Gold-catalyzed intramolecular hydroamination of α-amino allenamides as a route to enantiopure 2-vinylimidazolidinones

Article abstract of DOI:10.1016/j.tetlet.2009.06.011

An efficient gold-catalyzed procedure for the preparation of 2-vinylimidazolidinones has been developed. The starting materials for the synthesis of these compounds are α-amino allenamides which undergo heterocyclization by means of nucleophilic attack of

Full text of DOI:10.1016/j.tetlet.2009.06.011

Tetrahedron Letters 50 (2009) 4696–4699
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Tetrahedron Letters
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Gold-catalyzed intramolecular hydroamination of
route to enantiopure 2-vinylimidazolidinones
a-amino allenamides as a
a
b,
b
Angelo M. Manzo a, , Alcide D. Perboni , Gianluigi Broggini , Micol Rigamonti
*
*
a Chemical Development, GlaxoSmithKline Medicine Research Centre, Via Fleming 4, 37135 Verona, Italy
b Dipartimento di Scienze Chimiche e Ambientali, Università dell’Insubria, Via Valleggio 11, 22100 Como, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient gold-catalyzed procedure for the preparation of 2-vinylimidazolidinones has been developed.
Received 17 April 2009
Revised 27 May 2009
Accepted 2 June 2009
Available online 6 June 2009
The starting materials for the synthesis of these compounds are a-amino allenamides which undergo het-
erocyclization by means of nucleophilic attack of the amino group on the inside double bond of the 1,2-
diene moiety. This is the first example of a gold-catalyzed cyclization on allene substrates bearing an
amido group which, however, resulted inactive.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Allenes
Gold catalysis
Heterocyclization
Hydroamination
Imidazolidinones
Intramolecular hydroamination, the formal addition of N–H
group to carbon–carbon multiple bond, is a direct and efficient pro-
cedure for the synthesis of nitrogen-containing heterocycles.1
Cyclization of allenes with tethered amines represents a fruitful
route for this scope. Some alternative strategies based on basic2
or transition-metal catalysis3 have been used for this purpose.
Among the latter palladium,4 gold,5 silver,6 ruthenium,7 copper,8
cobalt,9 mercury,10 and titanium11 warrant a wide range of proce-
dures such as domino reactions, oxidative cyclizations, cyclocarb-
onylations, and cycloisomerizations which allow to achieve
differently functionalized products.
aim (i) to perform an alternative procedure to enter into optically
active nitrogen-containing heterocycles, and (ii) to investigate
the feasibility of gold-catalyzed heterocyclizations of compounds
having amine and allene groups tethered on an amido group.
Herein, we report our results concerning gold-catalyzed intra-
molecular hydroamination of allenamides 1 leading to enantiopure
5-substituted 2-vinylimidazolidinones. The imidazolidinone deriv-
atives are widespread in several natural products, many of them
having biological activities.16 Moreover, imidazolidinones have
proved to be effective in organic catalysis as activators for
a,b-
unsaturated aldehydes through formation of an iminium ion.17
In recent years homogeneous catalysis using gold salts has
emerged in organic synthesis as a powerful arm for interesting
and useful transformations.12 The success of the gold catalysis
involving allene substrates is related to its ability to coordinate
with C–C bonds, thereby allowing the attack of various nucleo-
philes in both inter- and intramolecular fashion.13
The starting materials were readily prepared as previously de-
scribed.15 Reaction conditions were optimized by using a variety
of Au(I) and Au(III) catalysts in the reaction of allenamide 1a aris-
ing from L-valine (Table 1).
First of all, in order to determine the need of a gold species for
achieving the cyclization process, a control investigation was per-
formed submitting the compound 1a to a reaction catalyzed by
protic acid. This procedure resulted in the formation of 4a in 15%
Taking into consideration recent works on heterocyclization of
a
-amino allenamides 1 under base-promoted14 and domino palla-
dium-catalyzed15 conditions to give dihydropyrazinone and imi-
dazolidinone derivatives 2 and 3, respectively (Scheme 1), we
thought to submit these substrates under a reaction in the pres-
ence of gold salts. This study was carried out with the double
Me
Boc
Boc
.
