Highly regio- and stereoselective palladium-catalyzed allylic carbonate amination. A practical route to dehydro-β-amino esters

Article abstract of DOI:10.1016/j.tet.2010.05.022

A pratical, highly enantioselective method for the synthesis of dehydro-β-amino acids was developed starting from easily accessible enantiopure allylic carbonates. The substitution with amines for C-N bond formation on these substrates bearing substituents on the Cα, Cβ, and Cγ position of the allylic system has received, until now, little attention. The reactions, carried out under palladium-catalyzed conditions, resulted in good yields and complete regioselectivity. Moreover, starting from enantiopure carbonates, complete retention of the configuration could be observed, affording enantiopure allylic amines.

Full text of DOI:10.1016/j.tet.2010.05.022

Tetrahedron 66 (2010) 4994e4999
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Highly regio- and stereoselective palladium-catalyzed allylic carbonate amination.
A practical route to dehydro-
b-amino esters
,
a
a
a
,
a
Giuliana Cardillo a , Luca Gentilucci , Elisa Mosconi , Alessandra Tolomelli , Stefano Troisi ,
*
*
Eusebio Juaristi b
a Department of Chemistry ‘G.Ciamician’, University of Bologna, Via Selmi 2, 40126 Bologna, Italy
b Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Col. San Pedro Zacatenco, Apartado Postal 14-740, 07000 Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
A pratical, highly enantioselective method for the synthesis of dehydro-b-amino acids was developed
Received 7 January 2010
Received in revised form
20 April 2010
Accepted 10 May 2010
Available online 13 May 2010
starting from easily accessible enantiopure allylic carbonates. The substitution with amines for CeN bond
formation on these substrates bearing substituents on the C , C , and C position of the allylic system
has received, until now, little attention. The reactions, carried out under palladium-catalyzed conditions,
resulted in good yields and complete regioselectivity. Moreover, starting from enantiopure carbonates,
complete retention of the configuration could be observed, affording enantiopure allylic amines.
Ó 2010 Elsevier Ltd. All rights reserved.
a
b
g
Keywords:
Dehydro-b-amino acids
Palladium catalyst
Allylic amination
Regioselectivity
Enantioselectivity
1. Introduction
2. Results and discussion
The CeN bond formation is one of the most important link-
ages in organic chemistry and allows the preparation of unusual
amino acids. The substitution of allylic acetates or carbonates is
a powerful method for the preparation of allylic amines and
represents one of the most attractive procedures for their
asymmetric synthesis.1 While primary allylic carbonates have
In our previous work we reported that the uncatalyzed reaction
proceeds via an SN2I mechanism affording exclusively the
regioisomer A (Fig. 1).5 On the other hand, under palladium-cata-
lyzed conditions,2,6 the substitution of carbonates with benzyl-
amine showed a strong solvent-dependent regiocontrol affording
almost exclusively one of the two possible regioisomers.7 In
particular, regioisomer B, which is the object of this study, is pre-
ferentially obtained when the reaction is performed in CH3CN. In
both cases, we observed a complete transfer of chirality from the
starting substrate to the products.
been widely studied, the substrates bearing substituents in C
, and C have received less attention. Recently, we reported
a pratical regio- and stereoselective synthesis of dehydro-
amino esters via amination of racemic and enantiomerically pure
allylic carbonates.2 Dehydro-
-amino esters are interesting
precursors of unsaturated or saturated -amino acids and also
-lactams.3 In an ongoing project dealing with the use of the b0
-amino acids, we envisaged their insertion as
a,
C
b
g
b
-
b
b
b
a, -
unsaturated
b
a rigid core in small constrained non-peptidic molecules mim-
icking the RGD motif. This sequence is present in a wide number
of extracellular matrix proteins like fibronectin, fibrinogen,
vitronectin capable of the inhibition of integrin subtypes such as
4
avb3 and a5b1
.
* Corresponding authors. E-mail address: giuliana.cardillo@unibo.it (G. Cardillo).
Figure 1. Allylic carbonate substitution.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.022

G. Cardillo et al. / Tetrahedron 66 (2010) 4994e4999
4995
To complete our work, we present here the development of
previously reported results under Pd catalyzed conditions using the
carbonates 1e4 and a variety of amines as nucleophiles.2 The re-
action was carried out in CH3CN. Initially, a series of experiments
was performed using racemic carbonates 1e4 with bifunctional-
ized amines in the presence of 2.5 mol % Pd2(dba)3/CHCl3.
The usual work-up2 and purification by column chromatogra-
phy provided the products (Table 1).
Table 1
Pd-catalyzed substitution on racemic carbonates 1e4
Entry
1
Reagent
Amine
Product
Yielda (%)
Z/E
40
5a
50/50
35b
2
3
5b
5f
35b
60
20/80
30/70
4
6a
47
95/5
5
6
6b
6c
45
40
95/5
95/5
7
8
6d
6e
60
60
95/5
92/8
9
6f
7f
65
70
95/5
10
90/10
11
8f
87
20/80
a
All experiments were performed using racemic carbonates 1e4 with bifunctionalized amines in the presence of 2.5% Pd2(dba)3/CHCl3 and refluxing in CH3CN for 12 h.
Yields were calculated after purification of the products by flash chromatography on silica gel.
b
The reaction was conducted with 5 mol % PPh3 as additive.

4996
G. Cardillo et al. / Tetrahedron 66 (2010) 4994e4999
Carbonate 1 reacted with N-methylpiperazine in the presence,
or in the absence, of PPh3 giving the expected regioisomer 5a in
4-aminomethylaniline acting as the nucleophile gave the corre-
sponding compounds 7f and 8f, isolated in good yield by flash
chromatography on silica gel. The 4-aminomethylaniline exclu-
sively reacted at the benzylamine function to give complete
regioselectivity (Table 1 entries 10 and 11). A good Z/E ratio could
be observed for 7f (90/10), while for 8f the preferential formation
of the E isomer was obtained (Z/E ratio 20:80), as already observed
for 5b and 5f.
