Intermolecular mono-and dihydroamination of activated alkenes using a recoverable gold catalyst

Article abstract of DOI:10.1002/ejoc.201200891

A combination of gold chloride organometallic complex and a silver salt was used to catalyze intermolecular hydroamination of activated alkenes, i.e aza-Michael reactions. The gold-catalyzed reactions of activated alkenes with nitrogen substrates were investigated and found to afford various mono-and dihydroamination products, the latter being rare and original. After flash chromatography, gold NHC catalyst could be recovered as a gold hydroxide NHC complex. When combined with a silver salt, the gold complex lead again to an active hydroamination catalyst.

Full text of DOI:10.1002/ejoc.201200891

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FULL PAPER
DOI: 10.1002/ejoc.201200891
Intermolecular Mono- and Dihydroamination of Activated Alkenes Using a
Recoverable Gold Catalyst
Florian Medina,[a,b,c] Christophe Michon,*[a,b,c] and Francine Agbossou-Niedercorn*[a,b,c]
Keywords: Homogeneous catalysis / Gold / Hydroamination / Aza-Michael reaction / Alkenes / Amines
A combination of gold chloride organometallic complex and
a silver salt was used to catalyze intermolecular hydroamin-
ation of activated alkenes, i.e aza-Michael reactions. The
gold-catalyzed reactions of activated alkenes with nitrogen
substrates were investigated and found to afford various
mono- and dihydroamination products, the latter being rare
and original. After flash chromatography, gold NHC catalyst
could be recovered as a gold hydroxide NHC complex. When
combined with a silver salt, the gold complex lead again to
an active hydroamination catalyst.
was crucial to the lowering of the energy barrier for the
proton transfer reaction. Toste, Goddard et al. studied,
using calculations and experiments, the intramolecular ami-
noauration of unactivated alkenes providing evidence of an
anti-addition mechanism for alkene aminoauration.[13]
However, once prepared, such putative catalytic intermedi-
ates did not allow the hydroamination reaction to proceed
affording only starting alkenes. The authors concluded this
was due to the high energy barrier calculated for proto-
deauration.[13] Finally, the mechanism of gold-catalyzed
asymmetric intramolecular hydroamination/hydroalkoxyl-
ation of allenes was recently investigated by Nguyen et al.
using a chiral phosphate counterion. The latter was shown
to act as a ligand phosphate counterion was shown to act
as a ligand for the gold species during all reactions.[14]
These, and other findings, support the idea that achieving
a deep understanding of gold catalyst activity in hydro-
amination reactions remains a challenging endeavor.
Introduction
Catalysis offers highly selective and atom-economic reac-
tions but challenges remain for some reactions like the syn-
thesis of amines through hydroamination reactions.[1] Re-
cently, group 11 metals have been highlighted by various
contributions in the field. Silver was recently shown to be
active for hydroamination of alkenes and dienes.[2] Copper
was successfully used for diamination,[3] carboamination[4]
and hydroamination[5] reactions. The usefulness of gold[6]
was pointed out using alkyne[1,6,7] alkene,[3,8,10e,10i] allene[9]
and diene[2,10] substrates for both intra- and intermolecular
hydroamination reactions as well as for diaminations.
Mechanistic investigations into gold-catalyzed hydroamin-
ation reactions by He et al., and later by Togni et al., have
demonstrated that gold precursor was the main catalyst; no
Brønsted acid was generated by reaction of cationic gold
complexes with amine reagents.[11] Interestingly, Ujaque et
al. have compared, by calculations, the mechanisms of acid-
and gold-catalyzed hydroamination of alkenes and
dienes.[12] Whereas the acid-catalyzed process was shown to
be concerted, the gold-catalyzed reaction was found to be
stepwise for two envisioned pathways, the nucleophile-
assisted and counterion-assisted pathways. Indeed, a pro-
ton-transfer agent, i.e the nucleophile or the counterion,
Following our interest in CuI and CuII catalysts for inter-
and intramolecular hydroamination of unactivated alk-
enes,[5g] we recently focused our attention on intermolecular
hydroamination of activated alkenes. Though the aza-
Michael reaction has been largely studied before,[15] organo-
metallic gold catalysts were, to the best of our knowledge,
never applied to this particular reaction. Herein, we report
on the advantages, scope and limits of gold catalysts in aza-
Michael reactions. The scope of reactivity for these catalysts
is limited to mono- and original dihydroamination reac-
tions. Results are highlighted by mechanistic investigations
focusing on the role of additives, the synthesis of potent
intermediates, and on kinetic studies.
[a] Université Lille Nord de France,
59000 Lille, France
[b] CNRS, UCCS UMR 8181,
59655 Villeneuve d’Ascq, France
[c] ENSCL, CCCF, Chimie-C7,
BP 90108, 59652 Villeneuve d’Ascq Cedex, France
Fax: +33-3-20436585
E-mail: christophe.michon@ensc-lille.fr
francine.agbossou@ensc-lille
Homepage: http://uccs.univ-lille1.fr/index.php/annuaire/15-
fiches-personnels/221-michon-christophe
http://uccs.univ-lille1.fr/index.php/annuaire/15-
fiches-personnels/81-agbossou-niedercorn-francine
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200891.
Results and Discussion
We initially studied various AuI and AuIII catalysts for
the addition of benzamide 2 to cyclohexenone 1 (Table 1).
