-
it gave the Mannich adduct as a 56:44 diastereomeric mix- rically hindered β-keto esters with substituents at the α-po-
ture in 95% yield at room temperature in 12 h (Table 1, en- sition were essayed with N-tosyl-α-imino ester 2a in the
try 4). The need for a NHC as ancillary ligand was demon- presence of IPrAuNTf2 (5 mol-%). The β-keto ester 1b pos-
strated by carrying out the reaction with AuCl(SCH3)2 sessing a methyl substituent reacted with 2a to give γ-keto
(5 mol-%; Table 1, entry 5), which afforded the product in α-amino acid ester 3ba in 74% yield with 64:36dr after 12 h
only 40% yield. Because free NHCs have been recently de- (Table 3, entry 1). As for 1b, five- and six-membered cyclic
scribed as organocatalysts in Michael additions of 1,3-di- β-keto esters 1c and 1d underwent the Mannich reaction
carbonyl compounds,[11] we carried out NMR spectroscopic to afford 3ca and 3da, respectively, in moderate yields and
experiments to check if dissociation of the IPr ligand from diastereoselectivities (Table 3, entries 2 and 3). In contrast,
the metal center had occurred. In this regard, a solution of longer reaction times were necessary to achieve good yields
IPrAuNTf2 was treated with B(C6F5)3, which is known to with β-keto ester 1e possessing an n-propyl substituent in
react with IPr carbene.[12] We monitored the reaction for the R1 position (Table 3, entries 4 and 5). The size of the
several hours and found no spectroscopic evidence for the ester moiety in the β-keto esters was also shown to have a
IPr-B(C6F5)3 adduct that could eventually form upon disso- significant influence on reactivity and diastereoselectivity.
ciation of the IPr ligand from the gold center. Additionally, Thus, the reaction of isopropyl derivative 1f afforded the
when we generated the IPr carbene in situ by treatment of product in 70% yield after 24 h with low diastereoselectivity
IPrH+Cl– with NaOtBu in CH2Cl2 or in THF, the Mannich (61:39dr; Table 3, entry 6), whereas tert-butyl analogue 1g
adduct was obtained in 25 or 28% yield, respectively. Fi- afforded the product in a decreased yield of 53%, although
nally, the gold(III) IPrAuBr3 complex was also tested as an increase in the diastereoselectivity was observed
a catalyst precursor in the presence of AgNTf2 (1 equiv.). (81:19dr; Table 3, entry 7).
Although active, only 51% yield was obtained under the
same reaction conditions (Table 1, entry 6).
1,3-Diketones have been employed to a lesser extent in
Mannich reactions. We are aware of just one example of its
Encouraged by these results, we decided to extend the use with phosphoric acid derivatives as organocatalysts.[5d]
study to other imines derived from simple aldehydes and We wondered if our system could be extended to acyclic
with different protecting groups (PGs). Therefore, we exam- and cyclic 1,3-diketones. Using the same reaction condi-
ined the reaction of 1a with N-p-toluenesulfonyl-protected tions (5 mol-% of IPrAuNTf2, CH2Cl2, r.t.), an array of 1,3-
imines 2b–d (Table 2, entries 1–3). As expected, the highest diketones were examined (Table 3, entries 8–12). In general,
yield was obtained with imine 2b bearing the NO2 electron- the reactivity did not vary significantly relative to that ob-
withdrawing group (Table 2, entry 1), whereas the yield de- served for β-keto esters. 1,3-Diketone 1i, with a methyl
creased when moving to more electron-donating groups (H group in the α-position, afforded Mannich adduct 3ia in
and MeO; Table 2, entries 2 and 3). We observed that the 74% yield (Table 3, entry 9). Moreover, five- and six-mem-
protecting group on the imine also affected the reaction: bered cyclic diketones 1j and 1k gave rise to the correspond-
the N-tosyl imines gave the products in the highest yields, ing Mannich adducts with moderate diastereoselectivity in
but the N-Boc (tert-butoxycarbonyl) and N-PMP (p-meth- 89 and 72% yield, respectively (Table 3, entries 10 and 11).
oxyphenyl) imines gave the products in significantly lower Diketone 1l with a bulkier tert-butyl group in the R3 posi-
yields (Table 2, entries 4 and 5).
tion proved to be less reactive (Table 3, entry 12).
32
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Eur. J. Org. Chem. 2013, 31–34

Gold-Catalyzed Mannich Addition Reactions
Table 3. Mannich addition of 1,3-dicarbonyl compounds 1b–l with would support a κ1 adduct, whereas in the latter case, the
N-tosyl-α-imino ester 2a catalyzed by IPrAuNTf2.
side-on coordination of the imine could be favored on the
basis of exclusive σ donation of the IPr ligand, which
would, therefore, allow π backdonation of the gold center
to the molecular orbital of the double bond of the imine.