Ph
Pd(0)
base
BocNH
R
N
N
N
N
ref. 14
PhI
ref. 15
N
Me
R
Me
Me
R
O
O
O
* Corresponding authors. Tel.: +39 0458219649; fax: +39 045 8218117 (A.M.M.);
tel.: +39 0312386444; fax: +39 031 2386449 (G.B.).
1
2
3
E-mail addresses: angelo.m.manzo@gsk.com (A.M. Manzo), gianluigi.broggi-
ni@uninsubria.it (G. Broggini).
Scheme 1. Base- and palladium-catalyzed cyclization of allenamides 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.011

A. M. Manzo et al. / Tetrahedron Letters 50 (2009) 4696–4699
4697
Table 1
Optimization of the cyclization conditions of 1a
Boc
.
BocNH
[Au]
N
N
N
Me
solvent, reflux
Me
O
O
4a
1a
Entry
Catalytic systema
Solvent
Reaction productsb (%)
1a
4a
5
6
7
c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H2SO4
AuCl
AuCl
MeCN
Toluene
MeCN
CH2Cl2
CH2Cl2
MeCN
—
15
—
—
85
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
—
—
—
—
—
—
95
93
90
92
—
7
10
8
10
10
10
5
5
10
5
PPh3AuCl, AgOTf
PPh3AuCl, AgOTf, AcOH
AuCl3
—
—
90d
10
—
AuCl3
AuCl3
AuCl3
Dioxanee
80
—
AcOHf
CH2Cl2
90
—
—
—
—
—
—
90
g
95
95
51
95
95
90
—
—
—
39
—
—
AuCl3, AgBF4
NaAuCl4ꢀ2H2O
NaAuCl4ꢀ2H2O
NaAuCl4ꢀ2H2O
AuCl3, AgOTf
AuCl3, AgOTf
Toluene
MeCN
g
CH2Cl2
Dioxane
MeCN
5
10
10
—
—
AcOHf
a
Au catalyst is used in 5 mol %.
b
c
d
e
f
Ratio determined by HPLC.
5 mol %.
As a 2.5:1 cis/trans diastereoisomeric mixture.
Working on DMF, MeOH, and toluene any conversion of 1a was observed.
At 70 °C.
At room temperature.
g
yield besides a large amount of deallenylation byproduct 5 making
its applicative interest of no value (entry 1). It should be outlined
that Yb(OTf)3 revealed a catalytic behavior similar to that of the
sulfuric acid, while others Lewis acids such as BF3ꢀEt2O and
Zn(OTf)2 afforded only tarry mixtures.
tion of the minor diastereoisomer was confirmed by the NOE inter-
action between Hb and Hc (Fig. 1).
HPLC analysis (Chiralcel ODH column) of cis- and trans-4a, per-
formed in comparison to samples of the corresponding racemic
mixture synthesized starting from the ( )-valine, proved an enan-
tiomeric purity better than 99.5%.
Treatment of
a-amino allenamide 1a with Au(I)-salts resulted
only in the formation of small amounts of the degradation product
6 (entries 2 and 3). The same behavior was observed by using of
PPh3AuCl complex, also in addition to AgOTf and AcOH (entries 4
Next we explored the scope of the reaction under the conditions
of entry 6 of Table 1. Thus, a selection of the behaviors of allena-
mides 1 is collected in Table 2. The reactions were completed in
1–3.5 h, always providing the cis-imidazolidinones as the major
products. Allenamides 1a–d led to cis and trans products in very
similar ratios and yields. The outcome of compound 1e resulted
in a tarry crude mixture that allowed to isolate cis diastereoisomer
in only 22% yield. Allenamide 1f, arising from L-phenylalanine, gave
rise to cyclization in a higher diastereoselective level that led to the
isolation of the sole cis-product in 65% yield.
and 5).