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First, we showed IPrAuCl was not catalysing the reaction unchanged when one equivalent of PhSiMe3 was used as a
by itself and, instead, needed to react with AgOTf to afford proton trap (Table 1, Entry 2). The results obtained herein
the active catalyst IPrAuOTf[16] (Table 1, Entry 2 vs. 3). using IPrAuOTf catalyst required reactions to be run for 20
Conversions into 3 were higher using AuI catalyst with elec- hours and at 100 °C. Relative to previously reported cata-
tron-rich phosphane (Table 1, Entries 7 vs. 1) or NHC li- lysts which allowed the synthesis of 3[15c,f] and other com-
gands (Table 1, Entries 4 and 2). The use of IAd ligand pounds[15] at room temp. or below, IPrAuOTf was not an
(Table 1, Entry 5) revealed the reaction limits with regards active catalyst. By contrast, AuCl and AuCl3·3H2O were
to steric hindrance when a NHC ligand was used. More- reported to be active catalysts for aza-Michael reactions at
over, the use of an additional benzotriazole ligand for room temperature within few hours.[15a]
AuI [17a] reduced conversion into 3 (Table 1, Entry 6 vs. 2).
We were particularly pleased to recover our AuI catalyst.
Tricoordinated AuI catalysts[17b,17c] combined with AgOTf Indeed, using a simple flash chromatography on silica gel
were active when TCE was used as a solvent (Table 1, En- for the purification of a crude reaction mixture with EtOAc
tries 8 and 9) whereas the use of toluene significantly de- and petroleum ether solvents, we isolated aza-Michael
creased conversion into 3 probably due to disproportiona- product 3 and a gold complex. The latter was identified as
tion of catalysts into other complexes.
IPrAuOH 5 and could be easily converted back into IP-
rAuCl by reaction with HCl. On the whole, this constitutes
a new synthetic pathway for the preparation of a useful rea-
gent like 5[18c,18d,18e] from cationic NHCAuI complex. Inter-
estingly enough, when 5 was combined with an equimolar
amount of AgOTf, the reaction of benzamide 2 with cyclo-
hexenone 1 was catalyzed again, affording 3 in a 48% con-
version (Scheme 1).
Table 1. Screening of various gold complexes.
Entry Catalyst[a,b]
Silver salt
Conv. of 3 (%)[c]
1
PPh3AuCl
IPrAuCl
IPrAuCl
ItBuAuCl
IAdAuCl
IPrAu[BtH]OTf
JohnPhosAuCl
L1AuCl
AgOTf (5 mol-%)
AgOTf (5 mol-%)
–
AgOTf (5 mol-%)
AgOTf (5 mol-%)
–
AgOTf (5 mol-%)
AgOTf (5 mol-%)
AgOTf (5 mol-%)
AgOTf (5 mol-%)
AgOTf (10 mol-%)
AgOTf (15 mol-%)
23
52
0
65
28
27
57
2[d]
3
4
5
6[e]
7
8
9
10
11
12
13 (0[f])
50 (20[f])
36
XantphosAuCl
IPrAuCl3
IPrAuCl3
Scheme 1. IPrAuOH 5 as a recovered and useful pre-catalyst.
36
18
It is worth noting that no Brønsted acid species could be
identified during aza-Michael reactions; 47% conversion
was obtained when one equivalent of PhSiMe3 was used as
a proton trap. Such a result was quite close to the 52%
conversion obtained using IPrAuOTf catalyst and demon-
strates the usefulness of the combination of AgI salts with
AuI hydroxy complexes to form catalytically active cationic
AuI complex. Moreover, the reaction conversion into 3 re-
mained unchanged upon removal of AgCl by filtration
IPrAuCl3
[a] Reactions performed in TCE (1,1Ј,2,2Ј-tetrachloroethane) un-
less otherwise stated, with 2 equiv. of 1 and 1 equiv. of 2 (0.5 mmol)
using 5 mol-% of gold catalyst and 5 mol-% of AgOTf. [b] IPr =
1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, ItBu
= 1,3-di-
tert-butylimidazol-2-ylidene, IAd = 1,3-bis(1-adamantyl)imidazol-
2-ylidene, JohnPhos = 2-(di-tert-butylphosphanyl)biphenyl, L1 =
P,PЈ-(9,9-dimethyl-9H-xanthene-4,5-diyl)bis[N,N,NЈ,NЈ-tetraethyl-
phosphonous diamide], Xantphos = 9,9-dimethyl-4,5-bis(diphenyl-
phosphanyl)xanthene. [c] Measured by GC. [d] Same result if
1 equiv. PhSi(Me)3 was added. [e] BtH for benzotriazol.[16] [f] Per- through CeliteTM of the IPrAuOTf species. Hence, no “sil-
ver effect” on the gold catalyst was observed.[17d] By way of
formed in toluene.
proof, IPrAuOH 5 was allowed to react first with AgBF4
Finally, cationic AuIII catalysts proved to be less active and latter with pyridine to afford already known complex
–
regardless of the amount of silver salts used (Table 1, En- [IPrAu(pyridine)]+BF4 6[19] in 86% yield.