Either way, the corresponding activated reactant would at-
tack a free, noncoordinated molecule of the other to induce
the formation of the Mannich adduct. We are currently ex-
ploring this transformation to ascertain the role of the gold
center in the overall reaction.
Entry
1
R1
R2
R3
t
[h]
Product,
dr[b]
yield[a] [%]
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1e
1f
1g
1h
1i
Me
Me OEt
OEt
12
24
12
12
24
24
24
12
12
12
12
24
3ba, 74
3ca, 70
3da, 62
3ea, 55
3ea, 70
3fa, 70
3ga, 53
3ha, 63
3ia, 74
3ja, 89
3ka, 72
3la, 65
64:36
80:20
72:28
74:26
70:30
61:39
81:19
–
(CH2)3
(CH2)4
nPr
nPr
Me
Me
Me
Me
OEt
H
H
H
H
H
OEt
OEt
OiPr
OtBu
Me
9
Me Me
Me
–
10
11
12
1j
1k
1l
(CH2)3
(CH2)4
Me
76:24
84:16
65:35
Me
tBu
H
[a] Isolated yield. [b] Diastereomeric ratio (major/minor); deter-
mined by analysis of the crude reaction mixture by 1H NMR spec-
troscopy.
Scheme 3. Possible gold(I) activation mechanisms in the Mannich
reactions.
From a mechanistic point of view, previous catalytic sys-
tems based on copper, palladium, magnesium, and calcium
have been proposed to proceed with the intermediacy of a
species with the dicarbonyl substrate bonded to the metal
in a κ2 fashion (Scheme 2).[6a,6c,6g,6i,6k] Sodeoka and co-
workers performed[6c] interesting NMR studies demonstrat-
ing that the keto enolate form prevails over the ester enol-
ate, and they also observed a significant shift in the 13C
NMR resonances of the carbonyl groups of the bonded and
nonbonded substrate. In our case, the well-known tendency
of gold(I) to form linear, two-coordinated complexes seems
to disfavor the chelating coordination of the dicarbonyl re-
actant. In fact, monitoring of a 1:1 mixture of the catalyst
precursor IPrAuNTf2 with 1a and 2a (as in Table 1) by
13C{1H} NMR spectroscopy showed no resonances that
could be attributable to carbonyl and/or imine coordina-
tion. Therefore, the activation of one or more substrates by
the metal center must occur at a rate that escapes the NMR
timescale.
Conclusions
In conclusion, we have found that the IPrAuNTf2 com-
plex efficiently catalyzes the Mannich addition reaction of
1,3-dicarbonyl compounds to N-protected imines. The ex-
amples provided herein are the first examples involving the
use of this metal for this transformation. Good yields were
obtained for an array of substrates under very mild reaction
conditions.
Experimental Section
General Catalytic Procedure for the Mannich Reactions: β-Keto
ester or diketone 1a–l (0.25 mmol), imine 2a–f (0.3 mmol),
IPrAuNTf2 (5 mol-%), and CH2Cl2 (2 mL) were added to a
Schlenk tube equipped with a magnetic stirring bar. The reaction
mixture was stirred at room temperature for 12–24 h under a N2
atmosphere. The volatiles were removed under vacuum, and the
residue was purified by column chromatography on silica gel.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, and 1H NMR
and 13C NMR spectra of the products.
Acknowledgments
Scheme 2. Metal enolate intermediate proposed in Mannich reac-
tions.
We thank Ministerio de Economía y Competitividad (MINECO)
(Proyecto CTQ2011-28942-CO2-01 and Proyecto CTQ2011-
24502), Consolider Ingenio 2010 (Grant CSD-2006-0003) and
Junta de Andalucía (FQM-6292) for financial support. M. D.-R.
thanks the Ministerio de Educación y Ciencia (MEC) for a FPU
fellowship. We wish to thank Prof. Pedro J. Pérez (Univ. Huelva)
for helpful comments and constant encouragement.
Given that Lewis acid catalysts have been described to
activate the reactants in Mannich-type reactions[13] through
the formation of an acid–base adduct, we believe this could
be a reasonable explanation in this gold-based system. As
shown in Scheme 3, coordination of the dicarbonyl[14] or
the imine could be invoked to trigger the catalytic reaction.
In the former case, the propensity for linear coordination
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M. Delgado-Rebollo, R. Moreno, M. R. Fructos, A. Prieto
SHORT COMMUNICATION
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Received: September 20, 2012
Published Online: November 26, 2012
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