We focused our attention on the products derived by the sub-
stitution reactions with 4-aminomethyaniline as they are in-
teresting intermediates for the synthesis of potential RGD
mimetics. Therefore, with these results in hand, we investigated
this reaction on enantiomerically pure carbonates. Resolution of
racemic allylic alcohols via Pseudomonas Cepacia lipase acetylation
afforded enantiomerically pure Z-(S)-allylic alcohols and Z-(R)-ac-
etates that were easily converted into the corresponding carbon-
ates.11 The results obtained on treating optically active carbonates
1e4 with 4-aminomethylaniline are reported in Table 2.
8
low yield and in both cases with complete isomerization of the
double bond (E/Z ratio 1:1, Table 1 entry 1).9 Similar results have
been obtained in the reaction of 1 with p-methoxybenzylaniline
and 5b was isolated in moderate yield as a mixture 80:20 of E/Z
isomers (entry 2). The configuration of the double bond was at-
tributed on the basis of the vinyl proton 1H NMR chemical shift and
confirmed by NOE experiments.3b,10a,10b,10c On reaction of 1 with 4-
aminomethylaniline as a nucleophile, 5f was obtained in higher
yield, in a 70:30 E/Z ratio of geometrical isomers (Table 1 entry 3).
The carbonate 2 also provided the corresponding products in
good yield, but in this case with preferential formation of the Z
isomer (Z/E ratio from 92:8 to 95:5). No trace of the regioisomer
deriving from the SN2I mechanism was detected in the 1H NMR of
the crude, while traces of about 10e20% of the unreacted starting
material were observed (Table 1 entries from 4e6, 8, and 9). The
benzyl L-proline (Table 1 entry 7) underwent substitution giving
Table 2
Reaction of enantiomerically pure carbonates 1e4 with 4-aminomethylaniline
Entry
1
Substrate
Producta
eeb(%)
Yield (%)
72
>99
2
3
4
5
6
>99
>99
>99
>99
>99
58
61
59
68
60
7
>99
>99
85
78
8
a
Reaction carried out in the presence of 2.5 mol % Pd2(dba)3/CHCl3 in refluxing CH3CN.
Determined by HPLC on chiral column on isolated pure compounds (Chiralcel AD column for 5f and 7f, Chiralcel IA column for 6f, Chiralcel OJ column for 8f).
b
almost exclusively the corresponding dehydro-
b
-amino esters
The enantiomeric excess of isolated products were determined
by HPLC on chiral column, after separation of the Z isomer from the
E isomer. The configuration of the newly created stereocentre was
unequivocally attributed on the basis of previously reported
with the Z geometry of the double bond (Z/E ratio 95:5) but as
a 1:1 mixture of diastereoisomers, with respect to the newly
formed CeN bond. Finally the reaction of carbonates 3 and 4 with

G. Cardillo et al. / Tetrahedron 66 (2010) 4994e4999
4997
research2 and on the basis of mechanistic considerations. In fact,
the mechanism for the palladium-catalyzed allylic amination is
generally accepted to proceed via a palladium/allyl complex that in
the second step is attacked directly by the amine nucleophile, in
analogy with the reaction mechanism for soft carbon nucleophiles.
Since both the oxidative addition leading to palladium complex and
the nucleophilic attack occur with inversion of configuration at the
reacting allylic carbon atom, the overall process proceeds with re-
tention of configuration.12
instrument with UV/vis detector and equipped with chiral column
(Chiralcel AD, OJ or IA columns) eluted with n-hexane/2-propanol.
Optical rotations were measured in a Perkin/Elmer 343 polarimeter
using a 1 dm cuvette and are referenced to the Na-D line value at 25
ꢀC. Melting points were determined on a Stuart Scientific SMP3
apparatus and are uncorrected.
3.2. General procedure for the preparation of the carbonates
1e4
Finally, in order to verify the usefulness of our procedure and to
optimize our methodologies on the basis of modern techniques, we
tested palladium nanoparticles as catalysts. In a recent paper Ranu
and co-workers13 explored the efficient allylic amination of allyl
alcohol derivatives catalyzed by palladium nanoparticles in the
presence of a base. This research group described a new protocol
that gave good yields of allylated amines. On the basis of the con-
siderable interest in the metal nanoparticles,14 we applied the
Ranu’s protocol to our substrate. The reaction was first performed
on the racemic 2, then on the (S)-2 carbonate. After the period of
time required for completion, the reaction was worked-up as usual
(Scheme 1).
To a solution of the Z-allylic alcohol (1 mmol) in dry THF
(10 mL), under an inert atmosphere at ꢁ78 ꢀC, LiHMDS (1.5 equiv,
1.5 mL 1 M solution in THF) was added dropwise. The solution was
stirred for 30 min and then methyl chloroformate (2 equiv, 2 mmol)
was added in one portion. After 40 min, the mixture was quenched
with water (2 mL) and THF removed under reduced pressure. The
residue was diluted with ethylacetate (10 mL) and washed twice
with water (5 mL). The two phases were separated, the organic
layer was dried over Na2SO4, and solvent was removed under re-
duced pressure. Carbonates 1e4 were isolated by flash chroma-
tography on silica gel (cyclohexane/ethylacetate 95/5 as eluant).