tries 10–12). No change in conversion was noticed whether
A probable mechanism for the IPrAuOTf-catalyzed reac-
in-situ or ex-situ Au catalyst synthesis was employed. More- tion of 1 and 2 is highlighted in Scheme 2. Whereas the π-
over, conversion into 3 remained unchanged upon filtration philic Lewis acidity of gold complexes to C–C multiple
through CeliteTM of the IPrAuOTf species;[16] no “silver ef- bonds has been extensively studied,[6,8] the oxophilic Lewis
fect” on gold catalyst could be observed.[17d] It was worth acidity of gold species has only recently been supported.[20]
noting that no Brønsted acid species was formed during Hence, coordination of IPrAuOTf to 1 can lead to three
the reaction since the completeness of conversion remained possible intermediates which further react with amide 2 to
2
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Dihydroaminations with a Recoverable Gold Catalyst
afford product 3 (Scheme 2). Despite efforts to identify such Table 2. Screening of reaction conditions.
intermediates, 13C NMR analyses failed to reveal any evi-
dence of AuI enone activation. The chemical shift of the
keto group was not seen, regardless of relaxation or acqui-
sition times used. Moreover, to determine whether the
benzamide reagent was activated by the AuI catalyst or not,
related amido IPrAuI complex 4 was prepared.[18a,18b] No
reaction was observed when 4 was subjected to the mixture
of 1 and 2 (Scheme 3). In addition, we recalled that AuI
catalysts are not likely to generate Brønsted–acid by reac-
tion with amine reagents. Therefore, AuI catalysts seemed
only to activate the alkene substrate, thus allowing reaction
of the resulting incipient carbocation with the amine nu-
cleophile.[11]
Entry[a]
Solvent
AgX
Alkene (equiv.) Conv. (%)[b]
1
2
3
4
5
6
7
8
TCE
TCE
TCE
TCE
TCE
TCE
TCE
TCE
TCE
AgOTf
AgOTf
AgOTf
AgOTf
AgSbF6
AgPNB
LiNTf2
AgNTf2
AgBF4
AgOTf
AgOTf
AgOTf
1
2
5
10
1
1
28
52
83
91
33
0
2
1
1
1
1
1
0
13
14
36
25
18[c]
9
10
11
12
toluene
dioxane
DME
[a] Reactions performed with 1 equiv. or more of 1 and 1 equiv.
of 2 (0.5 mmol) using 5 mol-% of IPrAuCl and 5 mol-% of AgX.
[b] Measured by GC. [c] Performed at reflux (e.g., 85 °C).
in lower conversions than those achieved with AuI catalysts
(Table 3, Entries 1–5). The use of an additional ligand did
not enhance the conversion (Table 3, Entries 6–10).
Table 3. Screening of various silver salts.
Scheme 2. Probable mechanism for IPrAuOTf-catalyzed reaction of
1 and 2.
Entry
Catalyst[a]
Additive[b]
Conv. (%)[c]
1[d]
2
3
AgOTf
AgOTf
AgSbF6
Ag2O
IPrAuCl
–
–
52
42
44
0
4
–
5
AgO2CPh
Ag2O
Ag2O + AgSbF6
AgSbF6
AgSbF6
AgSbF6
–
0
0
7
31
22
0
Scheme 3. IPrAu(NHCOPh) 4 as catalyst for the reaction of 1 and
2.
6[d]
7[d]
8
IPr·HCl
IPr·HCl
P(OPh)3
P(OPh)3
P(Ph)3
We next focused our attention on the influence of the
reaction parameters by varying the solvent, anion, and
amount of alkene 1 allowed to react with nucleophile 2
(Table 2). No significant solvent-dependent differences were
noted. Toluene proved to be useful in a fashion similar to
1,1Ј,2,2Ј-tetrachloroethane (TCE) or dioxane. DME was
less effective (Table 2, Entries 1, 10–12). Among the various
9[d]
10[d]
[a] Reactions performed with 2 equiv. of 1 and 1 equiv. (0.5 mmol)
of 2 using 5 mol-% of AgI salt. [b] 5 mol-% additive. [c] Conversion
measured by GC. [d] A pre-formed catalyst was used.
Next, in order to explore the scope of substrates for these
anions tested, triflate and hexafluoroantimonate anions ap- AuI-catalyzed hydroamination reactions, several weak nu-
peared to be most appropriate (Table 2, Entries 1, 5–9). Fi- cleophiles were allowed to react with 10 equiv. of methyl
nally, allowing an excess of alkene 1 to react with amine 2 vinyl ketone 9a in the presence of AuI catalyst (Table 4).
drastically improved conversions from 28 up to 91% for Although reactions of amines 2 or 7h needed heatings at
ten equivalents of 1 (Table 2, Entries 1–4). Such a reactivity 100 °C to react (Table 4, Entries 1 and 5), other reactions
enhancement has been previously noted for several catalytic proceeded well at 50 °C affording compounds 10c,f1,g in
hydroamination reactions of unactivated alkenes.[1c,1d,8e]
good yields (Table 4, Entries 2–4). At 50 °C, the catalyzed
Regarding the catalytic activity of AgI species for hydro- reaction of 9a with N-tosylallylamine 7f was shown to fol-
amination of alkenes and dienes,[2] we examined the poten- low a first order kinetic rate law (see Supporting Infor-
tial of various AgI salts to catalyze the reaction of activated mation, Figure S1). Moreover, no evidence for any intramo-
alkenes with amines. On the whole, the AgI-catalyzed reac- lecular hydroalkylation reaction between the alpha ketone
tions of benzamide 2 and cyclohexenone 1 lead to product 3 and the N-allyl functional group could be found.[21]
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Table 4. Amine reactivity towards methyl vinyl ketone 9a.
alkenes for these AuI-catalyzed hydroamination reactions
proved to be rather modest; terminal enones were the most
active substrates (see Supporting Information, Tables S1
and S2). In general, the poor activity of IPrAuOTf con-
trasts with previously reported catalysts that facilitate the
addition of amides, carbamates and other nucleophiles
upon various activated alkenes at room temperature.[15]
Table 5. Secondary amines reactivity towards butyl acrylate 9b.