OAc
CHO
BocNH
BocNH
NH
Boc
H
N
N
N
Me
Me
Me
O
O
O
5
6
7
The inertness of Au(I) catalysts prompted us to study the behav-
ior of a substrate having a more nucleophilic amino group. So, the
Working in the presence of AuCl3 (5 mol %) in acetonitrile as the
solvent at reflux, a mixture of imidazolidinones 4a was obtained in
a satisfactory yield (entry 6). Other solvents such as dioxane, DMF,
MeOH, and toluene were tried without improvement in the cycli-
zation outcome. By performing the reaction in AcOH as the solvent
at 70 °C only the open-chain derivative 7 was recovered (entries 8
and 15). The use of NaAuCl4 in acetonitrile instead of AuCl3 affor-
ded 4a in lower yields (entry 11).
a-benzylamino allenamide 8 was submitted to a treatment with
Au(I) and Au(III) catalysts. Although even in this case the latter re-
sulted the most efficient catalyst, PPh3AuCl was operative in the
promotion of the 5-exo-allylic cyclization (Table 3). The reaction
carried out in the presence of AuCl3 was faster than the cyclizations
tried on allenamide 1a (0.20 h vs 2.5 h) giving the cis isomer as the
The presence of silver salts in addition to the Au(III) catalysts to
form cationic gold species seems to inhibit the reaction (entries 10
and 14).
The cyclization ran in 5-exo-allylic manner leading to the imi-
dazolidinones 4a in 2.5:1 diastereoisomeric ratio.18 The absolute
stereochemistry of the cis and trans diastereoisomers 4a was as-
signed by NOE measurements. In particular, NOE enhancement be-
tween Hb and Ha has been the determinant to identify the cis-
configuration of the major diastereoisomer. The trans-configura-
Me
N
Hc
Me
N
Hb
O
O
Hb
O
Hc
O
Me
Me
N
N
Me
Me
Me
Me
Ha
Me
Ha
Me
Me
O
cis
Me
O
-4a
trans-4a
Figure 1. NOE enhancements observed in cis and trans diastereoisomers.

4698
A. M. Manzo et al. / Tetrahedron Letters 50 (2009) 4696–4699
Table 3
Cyclization of
major product, although with a lower cis/trans ratio. The catalytic
system PPh3AuCl/AgBF4 furnished the cis and trans imidazolidinon-
es 9 with the same diastereoisomeric ratio found using AuCl3 as the
catalyst, although in lower yield.
a
-benzylamino allenamide 8
Ph
Ph
Ph
.
N
N
A plausible mechanism for the gold-catalyzed heterocyclization
is shown in Scheme 2. The inside C–C double bond of the 1,2-diene
moiety is activated by the coordination of both Au(I) and Au(III)
NH
AuLn
N
N
+
N
Me
Me
MeCN
reflux
Me
O
O
O
species (intermediate A or A0). The so-generated
p-olefin complex
cis-9
trans-9
8
undergoes intramolecular nucleophilic attack by the nitrogen atom
of the amino group affording the cyclic vinyl-gold intermediate B.
However, the development of the C–N bond can be achieved on the
Entry
Catalytic system
Time (h)
Yields of products (%)
1
2
PPh3AuCl/AgBF4
AuCl3
2.5
0.20
cis-9 (21%)
cis-9 (36%)
trans-9 (14%)
trans-9 (24%)
p
-olefin-Au(III) complex by both Boc- and Bn-amino groups,
whereas only the more reactive Bn-amino group can interact with
-olefin-Au(I) complex. Protonolysis of the gold-carbon bond of B
p
gives imidazolidinone derivatives 4 and/or 9 and regenerates the
gold catalyst.
cis-(4 and/or 9)
+
1
AuLn
trans-(4 and/or 9)
In summary, allenamides were proven to be efficient substrates
for gold-catalyzed cyclization, increasing the range of their syn-
thetic interests.19 The procedure represents the first example of a
gold-catalyzed cyclization on allenes bearing an amido group
which, however, resulted inactive. Moreover, the obtained imi-
dazolidinones bear a useful vinyl group in position 2 that allows
_
AuLn
AuLn
AuLn
R'
+
H
R'
.
R'
.
N
NH
or
NH
N
N
N
Me
R
R
R
Me
Me
O
A'
O
A
O
B
Table 2
Reaction scope
Boc
R
Boc
R
Scheme 2. Proposed mechanism for the formation of 2-vinylimidazolidinones 4.