3.2.1. Compound 1. Yellow oil; Rf (30% ethylacetate/70% cyclohex-
ane) 0.64; 1H NMR (CDCl3, 200 MHz)
d
1.45 (d, J¼6.6 Hz, 3H,
CH3CHO),1.51 (s, 9H, OC(CH3)3), 1.99 (d, J¼7.2 Hz, 3H, CH3CHC), 3.76
(s, 3H, CH3OCO), 5.48 (q, J¼6.6 Hz, 1H, CH3CHO), 6.23 (q, J¼7.2 Hz,
1H, CH3CHC); 13C NMR (CDCl3, 75 MHz) dC 15.3, 20.0, 28.3 (3C),
54.6, 74.1, 81.3, 134.4, 135.8, 155.0, 165.5; IR (neat, cmꢁ1) 792, 852,
941, 1047, 1155, 1264, 1368, 1443, 1725, 1751, 2976. (S) Enantiomer:
[
a
]
D ꢁ24.6 (c 1 in CHCl3); (R) enantiomer: [ D þ25.0 (c 1 in CHCl3);
a
]
LC-ESI-MS rt 9.77 min, m/z 244 (M), 267 (MþNa). Anal. Calcd for
C12H20O5(244.13): C 59.00, H 8.25; found C 59.09, H 8.28.
Scheme 1. Pd-nanoparticles catalyzed reaction.
3.2.2. Compound 2. Pale yellow oil; Rf (30% ethylacetate/70%
cyclohexane) 0.78; 1H NMR (CDCl3, 200 MHz)
d
1.01 (d, J¼6.6 Hz,
The regioisomers (S)-6f and (R)-95 were obtained in 60:40 ratio
and were separated by flash chromatography. The 1H NMR spec-
trum of (S)-6f showed the exclusive presence of the Z isomer and
the chiral HPLC analysis showed only the (S) enantiomer. On the
contrary, (R)-9 was isolated as a 1:1 mixture of Z/E isomers. This
protocol lacked in regioselectivity, affording both 6f and 9, but
a high stereoselectivity could be observed in the double bond and
the stereocentre formation of 6f.
6H, CH3CHCH3), 1.42 (d, J¼6.6 Hz, 3H, CH3CHO), 1.50 (s, 9H, OC
(CH3)3), 3.02e3.17 (m,1H, CH3CHCH3), 3.77 (s, 3H, CH3OCO), 5.46 (q,
J¼6.6 Hz, 1H, CH3CHO), 5.84 (d, J¼9.6 Hz, 1H, CHCHC); 13C NMR
(CDCl3, 75 MHz) dC 19.8, 22.5 (2C), 26.2, 28.1 (3C), 54.5, 74.0, 81.2,
131.3, 146.7, 155.0, 165.6; IR (neat, cmꢁ1) 792, 941, 1047, 1154, 1269,
1344, 1368, 1442, 1717, 1750, 2871, 2975. (S) Enantiomer: [
(c 1 in CHCl3); (R) enantiomer: [
a]
D ꢁ30.0
a
]
D þ28.9 (c 1 in CHCl3); LC-ESI-MS
rt 11.82 min, m/z 272 (M), 295 (MþNa). Anal. Calcd for
In conclusion, we have reported herein some examples on the
substitution of bifunctionalized amines on allylic carbonates via
a regio- and stereoselective Pd-catalyzed reaction. Optimized
C14H24O5(272.16): C 61.74, H 8.88; found C 61.76, H 8.86.
3.2.3. Compound 3. Pale yellow oil; Rf (30% ethylacetate/70%
cyclohexane) 0.81; 1H NMR (CDCl3, 200 MHz)
d 0.86e1.30 (m, 6H,
conditions gave access to dehydro-b-amino esters generally in good
yields. Starting from enantiopure derivatives, we observed
complete retention of the initial stereochemistry. A new procedure,
taking advantage of Pd-nanoparticles technology was also tested,
showing unfortunately a lack of regioselectivity.
cyclohexyl), 1.39 (d, J¼6.2 Hz, 3H, CH3CHO), 1.47 (s, 9H, OC(CH3)3),
1.66e1.79 (m, 4H, cyclohexyl), 2.78 (bq, J¼10.4 Hz 1H, CH cyclo-
hexyl), 3.74 (s, 3H, CH3OCO), 5.43 (q, J¼6.2 Hz,1H, CH3CHO), 5.83 (d,
J¼9.4 Hz, 1H, CHCHC); 13C NMR (CDCl3, 75 MHz) dC 19.9, 25.5, 25.8,
28.1 (3C), 32.4 (2C), 37.7 (2C), 54.5, 74.0, 81.0, 131.5, 145.4, 154.8,
165.5; IR (neat, cmꢁ1) 734, 791, 846, 941, 966, 1003, 1848, 1086,
1153, 1223, 1265, 1368, 1393, 1448, 1718, 1751, 2852, 2926. (S) En-
3. Experimental section
3.1. General
antiomer: [
a
]
D ꢁ25.2 (c 1 in CHCl3); (R) enantiomer: [ D þ26.7 (c 1
a
]
in CHCl3); LC-ESI-MS rt 10.81 min, m/z 312 (M), 335(MþNa). Anal.
All chemicals were purchased from commercial suppliers and
used without further purification. Anhydrous solvents were pur-
chased in Sure/Seal bottles (250 mL) over molecular sieves and used
without further drying. Flash chromatography was performed on
silica gel (230e400 mesh). NMR Spectra were recorded with Varian
Gemini 200, Mercury Plus 400 or Unity Inova 600 MHz spectrome-
Calcd for C17H28O5(312.19): C 65.36, H 9.03; found C 65.51, H 9.05.
3.2.4. Compound 4. Yellow oil; Rf (30% ethylacetate/70% cyclo-
hexane) 0.70; 1H NMR (CDCl3, 200 MHz)
d
1.49 (s, 9H, OC(CH3)3),1.53
(d, J¼6.6 Hz, 3H, CH3CHO), 3.78 (s, 3H, CH3OCO), 5.51 (q, J¼6.6 Hz,
1H, CH3CHO), 6.72 (s, 1H, CCHC), 7.14e7.31 (m, 3H, thiophenyl); 13
C
ters. Chemical shifts were reported as
d
values (ppm) relative to the
NMR (CDCl3, 75 MHz) dC 20.1, 28.0 (3C), 54.8, 75.3, 82.1, 125.3, 126.5,
126.7, 128.2, 133.2, 136.1, 155.0, 166.6; IR (neat, cmꢁ1) 790, 845, 937,
986,1008, 1049,1086, 1146, 1268,1367, 1406, 1442, 1647,1716, 2552,
solvent peak of CDCl3 set at
d
¼7.27 (1H NMR) or
d
¼77.0 (13C NMR).