[a] Isolated yield. [b] Performed at 100 °C for 20 h; conversions
measured by 1H NMR spectroscopy. [c] Performed at 100 °C.
[d] When at 100 °C in toluene, 65% of 10f1 and 32% of 10f2. [e] Per-
formed in toluene at 100 °C for 40 h.
The reaction carried out at 100 °C afforded some hydro-
alkylated product 10f2 (Table 4, Entry 3). When no catalyst
was used, reaction of 9a proceeded only with amine 7h most
likely because of 7h higher nucleophilicity (Table 4, Entry
5). Though not always addressed, literature reports of such
[a] Isolated yields. [b] 20 h reaction. [c] TCE as solvent. [d] 23 h re-
action. [e] 26 h reaction. [f] Compounds 11e1 and 11e2. [g] Mea-
1
sured by H NMR spectroscopy.
The reactivity of primary amines 7l–r towards butyl
uncatalyzed “background” reactions relative to aza- acrylate 9b was studied and found to reveal interesting fea-
Michael additions are known.[5c,22,23] By comparing reacti- tures (Table 6). Using AuI catalyst, reactions with amines
vity and pKa values in DMSO of the amine reagents in- 7l–r lead to some monohydroamination products 11l–r, but
volved, we found that imine 7h (pKa 31.0) was the strongest predominantly afforded dihydroamination products 12l–r.
nucleophile of the series and gave a lower yield than oxazol- Strikingly, use of amines 7o and 7q led selectively to
idone 7c (pKa 20.8) or other amines in the catalytic reac- monohydroamination products 11o and 11q (Table 6, En-
tions. Hence, we envisioned that nucleophile reactivity de- tries 4 and 6) whereas reactions with amine 7p and hydraz-
pends, to some extent, on potential steric hindrance around ine 7r afforded single dihydroamination products 12p and
the nitrogen atom.
12r in high yields (Table 6, Entries 5 and 7). Consequently,
We studied the reactivity of butyl acrylate 9b with some we postulated that sterically bulky primary amine reagents
secondary amines at 100 °C (Table 5). With the exception favored the synthesis of monohydroamination products
[24]
of amine 7e which gave isomers 11e1 and 11e2
in poor whereas less hindered amines mainly led to dihydroamin-
yields (Table 5, Entry 1), the uncatalyzed reactions pro- ation products. Such a trend was also confirmed by reac-
ceeded at 100 °C with efficiencies being on par with the tions carried out at 100 °C in the absence of catalyst; these
AuI-catalyzed ones, the latter allowing most amines to react reactions afforded compounds 11l–r and/or 12l–r, except for
(Table 5, Entries 2–4). The fact that no conversion was ob- the reaction involving amine 7o (Table 6, Entry 4). Reac-
tained for N-methylaniline and diisopropylamine (Table 5, tions using no catalyst were found to lack the previously
Entries 5 and 6) supports the notion that less hindered noted selectivity for dihydroamination products (Table 6,
amines are more effective reagents in hydroamination reac- Entries 1–3). Moreover, lowering the temperature to 30 °C
tion than the sterically hindered ones. The scope of useful induced selective formation of compounds 11l–n,p (Table 6,
4
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Dihydroaminations with a Recoverable Gold Catalyst
Table 6. Butyl acrylate 9b reactivity towards various primary amines.
Entry
Amine 7l–r
Time
[h]
Yield (%)[a]
[11 + 12]
Yield (%)[a] at 100 °C
without catalyst [11 + 12]
Yield (%)[a,b] at 30 °C
without catalyst [11 + 12]
1
2
3
4
5
6
7
7l iPrNH2
40
20
30
70
20
20
20
70 [0 + 70]
99 [17 + 82]
99 [39 + 60]
65 [65 + 0]
97 [0 + 97]
28 [28 + 0]
100 [0 + 100]
75 [37 + 38][c]
100 [53 + 47][d]
100 [100 + 0]
0
90 [0 + 90]
32 [32 + 0]
100 [0 + 100]
8 [8 + 0]
25 [25 + 0][d]
23 [23 + 0]
–
44 [44 + 0]
0
7m BnNH2
7n CyNH2
7o PhNH2
7p nBuNH2
7q tBuNH2
7r BzNHNH2
5 [0 + 5]
[a] Isolated yield; all reactions performed with 0.5 mmol of amine. [b] 20 h reactions. [c] 40 h reactions. [d] Performed with 5 equiv. of
alkene.
Entries 1–3, 5). As a general trend, whenever the di-ad- Table 7. Reaction of butyl acrylate 9b and benzylamine 7m; selec-
tivity change depending variation of conditions.
dition product was obtained, a higher selectivity was ob-
tained by using a cationic AuI catalyst. To the best of our
knowledge, such results are rare examples of dihydroamin-
ation reactions with or without the use of an AuI cata-
lyst.[25] Interestingly, mono- and dihydroarylation reactions
between electron-rich arenes and activated alkenes were
previously reported by Hashmi et al. using an AuIII cata-
lyst.[26]
To deepen our knowledge of the synthesis of these mono-
Entry
Temp.