N
N
5 mol % AuCl3
MeCN, reflux
1
N
N
+
Me
Me
further functionalizations in order to investigate their potential
effectiveness as organocatalysts.
O
O
cis-4
trans-4
Entry
Allene
R
Time (h)
2.5
Yields of products (%)
Acknowledgments
Boc
N
Boc
The authors thank the Ministero dell’Università e della Ricerca
for financial support (Prin 2006-2008) and Stefano Provera for
the spectroscopic characterization of the compounds and for the
valuable discussion.
N
N
N
1
1a
i-Pr
Me
Me
i-Pr
i-Pr
O
cis-4a
O
(41%)
N
trans-4a (12%)
Boc
Boc
References and notes
N
N
N
2
3
4
5
6
1b
1c
1d
1e
1f
Me
Et
1.5
Me
Me
Me
Me
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(50%)
N
cis-4b
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trans-4b
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N
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N
1
Me
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Et
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O
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(50%)
N
(12%)
cis-4c
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trans-4c
Boc
N
N
N
Ph
1.5
3.5
1.5
Me
Me
Ph
Ph
O
O
trans-4d
Boc
(40%)
(4%)
N
cis-4d
Boc
N
N
N
t-Bu
Bn
Me
Me
t-Bu
t-Bu
O
O
(10%)
(22%)
cis-4e
Boc
trans-4e
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—
Me
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dryness. Purification and separation of the two diastereomers by flash column
chromatography (toluene/AcOEt 7:3) afforded 5-substituted (2S,5S)- and (2S,5R)-
3-methyl-1-terbutyloxycarbonyl-2-vinylimidazolidin-4-ones 4.
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Characterization of (2S,5S)-4a, trans diastereoisomer: Pale yellow oil. 1H NMR
(599.71 MHz, CDCl3, T = 50 °C): d 5.38–5.59 (m, 3H), 5.05–5.16 (m, 1H), 4.02–4.13
(m, 1H), 2.77 (s, 3H), 2.61–2.72 (1H, m), 1.46 (s, 9H), 1.16 (d, 3H, J = 7.1 Hz), 0.86(d,
3H, J = 6.9 Hz). 13C NMR (150.81 MHz, CDCl3, T = 50 °C): d 169.3 (C), 154.1 (C),
135.8 (CH), 121.2 (CH2), 81.8 (C), 76.7 (CH), 63.2 (CH), 28.5 (CH3), 28.5 (CH3), 28.5
(CH3), 26.6 (CH), 18.5 (CH3), 16.3 (CH3). IR (nujol): 1645, 1706 cmꢁ1. ½a D23
ꢂ
+52.3 (c
0.69, CHCl3).
Characterization of (2S,5R)-4a, cis diastereoisomer: Pale yellow oil. 1H NMR
(599.71 MHz, CDCl3, T = 50 °C): d 5.69 (ddd, 1H, J = 17.3, 9.9, 8.0 Hz); 5.50 (d, 1H,
J = 17 Hz); 5.43 (d, 1H, J = 10.2 Hz); 5.16 (d, 1H, J = 7.7 Hz); 4.05 (br s, 1H); 2.79 (s,
3H);2.17–2.30 (m, 1H);1.46(s, 9H); 1.08(d,3H, J = 7.1 Hz); 1.01(d,3H, J = 7.1 Hz).
13C NMR (150.81 MHz, CDCl3, T = 50 °C): d 169.5 (C), 154.1 (C), 135.1 (CH), 121.1
(CH2), 81.1 (C), 76.0 (CH), 64.0 (CH), 31.2 (CH3), 28.3 (CH3), 28.3 (CH3), 28.3 (CH3),
14. Broggini, G.; Galli, S.; Rigamonti, M.; Sottocornola, S.; Zecchi, G. Tetrahedron
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26.4 (CH), 18.6 (CH3), 18.2 (CH3). IR (nujol): 1648, 1714 cmꢁ1. ½a D23
ꢂ
= +10.5 (c 0.91,
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