Coupling constants are given in hertz. The enantiomeric excesses of
products were determined by HPLC analyses performed an HP1100
2932, 2980, 3101, 3362. (S) Enantiomer: [
a
]D þ46.0 (c 1 in CHCl3); (R)

4998
G. Cardillo et al. / Tetrahedron 66 (2010) 4994e4999
enantiomer: [
a
]
D ꢁ42.0 (c 1 in CHCl3); LC-ESI-MS rt 10.59 min, m/z
CHCHC); 13C NMR (75 MHz, CDCl3)
d 12.8, 22.9 (2C), 28.4 (3C), 28.6,
312 (M), 335(MþNa). Anal. Calcd for C15H20O5S(312.1): C 57.67, H
46.1, 55.7 (4C), 60.9, 80,3, 135.6, 140.4, 167.2; IR (neat, cmꢁ1) 1014,
1148, 1239, 1322, 1366, 1455, 1716, 2793, 2869, 2935, 2969. LC-MS-
ESI rt 1.73, 297 (Mþ1). Anal. Cacld for C17H32N2O2 (296.4): C 68.88,
H 10.88, N 9.45; found C 68.93, H 10.89, N 9.43.
6.45, S 10.26; found C 57.85, H 6.44, S 10.29.
3.3. General procedure for the preparation of the dehydro-
b-
amino esters
3.3.5. Compound 6b. Yellow oil (45%), (95:5 Z/E mixture); Rf (30%
ethylacetate/70% cyclohexane) 0.33; 1H NMR (200 MHz, CDCl3) (Z):
To a solution of the carbonate 1e4 (0.2 mmol) in dry CH3CN
(2 mL), under nitrogen atmosphere, Pd2(dba)3/CHCl3 (2.5%,
0.005 mmol) was added in one portion. After stirring the solution at
room temperature for 30 min, the amine (1.2 equiv) was added. The
solution was refluxed for 12 h and then the mixture was filtered
through a Celite pad and concentrated under reduced pressure. The
d
1.03 (d, J¼6.6 Hz, 3H, CH3CHCH3), 1.07 (d, J¼6.6 Hz, 3H,
CH3CHCH3), 1.25 (d, J¼6.6 Hz, 3H, CH3CHN), 1.53 (s, 9H, OC(CH3)3),
1.82 (br s, 1H, NH), 2.84e3.06 (m, 1H, CH3CHCH3), 3.32 (q, J¼6.6 Hz,
1H, CH3CHN), 3.53 (d, J¼12.6 Hz,1H, HNCH2), 3.73 (d, J¼12.6 Hz,1H,
HNCH2), 3.80 (s, 3H, OCH3), 5.55 (d, J¼10.0 Hz, 1H, CHCHC) 6.86 (d,
J¼8.8 Hz, 2H, phenyl), 7.25 (d, J¼8.8 Hz, 2H, phenyl); 13C NMR
dehydro-b-amino ester was isolated by flash chromatography on
(75 MHz, CDCl3)
d 21.4, 22.8, 23.2, 28.4 (3C), 28.7, 50.5, 55.3, 57.0,
silica gel.
80.9, 113.8 (2C), 129.5 (2C), 132.9, 133.7, 144.4, 158.6, 167.9; IR (neat,
cmꢁ1) 829, 848, 1037, 1152, 1246, 1300, 1320, 1367, 1392, 1465, 1512,
1611, 1707, 2834, 2868, 2932, 2966. LC-MS-ESI rt 4.13, 334 (Mþ1).
Anal. Calcd for C20H31NO3 (333.4): C 72.04, H 9.37, N 4.20; found C
71.95, H 9.40, N 4.18.
3.3.1. Compound 5a. Orange oil (40%), (1:1 E/Z mixture); Rf (30%
ethylacetate/70% cyclohexane) 0.10; 1H NMR (200 MHz, CDCl3) (E)
d
1.09 (d, J¼6.6 Hz, 3H, CH3CHN), 1.46 (s, 9H, OC(CH3)3), 1.84 (d,
J¼7.4 Hz, 3H, CH3CHC), 2.44 (s, 3H, CH3N), 2.50e2.80 (m, 8H,
piperazine), 3.42 (q, J¼7.4 Hz, 1H, CH3CHN), 6.63 (q, J¼6.6 Hz, 1H,
3.3.6. Compound 6c. Yellow oil (40%), (95:5 Z/E mixture); Rf (30%
ethylacetate/70% cyclohexane) 0.35; 1H NMR (200 MHz, CDCl3) (Z):
d
CH3CHC); (Z)
d
1.26 (d, J¼6.6 Hz, 3H, CH3CHN), 1.42 (s, 9H, OC
(CH3)3), 1.78 (d, J¼7.4 Hz, 3H, CH3CHC), 2.44 (s, 3H, CH3N),
0.98 (d, J¼6.2 Hz, 3H, CH3CHCH3), 1.04 (d, J¼6.2 Hz, 3H,
2.50e2.80 (m, 8H, piperazine), 3.42 (q, J¼7.4 Hz, 1H, CH3CHN), 5.70
CH3CHCH3), 1.24 (d, J¼6.6 Hz, 3H, CH3CHN), 1.51(s, 9H, OC(CH3)3),
1.77 (br s, 1H, NH), 2.86e3.02 (m, 1H, CH3CHCH3), 3.27 (q, J¼6.6 Hz,
1H, CH3CHN), 3.65 (d, J¼13.4 Hz,1H, HNCH2), 3.84 (d, J¼13.4 Hz,1H,
HNCH2), 3.92 (s, 3H, OCH3), 5.51 (d, J¼9.8 Hz, 1H, CHCHC), 7.40 (d,
J¼8.4 Hz, 2H, phenyl), 7.99 (d, J¼8.4 Hz, 2H, phenyl); 13C NMR
(q, J¼6.6 Hz,1H, CH3CHC);13C NMR (75 MHz, CDCl3)
d 15.6,17.7, 28.3
(3C), 47.6, 55.8, 57.0 (2C), 57.4 (2C), 90.0,132.3,135.9,164.3; IR (neat,
cmꢁ1) 696, 721, 802, 1014, 1119, 1152, 1261, 1367, 1392, 1454, 1622,
1712, 2795, 2852, 2930, 2964, 3364. Anal. Calcd for C15H28N2O2
(268.4): C 67.13, H 10.52, N 10.44; found C 67.07, H 10.52, N 10.46.