[°C]
Time
[h]
Alkene
(equiv.)
Yield (%)[a]
[11m + 12m]
and dihydroamination products, we studied AuI-catalyzed
reaction of amine 7m with alkene 9b by changing reaction
condition variables one at a time (Table 7). By using a single
equivalent of reagent 9b, monohydroamination product
11m was formed preferentially over 12m in 5 hours. An in-
crease of the reaction time implied minor changes in the
ratio of the two products (Table 7, Entries 2 and 3). The
use of 5 equiv. of alkene 9b improved the yield of dihy-
droamination product 12m; which could be drastically en-
hanced by switching the reaction time from 5 to 10 hours
(Table 7, Entries 1, 4, 5). Decreasing reaction temperature
favoured synthesis of 11m over 12m despite the use of
5 equiv. of alkene 9c (Table 7, Entries 7–15). At 60 °C, com-
pound 11m was obtained selectively in high yield without
the use of any catalyst (Table 7, Entry 10 vs. 1, 11) whereas
the same reaction outcome was reached at only 40 °C with
the use of either AuI or AgI catalysts (Table 7, Entries 12
and 13). In addition, reaction of amine 7m with alkene 9b
proved to be sensitive to the nature of the solvent used; the
neat reaction proceeded extremely well. It was worth noting
1[b]
2
3
4
5
6
7
8
100
100
100
100
100
100
80
60
60
60
40
20
5
10
5
5
1
1
5
5
5
5
5
5
5
5
5
5
2
2
100 [53 + 47]
84 [81 + 3]
94 [85 + 9]
100 [61 + 39]
94 [20 + 74]
96 [23 + 73]
97 [48 + 49]
100 [86 + 14]
100 [79 + 21]
86 [86 + 0]
25 [25 + 0]
83 [83 + 0]
98 [98 + 0]
40 [40 + 0]
15 [15 + 0]
10
20
20
20
20
20
20
20
20
20
20
9[c]
10[b]
11[b]
12[c]
13[d]
14[e]
15[e,f]
40
40
0
0
[a] Isolated yield. [b] Performed without gold(I) and silver(I) cata-
lysts. [c] Catalyst was synthesized prior to use (room temp., 2 h).
[d] Performed with only AgOTf. [e] Performed in CH2Cl2. [f] Per-
formed with no AuI and AgI catalysts at 0.2 mmol scale for
BnNH2.
that addition of water to the reaction medium significantly lower yield of 11m relative to the reaction run without cata-
increased yields of 11m (Tables S3 and S4 of Supporting lyst (Scheme 4); no autocatalysis from 11m could be sup-
Information). Such rate enhancements in aza-Michael reac- ported.
tions have been previously observed when using various ad-
To gain more insight into these mono- and dihydroamin-
ation reactions, we performed a kinetic study on the reac-
ditives.[27]
In an attempt to see if reaction of amine 7m and alkene tion of 7m and 9b without any catalyst. First, that reaction
9b would be autocatalytic,[28] we allowed monohydroamin- was performed at 23 °C and the plot of yields vs. time re-
ation product 11m to catalyze the reaction of 7m and 9b. vealed that the maximum yield of monohydroamination
The reaction using 10 mol-% of 11m as catalyst afforded a product 11m was reached after 2000 minutes (Figure 1). Af-
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F. Medina, C. Michon, F. Agbossou-Niedercorn
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likely due to an equilibrium for the second addition be-
tween the aza-Michael reaction and its retro-reaction (see
Supporting Information, Figure S2).[29]
The plot of ln(namine 7m) vs. time (min) for about three
half-lives (one half-life being 990 min) gave a linear curve
which could be fitted with a first-order kinetic law (R2 =
0.9938) by use of the linear least-squares technique. Such a
rate law could be expected as long as ten equivalents of
alkene were used with respect to the amine (Figure 1). Next,
another kinetic study was performed on the reaction of 7m
and 9b at 23 °C using IPrAuOTf as catalyst. As shown by
the plot of yields vs. time, reaction was noticeably ac-
celerated relative to the previous run without any catalyst.
Indeed, an 80% maximum yield of monohydroamination
product 11m was reached after 500 minutes (Figure 2). Af-
ter that point, a clear linear conversion of 11m into 12m
could be seen by reaction with 9b. Indeed, dihydroamin-
ation was significantly accelerated by the use of AuI catalyst
with a 20% yield of 12m reached in 900 minutes (Figure 2).
Moreover, the previously observed retro–aza–Michael reac-
tion was prevented by the use of AuI catalyst as long as a
linear conversion of 11m into 12m could be seen along time.
Scheme 4. Reaction between 9b and 7m for probing autocatalysis
by 11m.
ter this point in time curves showed conversion of 11m into
dihydroamination product 12m by reacting again with alk-
ene 9b to afford a 20% yield of 12m in 3600 minutes (see
Figure 1). However, after reaching a 65% value, conversion
of 11m into 12m remained at a plateau for a long time, most
Figure 1. Kinetic profiles for the uncatalyzed reaction of 9b with
7m at 23 °C in TCE-d2.
Figure 2. Kinetic profiles for the reaction of 9b with 7m at 23 °C
in TCE-d2 catalyzed by 10 mol-% of IPrAuOTf.