(75 MHz, CDCl3)
d 21.2, 22.7, 23.2, 28.4, 28.6, 50.7, 52.1, 57.4, 81.1,
128.1, 128.2 (2C), 128.8, 129.7 (2C), 144.8, 146.0, 163.5, 164.2; IR
(neat, cmꢁ1) 699, 759, 1019, 1151, 1278, 1367, 1435, 1615, 1656, 1683,
1722, 2868, 2930, 2965. LC-MS-ESI rt 5.33, 362 (Mþ1). Anal. Calcd
for C21H31NO4 (361.4): C 69.78, H 8.64, N 3.87; found C 69.52, H
8.63, N 3.87.
3.3.2. Compound 5b. Yellow oil (35%), (80:20 E/Z mixture); Rf (30%
ethylacetate/70% cyclohexane) 0.10; 1H NMR (200 MHz, CDCl3) (E)
d
1.34 (d, J¼6.6 Hz, 3H, CH3CHN), 1.52 (s, 9H, OC(CH3)3), 1.74 (d,
J¼7.4 Hz, 3H, CH3CHC), 2.58 (br s, 1H, NH), 3.53 (d, J¼12.4 Hz, 1H,
HNCH2), 3.69 (d, J¼12.4 Hz, 1H, HNCH2), 3.73 (q, J¼6.6 Hz, 1H,
CH3CHN), 3.81 (s, 3H, OCH3), 6.80e6.86 (m, 1H, CH3CHC), 6.85 (d,
J¼8.4 Hz, 2H, phenyl), 7.24 (d, J¼8.4 Hz, 2H, phenyl); 13C NMR
3.3.7. Compound 6d. Yellow oil (60%); (95:5 Z/E mixture; 1:1 di-
astereomeric mix); Rf (30% ethylacetate/70% cyclohexane) 0.40;
(75 MHz, CDCl3)
d 13.8, 20.6, 28.3 (3C), 50.0, 50.7, 55.3, 80.7, 113.8
Z-isomer A; 1H NMR (200 MHz, CDCl3)
d 0.92e1.00 (m, 6H,
(2C), 129.5 (2C), 132.0, 135.9, 137.9, 151.1, 166.7; IR (neat, cmꢁ1) 699,
766, 832, 1031, 1097, 1160, 1258, 1339, 1449, 1511, 1577, 1604, 1651,
1698, 2850, 2926, 2961, 3366. Anal. Calcd for C18H27NO3 (305.4): C
70.79, H 8.91, N 4.59; found C 70.52, H 8.94, N 10.47.
CH3CHCH3), 1.25 (d, J¼7 Hz, 3H, CH3CHN), 1.48 (s, 9H, OC(CH3)3),
1.76e1.92 (m, 4H, NCH2CH2CH2), 2.63e2.83 (m, 2H, NCH2),
3.00e3.10 (m, 1H, CH3CHCH3), 3.54e3.68 (m, 2H, CH3CHN, NCHCO),
5.12 (s, 2H, CH2Ph), 5.48 (d, J¼9.8 Hz,1H, CHCHC), 7.28e7.41 (m, 5H,
phenyl); Z-isomer B: 1H NMR (200 MHz, CDCl3)
d 0.94 (m, 6H,
3.3.3. Compound 5f. Yellow oil (60%), (70:30 E/Z mixture); Rf (50%
ethylacetate/50% cyclohexane on alumina plates) 0.23; 1H NMR
CH3CHCH3), 1.18 (d, J¼7 Hz, 3H, CH3CHN), 1.50 (s, 9H, OC(CH3)3),
1.76e1.92 (m, 4H, NCH2CH2CH2), 2.63e2.83 (m, 2H, NCH2),
3.00e3.10 (m, 1H, CH3CHCH3), 3.54e3.68 (m, 2H, CH3CHN, NCHCO),
5.12 (s, 2H, CH2Ph), 5.55 (d, J¼9.8 Hz, 1H, CHCHC), 7.28e7.41 (m, 5H,
(CDCl3, 200 MHz) (E)
d
1.31 (d, J¼7 Hz, 3H, CH3CHN), 1.50 (s, 9H, OC
(CH3)3), 1.72 (d, J¼7.4 Hz, 3H, CH3CHC), 3.43 (d, J¼12.4 Hz, 1H,
HNCH2), 3.60 (d, J¼12.4 Hz, 1H, HNCH2), 3.72 (q, J¼6.6 Hz, 1H,
CH3CHN), 6.63 (d, J¼8 Hz, 2H, phenyl), 6.81 (q, J¼7.4 Hz, 1H,
CH3CHC), 7.08 (d, J¼8 Hz, 2H, phenyl); 13C NMR (CDCl3, 75 MHz)
phenyl); 13C NMR (75 MHz, CDCl3)
d 17.8, 22.8, 23.4, 27.0, 28.3, 28.6,
30.1, 49.2, 59.1, 62.3, 66.0, 80.7, 128.1 (2C), 128.2(2C), 128.6(2C),
136.2, 143.3, 168.4, 175.1; IR (neat, cmꢁ1) 697, 750, 1149, 1241, 1270,
1367, 1392, 1455, 1732, 2869, 2971; LC-MS-ESI rt 5.57, 402 (Mþ1).
LC-MS-ESI rt 5.61, 402 (Mþ1). Anal. Calcd for C24H35NO4 (401.5): C
71.79, H 8.79, N 3.49; found C 72.03, H 8.78, N 3.48.
d
13.8, 20.7, 28.4 (3C), 49.9, 51.0, 80.5, 115.2 (2C), 129.4 (2C), 130.6,
136.3, 137.7, 145.2, 166.7; IR (neat, cmꢁ1)1141, 1278, 1367, 1392,
1453, 1517, 1632, 1695, 2929, 2975, 3216, 3368, 3445. LC-ESI-MS rt
8.39 min, m/z 290 (M), 313 (MþNa). Chiral HPLC analysis 99:1 to
96:4 n-hexane/2-propanol in 30 min, 1.0 mL/min, AD column, rt
3.3.8. Compound 6e. Brown oil (60%) (95:5 Z/E mixture); Rf (30%
ethylacetate/70% cyclohexane) 0.12; 1H NMR (200 MHz, CDCl3) (Z)
23.52 min for [E-(R)-5f] and 26.12 min [E-(S)-5f]; E-(S)-5f [a]
D
ꢁ14.0 (c 1 in CHCl3); E-(R)-5f [ D þ14.0 (c 1 in CHCl3). Anal. Calcd
a
]
d
0.97 (d, J¼6.6 Hz, 3H, CH3CHCH3), 0.98 (d, J¼6.6 Hz, 3H,
for C17H26N2O2 (290.2): C 70.31, H 9.02, N 9.65; found C 70.08, H
9.00, N 9.65.
CH3CHCH3), 1.23 (d, J¼6.6 Hz, 3H, CH3CHN), 1.41 (s, 9H, OC(CH3)3),
1.98 (br s,1H, NH), 2.79e3.00 (m, 5H, NCH2CH2, CH3CHCH3), 3.37 (q,
J¼6.6 Hz, 1H, CH3CHN), 5.52 (d, J¼9.4 Hz, 1H, CHCHC), 7.01 (s, 1H,
NCH aromatic), 7.01e7.21 (m, 2H, phenyl), 7.34 (d, J¼7.4 Hz, 1H,
phenyl), 7.61 (d, J¼7.8 Hz, 1H, phenyl), 8.29 (br s, 1H, NH aromatic);
3.3.4. Compound 6a. Orange oil (47%), (95:5 Z/E mixture); Rf (40%
ethylacetate/60% cyclohexane) 0.12; 1H NMR (200 MHz, CDCl3) (Z):
d
0.96 (d, J¼6.6 Hz, 3H, CH3CHCH3), 0.99 (d, J¼6.6 Hz, 3H,
CH3CHCH3), 1.09 (d, J¼7 Hz, 3H, CH3CHN), 1.49 (s, 9H, OC(CH3)3),
2.24 (s, 3H, CH3N), 2.25e2.40 (m, 8H, piperazine), 2.65e2.83 (m, 1H,
CH3CHCH3), 3.40 (q, J¼7 Hz, 1H, CH3CHN), 5.33 (d, J¼9.6 Hz, 1H,
13C NMR (75 MHz, CDCl3)
d 21.4, 22.8, 23.1, 26.1, 28.2 (3C), 28.5, 47.3,
57.5, 81.0, 111.2, 114.2, 119.0, 119.2, 121.9, 128.5, 128.8, 132.1, 136.5,
144.8, 167.7; IR (neat, cmꢁ1) 739, 1120, 1152, 1244, 1367, 1455, 1703,

G. Cardillo et al. / Tetrahedron 66 (2010) 4994e4999
4999
2868, 2927, 2971, 3057, 3408; LC-MS-ESI rt 5.57, 357 (Mþ1). Anal.
Calcd for C22H32N2O2 (356.5): C 74.12, H 9.05, N 7.86; found C 73.84,
H 9.02, N 7.86.
on silica [hexane/ethylacetate (70:30)e(50:50)] to provide prod-
ucts. The remaining black Pd nanoparticles, after extraction with
ether, were further washed with ether and dried for reuse.
Acknowledgements
3.3.9. Compound 6f. Yellow oil (65%), (95:5 Z/E mixture); Rf (40%
ethylacetate/60% cyclohexane) 0.14; 1H NMR (CDCl3, 200 MHz) (Z):
This study has been carried out with the fundamental contribu-
tion of ‘Fondazione del Monte di Bologna e Ravenna’. We also thank
MAE (Italian Minister for Foreign Affair, General Direction for the
Cultural Promotion and Cooperation) for financial support to a bi-
lateral projects of between Italy and Mexico. MIUR (PRIN 2006 prot.
n. 2006030449_003), and University of Bologna (Strategic project ID
450) are also acknowledged for financial support. Mr. Andrea Garelli
is gratefully acknowledged for the LC-ESI-MS analysis.