6
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Job/Unit: O20891
/KAP1
Date: 24-09-12 17:19:01
Pages: 11
Dihydroaminations with a Recoverable Gold Catalyst
were performed at CUMA-University Lille Nord de-France. Ele-
mental analyses were performed with an Elementar Vario Micro
Cube apparatus at UCCS, University Lille Nord de France. See
Supporting Information for other details.
The plot of ln(namine 7m) vs. time (min) for about two half-
lives (one half-life being 347 min) gave a linear curve which
could be fitted with a first-order kinetic law (R2 = 0.9988)
by use of the linear least-squares technique. Again, the use
of ten equivalents of alkene with respect to the amine logi-
cally implied such a rate law (Figure 2).
A last kinetic study was performed on the uncatalyzed
reaction of mono-hydroamination product 11m and alkene
9b at 100 °C. A maximum yield of 70% in dihydroamin-
ation product 12m was quickly obtained in 500 min. The
resulting kinetic curve was fitted with a first–order kinetic
law in a way similar to that used for the IPrAuOTf-cata-
lyzed reaction of alkene 9a with tosyl allylamine 7f (see
Supporting Information, Figures S1 and S3).
General Procedure for Catalysis Conditions Screening: IPrAuCl
(0.025 mmol, 15.5 mg) was dried during 30 min under vacuum and
then AgOTf (0.025 mmol, 6.4 mg) was added (in a glovebox). Next,
dry toluene (1 mL), and freshly distilled benzylamine (0.5 mmol,
55 μL) were added under a nitrogen atmosphere. After stirring at
the corresponding time and temperature, the mixture was concen-
trated under vacuum, and the resulting product was isolated by
flash chromatography.
General Procedure for Activated Alkene Screening: IPrAuCl
(0.025 mmol, 15.5 mg), benzotriazole (0.5 mmol, 59.6 mg) and acti-
vated alkene (5.0 mmol) (if solid) were added in a Schlenk flask.
These solids were dried during 30 min under vacuum and AgOTf
(0.025 mmol, 6.4 mg) was added (in a glovebox). Then, dry
1,1Ј,2,2Ј-tetrachloroethane (1 mL), and activated alkene (5.0 mmol)
(if liquid) were added under a nitrogen atmosphere. After stirring
at 100 °C for the corresponding time, the mixture was concentrated
under vacuum, and the corresponding product was isolated by
flash chromatography.
Conclusions
The gold-catalyzed addition of amines to various acti-
vated alkenes was investigated and found to produce
monohydroamination and dihydroamination products. By
requiring a 100 °C heating, IPrAuOTf catalyst proved to be
a less active catalyst for aza-Michael reactions relative to
previously reported metal catalysts which allowed reactions
to proceed primarily at room temperature or below. How-
ever, the IPrAuOTf catalyst could be recovered as IP-
rAuOH, an inert gold hydroxide complex which lead again
to active IPrAuOTf catalyst when combined with silver
triflate. Moreover, the double–addition of an amine on two
equivalents of alkene, i.e. dihydroamination reaction, was
favored using the AuI catalyst and led to rare and original
examples of dihydroamination products. Steric hindrance of
the amine was shown to control selectivity of mono- and
General Procedure for Amine Substrate Screening: IPrAuCl
(0.025 mmol, 15.5 mg), and amine substrate (0.5 mmol) (if solid)
were added in a Schlenk flask. These solids were dried during
30 min under vacuum and AgOTf (0.025 mmol, 6.4 mg) was added
(in
a glovebox). Then, dry toluene (1 mL), butyl acrylate
(5.0 mmol, 0.7 mL), and freshly distilled amine substrate
(0.5 mmol) (if liquid) were added under a nitrogen atmosphere. Af-
ter stirring at 100 °C for the corresponding time, the mixture was
concentrated under vacuum, and the resulting product was isolated
by flash chromatography.
General Procedure for Amine Reactivity Screening with Methyl
Vinyl Ketone: IPrAuCl (0.025 mmol, 15.5 mg) and amine substrate
dihydroamination reactions. Further investigations will be (0.5 mmol) (if solid) were added in a Schlenk flask and dried under
vacuum for 30 min. Next, in a glovebox, AgOTf (0.025 mmol,
6.4 mg) was added followed by dry 1,1Ј,2,2Ј-tetrachloroethane
(1 mL), methyl vinyl ketone (5.0 mmol, 0.4 mL), and amine sub-
strate (0.5 mmol) (if liquid). After stirring at 50 °C at the corre-
sponding time, the mixture was concentrated under vacuum, and
the resulting product was isolated by flash chromatography.
reported in due course.
Experimental Section
General Remarks: All solvents were dried using standard methods.
Alkenes were distilled under vacuum over CaH2 and stored over
molecular sieves (4 Å). Amine substrates were placed under vac-
uum during one hour before use, or distilled from CaH2 if they
were liquid. All silver salts, gold salts and ligands were weighed
inside a glovebox. All reactions were carried out under a dry nitro-
gen atmosphere. Analytical thin layer chromatography (TLC) was
performed on Merck pre-coated 0.20 mm silica gel Alugram Sil 60
G/UV254 plates. Flash chromatography was carried out with Mach-
erey silica gel 60 M. 1H (300 MHz or 400 MHz), 13C (75 MHz) and
31P (121 MHz) NMR spectra were acquired with Bruker Avance
spectrometers. Chemical shifts are reported downfield of Me4Si and
coupling constants are expressed in Hz. 1,3,5-trimethoxybenzene
and 1,2,4,5-tetrachlorobenzene were used as internal standards
when needed. Gas chromatography analyses were done with GC
Varian 3900 and 430 using Alltech EconoCap EC-5TM column
(30 m, 0.25 mm, 0.25 μm) with program (5 °C/min, 100–230 °C,
36 min.) and with tetradecane as internal standard. GC–MS analy-
ses were performed on a Shimadzu QP2010+ using Supelco column
SLBTM-5 ms (30 m, 0.25 mm, 0.25 μm). Infrared spectra were re-
corded using a ThermoScientific-Nicolet 6700 spectrometer; the
samples being prepared with KBr powder. HRMS-ESI analyses
Butyl 3-(Dibutylamino)propanoate (11j): Isolated after flash
chromatography with petroleum ether/NEt3 (9:1), as a colourless
oil (0.45 mmol, 116 mg, 90% yield). 1H NMR (300 MHz, CDCl3,):
δ = 0.85–0.95 (q*, 9 H), 1.20–1.45 (m, 10 H), 1.58 [quin, J(H,H) =
7.2 Hz, 2 H], 2.30–2.45 (m, 6 H), 2.75 [t, J(H,H) = 7.5 Hz, 2 H],
4.05 [t, J(H,H) = 6.7 Hz, 2 H] ppm. 13C NMR (75 MHz, CDCl3):
δ = 13.7 (CH3), 14.1 (2 CH3), 19.1 (CH2), 20.6 (2 CH2), 29.3 (2
CH2), 30.7 (CH2), 32.4 (CH2), 49.4 (CH2), 53.6 (2 CH2), 64.2
(CH ), 173.1 (C) ppm. IR (KBr): ν = 2959, 2933, 2873, 1717,
˜
2
1202 cm–1. HRMS (ESI) m/z calcd. for C15H32NO2: 258.2428 [M
+ H]+, found 258.2423.
Butyl 3-[Benzyl(methyl)amino]propanoate (11k): Isolated after flash
chromatography with petroleum ether/ethyl acetate/NEt3 (9:1:1),
1
(Rf = 0.75) as a colourless oil (0.48 mmol, 120 mg, 96% yield). H
NMR (300 MHz, CDCl3,): δ = 0.95 [t, J(H,H) = 7.4 Hz, 3 H], 1.39
[sext, J(H,H) = 7.4 Hz, 2 H], 1.63 [quin, J(H,H) = 7.1 Hz, 2 H],
2.22 (s, 3 H), 2.54 [t, J(H,H) = 7.2 Hz, 2 H], 2.77 [t, J(H,H) =
7.2 Hz, 2 H], 3.53 (s, 2 H), 4.10 [t, J(H,H) = 6.7 Hz, 2 H], 7.20–
7.40 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.8 (CH3),
19.2 (CH2), 30.7 (CH2), 33.0 (CH2), 41.8 (CH3), 52.9 (CH2), 62.1
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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/KAP1
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Pages: 11
F. Medina, C. Michon, F. Agbossou-Niedercorn
131.8 (CH), 133.0 (C), 166.6 (C), 172.8 (2 C) ppm. IR (KBr): ν =
FULL PAPER
(CH2), 64.3 (CH2), 127.0 (CH), 128.2 (2 CH), 129.0 (2 CH), 138.9
˜
(C), 172.7 (C) ppm. IR (KBr): ν = 2954, 2841, 2791, 1734, 3226, 2958, 2871, 1730, 1649, 1180 cm–1. C21H32N2O5 (392.49):
˜
1124 cm–1. HRMS (ESI) m/z calcd. for C15H24NO2: 250.1802 [M
calcd. C 64.26, H 8.22, N 7.14; found C 64.24, H 8.10, N 6.72.
HRMS (ESI) m/z calcd. for C21H33N2O5: 393.2384 [M]+, found
393.2376.
+ H]+, found 250.1798.
Dibutyl 3,3Ј-(Isopropylazanediyl)dipropanoate (12l): Isolated after
flash chromatography with petroleum ether/NEt3 (9:1) as a colour-
less oil (0.351 mmol, 111 mg, 70% yield). 1H NMR (300 MHz,
CDCl3,): δ = 0.85–1.00 (m, 12 H), 1.34 [sext, J(H,H) = 7.5 Hz, 4
H], 1.57 [quin, J(H,H) = 6.9 Hz, 4 H], 2.38 [t, J(H,H) = 7.2 Hz, 4
H], 2.68 [t, J(H,H) = 7.2 Hz, 4 H], 2.85 [sept, J(H,H) = 6.6 Hz, 1
H], 4.03 [t, J(H,H) = 6.6 Hz, 4 H] ppm. 13C NMR (75 MHz,
CDCl3): δ = 13.8 (2 CH3), 18.4 (2 CH3), 19.2 (2 CH2), 30.8 (2
CH2), 34.8 (2 CH2), 45.8 (2 CH2), 50.7 (CH), 64.2 (2 CH2), 173.0
Supporting Information (see footnote on the first page of this arti-
cle): Additional data, all experimental procedures and characteriza-
tions, copies of 1H and 13C NMR spectra of all final products,
copies of HR mass spectra of new compounds.