d
1.02 (d, J¼5.4 Hz, 3H, CH3CHCH3), 1.05 (d, J¼5.4 Hz, 3H,
CH3CHCH3), 1.23 (d, J¼7.8 Hz, 3H, CH3CHN), 1.51 (s, 9H, OC(CH3)3),
2.86e3.02 (m, 1H, CH3CHCH3), 3.31 (q, J¼6.6 Hz, 1H, CH3CHN), 3.46
(d, J¼12.6 Hz, 1H, HNCH2), 3.66 (d, J¼12.6 Hz, 1H, HNCH2), 5.55 (d,
J¼9.6 Hz, 1H, CHCHC), 6.63 (d, J¼7.8 Hz, 2H, phenyl), 7.10 (d,
J¼7.8 Hz, 2H, phenyl); 13C NMR (CDCl3, 75 MHz)
d 21.5, 22.8, 23.3,
28.4 (3C), 28.6, 50.6, 56.9, 80.9, 115.2 (2C), 129.4 (2C), 130.7, 133.7,
144.5,145.3,167.9; IR (neat, cmꢁ1) 1152,1241,1277,1367,1392,1454,
1518, 1622, 1700, 2868, 2929, 2969, 3218, 3372. LC-MS-ESI: rt
Supplementary data
2.9 min 319 (Mþ1); [Z-(R)-6f]: [
a
]
ꢁ4.8 (c 1 in CHCl3); [Z-(S)-6f]:
D
[
a
]
D þ6.6 (c 1 in CHCl3). Chiral HPLC analysis 98:2 to 90:10 n-hex-
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.05.022.
ane/2-propanol in 25 min, 0.8 mL/min, IA column, rt 15.10 min for
[Z-(R)-6f] and 15.61 min for [Z-(S)-6f]. Anal. Calcd for C19H30N2O2
(318.4): C 71.66, H 9.50, N 8.80; found C 71.69, H 9.46, N 8.82.
References and notes
3.3.10. Compound 7f. Yellow oil (70%), (90:10 Z/E mixture); Rf (30%
ethylacetate/70% cyclohexane) 0.13; 1H NMR (CDCl3, 200 MHz) (Z):
1. (a) Magid, R. M. Tetrahedron 1980, 36, 1901e1930; (b) Trost, B. M.; Van Vraken,
D. L. Chem. Rev. 1996, 96, 395e442; (c) Pfaltz, A.; Lautens, M. Comprehensive
Asymmetric Catalysis; Springer-Verlag: Berlin Hiedelberg, 1999; Vol. 2;
833e884; (d) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921e2943; (e)
Kar, A.; Argade, N. P. Synthesis 2005, 18, 2995e3002; (f) Helmchen, G. Asymm.
Synth. 2007, 95, 95e99; (g) Magriotis, P. A. Angew. Chem., Int. Ed. 2001, 40,
4377e4379; (h) Hultzsch, K. C. Adv. Synth. Catal. 2005, 347, 367e391; (i) Xu, L.-
W.; Xia, C. G. Eur. J. Org. Chem. 2005, 633e639; (j) Watson, I. D. G.; Yu, L.; Yudin,
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tinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318e5365; (l) Ling, R.;
Yoshida, M.; Mariano, P. S. J. Org. Chem. 1996, 61, 4439e4449.
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10, 2425e2428.
3. (a) Wasek, T.; Olczak, J.; Janecki, T. Synlett 2006, 1507e1510 and references
therein cited; (b) Abdel-Magid, A. F.; Cohen, J. H.; Maryanoff, C. A. Curr. Med.
Chem. 1999, 6, 955e969; (c) Juaristi, E. In Enantioselective Synthesis of b-amino
acids; Wiley-VCH: New York, NY, 2005; (d) Alcaide, B.; Plumet, J.; Rodriguez-
Lopez, J.; Sanchez-Cantalejo, Y. M. Tetrahedron Lett. 1990, 31, 2493e2496; (e)
Buchholz, R.; Hoffmann, H.; Martin, R. Helv. Chim. Acta 1991, 74, 1213e1220; (f)
Toyofuku, M.; Fujiwara, S.-I.; Shin-ike, T.; Kuniyasu, H.; Kambe, N. J. Am. Chem.
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Org. Chem. 2009, 74, 2798e2803 and references therein cited.
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Bioorg. Med. Chem. 1995, 3, 337e360; (e) Georges-Labousse, E.; Messaddeq, N.;
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Org. Chem. 2009, 34, 5991e5997.
6. For comprehensive studies on palladium catalyzed allylic amination see: (a)
Trost, B. M.; Fandrick, D. R. Aldrichimica Acta 2007, 40, 59e72; (b) Trost, B. M.;
Brennan, M. K. Org. Lett. 2007, 9, 3961e3964.
7. (a) Rajesh, S.; Banerij, B.; Iqbal, J. J. Org. Chem. 2002, 67, 7852e7857; (b) Watson,
I. G.; Yudin, A. K. J. Am. Chem. Soc. 2005, 127, 17516e17529.
8. Amatore, C.; Jutard, A.; Meyer, G.; Mottier, L. Chem.dEur. J. 1999, 5, 466e473.
9. (a) Shi, Y.-L.; Shi, M. Tetrahedron 2006, 62, 461e475; (b) Shi, Y.-L.; Xu, Y.-M.; Shi,
M. Adv. Synth. Catal. 2004, 346, 1220e1230.
d
1.00e1.10, (m, 6H, cyclohexyl), 1.25 (d, J¼Hz, 3H, CH3CHN), 1.52 (s,
9H, OC(CH3)3), 1.60e1.80 (m, 4H, cyclohexyl), 2.52e2.68 (m, 1H, CH
cyclohexyl), 3.31 (q, J¼6.6 Hz, 1H, CH3CHN),3.45 (d, J¼13 Hz, 1H,
HNCH2), 3.65 (d, J¼13 Hz,1H, HNCH2), 5.57, (d, J¼9.6 Hz,1H, CHCHC),
6.63 (d, J¼7.8 Hz, 2H, phenyl), 7.09 (d, J¼7.8 Hz, 2H, phenyl); 13C NMR
(CDCl3, 75 MHz) d 21.5, 25.8, 28.4 (3C), 32.9 (2C), 33.3 (2C), 38.3, 50.6,
56.9, 80.8, 115.2 (2C), 129.4 (2C), 130.7, 134.1, 142.9, 145.3, 167.9; IR
(neat, cmꢁ1) 826, 489, 1111, 1152, 1221, 1252, 1267, 1367, 1392, 1448,
1518, 1622, 1698, 2850, 2925, 2974, 3218, 3372. [Z-(R)-7f]: [
a
]
D ꢁ6.1
(c 1 in CHCl3); [Z-(S)-7f]: [
a]
D þ7.8 (c 1 in CHCl3), LC-MS-ESI rt 5.56,
359 (Mþ1). Chiral HPLC analysis 95:5 to 90:10 n-hexane/2-propanol
in 25 min, 1.0 mL/min, AD column, rt 11.10 min for [Z-(R)-7f] and
14.08 min for [Z-(S)-7f]. Anal. Calcd for C22H34N2O2 (358.5): C 73.70,
H 9.56, N 7.81; found C 73.77, H 9.53, N 7.82.
3.3.11. Compound 8f. Orange oil (87%), (80:20 E/Z mixture); Rf (40%
ethylacetate/60% cyclohexane) 0.12; 1H NMR (CDCl3, 200 MHz) (E):
d
1.32 (d, J¼7 Hz, 3H, CH3CHN), 1.57 (s, 9H, OC(CH3)3), 3.42 (d,
J¼12 Hz, 1H, HNCH2), 3.60 (d, J¼12 Hz, 1H, HNCH2), 4.10 (q, J¼7 Hz,
1H, CH3CHN), 6.57 (d, J¼8.4 Hz, 2H, phenyl), 6.66 (d, J¼7.6 Hz, 1H,
thiophenyl), 6.99 (d, J¼8.4 Hz, 2H, phenyl), 7.08e7.19 (m, 1H, thio-
phenyl), 7.28e7.34 (m, 1H, thiophenyl), 7.61 (s, 1H, CCHC); 13C NMR
(CDCl3, 75 MHz)
d 20.6, 28.3 (3C), 50.6, 50.9, 81.0, 115.1 (2C), 125.7,
126.4, 128.7, 129.3 (2C), 130.3, 133.4, 135.9, 136.4, 145.2, 166.9; IR
(neat, cmꢁ1) 729, 793, 841, 1163, 1249, 1306, 1392, 1455, 1519, 1568,
1593, 1699, 2851, 2925, 2974, 3371. [E-(R)-8f]: [
CHCl3); [E-(S)-8f]: [
(Mþ1). Chiral HPLC analysis 95:5 to 90:10 n-hexane/2-propanol in
20 min, 0.8 mL/min, OJ column, rt 35.80 min for [E-(S)-8f] and
38.58 min for [E-(R)-8f]. Anal. Calcd for C20H26N2O2S (358.5): C
67.01, H 7.31, N 7.81; found C 66.83, H 7.28, N 7.81.
a
]
þ5.0 (c 1 in
D
a]
ꢁ4.2 (c 1 in CHCl3), LC-MS-ESI rt 2.77, 359
D
10. (a) Otto, H. H.; Bergmann, H. J.; Mayrhofer, R. Arch. Pharmacol. 1986, 319,
203e216; (b) Anklam, S.; Liebscher, J. Tetrahedron 1998, 54, 6369e6384; (c)
Chernega, A.; Davies, S. G.; Elend, D. L.; Smethurst, C. A. P.; Roberts, P. M.; Smith,
A. D.; Darren Smyth, G. Tetrahedron 2007, 63, 7036e7046.
11. Benfatti, F.; Cardillo, G.; Gentilucci, L.; Mosconi, E.; Tolomelli, A. Tetrahedron:
3.4. Representative procedure for Pd-nanoparticles catalyzed
reaction
Asymmetry 2007, 18, 2227e2232.
12. (a) Jacquet, O.; Legros, J.-Y.; Coliboeuf, M.; Fiaud, J.-C. Tetrahedron 2008, 64,
6530e6536; (b) Moreno-Manas, M.; Morral, L.; Pleixats, R. J. Org. Chem. 1998,
63, 6160e6166; (c) Hayashi, T. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
VCH Verlagsgesellschaft mbH: Weinheim, 1993; pp 325; (d) Johannsen, M.;
Jørgensen, K. A. Chem. Rev. 1998, 98, 1689e1708.
13. Adak, L.; Chattopadhyay, K.; Ranu, B. C. J. Org. Chem. 2009, 74, 3982e3985.
14. (a) Astruc, D. Inorg. Chem. 2007, 46, 1884e1894; (b) Astruc, D.; Lu, F.; Aranzaes,
J. R. Angew. Chem., Int. Ed. 2005, 44, 7852e7872; (c) Polshettiwar, V.; Baruwati,
B.; Varma, R. S. Green Chem. 2009, 11, 127e131; (d) Reetz, M. T.; Westermann, E.
Angew. Chem., Int. Ed. 2000, 39, 165e168; (e) Tamura, M.; Fujihara, H. J. Am.
Chem. Soc. 2003, 125, 15742e15743; (f) Jansat, S.; Gomez, M.; Philippot, K.;
Muller, G.; Guiu, E.; Claver, C.; Castillon, S.; Chaudret, B. J. Am. Chem. Soc. 2004,
126, 1592e1593.
A mixture of amine (1 mmol), allyl carbonate (3 mmol), PdCl2
(0.045 mmol), tetrabutylammonium iodide (1 mmol), and K2CO3
(2 mmol) in toluene (3 mL) was stirred at 85 ꢀC for 10 h. The re-
action was monitored by TLC and quenched with water upon dis-
appearance of the starting carbonate. The reaction mixture was
extracted with Et2O (3ꢂ10 mL). The extract was washed with water
and brine then dried (Na2SO4). Evaporation of solvent afforded the
crude products, which were purified by column chromatography