Acknowledgments
(2 C) ppm. IR (KBr): ν = 2979, 1733, 1137 cm–1. HRMS (ESI) m/z
This work was first financed by the French National Research Ag-
ency (ANR) (project ANR-09-BLAN-0032-02 with a PhD fellow-
ship to F. M). Support from Centre National de la Recherche Sci-
entifique (CNRS) is also highly appreciated. Partial funding from
Région Nord-Pas de Calais (Projet Prim: Etat-Région) and support
from the Fonds Européen de Développement Régional (FEDER)
are also acknowledged. Catherine Méliet (UCCS) is thanked for
elemental analyses. Céline Delabre (UCCS) is thanked for GC–MS
analyses. Nathalie Duhal (CUMA-Univ. Lille Nord de France) is
thanked for HRMS analyses. Marc Bria (CCMRMN, Univ. Lille
Nord de France) is thanked for assistance with some NMR kinetic
experiments. Dr. Christophe Michon dedicated personally this full
paper to Professor Motokazu Uemura (Kyoto Pharm. University)
in memory of his postdoctoral stay in Japan where he learned about
the usefulness of gold catalysts.
˜
calcd. for C17H34NO4: 316.24824 [M + H]+, found 316.24873.
Dibutyl 3,3Ј-(Benzylazanediyl)dipropanoate (12m): Isolated after
flash chromatography with petroleum ether/ethyl acetate/NEt3
(8:2:1), Rf = 0.7, as a colourless oil (0.411 mmol, 150 mg, 82%
yield). 1H NMR (300 MHz, CDCl3,): δ = 0.85 [t, J(H,H) = 7.3 Hz,
6 H], 1.28 [sext, J(H,H) = 7.3 Hz, 4 H], 1.49 [quin, J(H,H) =
6.9 Hz, 4 H], 2.38 [t, J(H,H) = 7.2 Hz, 4 H], 2.73 [t, J(H,H) =
7.2 Hz, 4 H], 3.52 (s, 2 H), 3.98 [t, J(H,H) = 6.7 Hz, 4 H], 7.15–
7.25 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.7 (2 CH3),
19.1 (2 CH2), 30.6 (2 CH2), 32.7 (2 CH2), 49.2 (2 CH2), 58.2 (CH2),
64.3 (2 CH2), 127.0 (CH), 128.2 (2 CH), 128.7 (2 CH), 139.1 (C),
172.7 (2 C) ppm. IR (KBr): ν = 2959, 2873, 1734, 1176 cm–1.
˜
HRMS (ESI) m/z calcd. for C21H34NO4: 364.2482 [M + H]+, found
364.2475.
Dibutyl 3,3Ј-(Cyclohexylazanediyl)dipropanoate (12n): Isolated after
flash chromatography with petroleum ether/NEt3 (9:1) as a colour-
less oil (0.300 mmol, 107 mg, 60% yield). 1H NMR (300 MHz,
CDCl3,): δ = 0.88 [t, J(H,H) = 7.4 Hz, 6 H], 0.95–1.25 (m, 5 H),
1.32 [sext, J(H,H) = 7.5 Hz, 4 H], 1.55 [quin, J(H,H) = 6.9 Hz, 5
H], 1.60–1.80 (m, 4 H), 2.36 [t, J(H,H) = 7.2 Hz, 5 H], 2.73 [t,
J(H,H) = 7.2 Hz, 4 H], 4.01 [t, J(H,H) = 6.6 Hz, 4 H] ppm. 13C
NMR (75 MHz, CDCl3): δ = 13.8 (2 CH3), 19.6 (2 CH2), 26.2 (2
CH2), 26.3 (CH2), 29.2 (2 CH2), 30.7 (2 CH2), 34.9 (2 CH2), 46.3
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2934, 2878, 1730, 1181 cm–1. HRMS (ESI) m/z calcd. for
C20H38NO4: 356.27954 [M + H]+, found 356.2797.
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7.5 Hz, 4 H], 2.35 [q, J(H,H) = 7.5 Hz, 6 H], 2.71 [t, J(H,H) =
7.3 Hz, 4 H], 4.01 [t, J(H,H) = 6.7 Hz, 4 H] ppm. 13C NMR
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lated after flash chromatography with petroleum ether/ethyl acetate
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CDCl3): δ = 13.7 (2 CH3), 19.0 (2 CH2), 30.5 (2 CH2), 32.7 (2
CH2), 52.6 (2 CH2), 64.6 (2 CH2), 127.0 (2 CH), 128.6 (2 CH),
8
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/KAP1
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Dihydroaminations with a Recoverable Gold Catalyst
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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/KAP1
Date: 24-09-12 17:19:01
Pages: 11
F. Medina, C. Michon, F. Agbossou-Niedercorn
FULL PAPER
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www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20891
/KAP1
Date: 24-09-12 17:19:01
Pages: 11
Dihydroaminations with a Recoverable Gold Catalyst
Transition–Metal Catalysis
Gold-catalyzed hydroamination reactions
of activated alkenes with nitrogen sub-
strates were investigated. Among the vari-
ous products obtained from these aza-
Michael reactions, rare and original dihy-
droamination products were synthesized
with good selectivities. Gold NHC catalyst
could be recovered as the hydroxy complex
and reused for catalysis when combined
with silver triflate.
F. Medina, C. Michon,*
F. Agbossou-Niedercorn* ................ 1–11
Intermolecular Mono- and Dihydroamin-
ation of Activated Alkenes Using a Recov-
erable Gold Catalyst
Keywords: Homogeneous catalysis / Gold /
Hydroamination / Aza-Michael reaction /
Alkenes / Amines
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11