Synthesis of dehydro-β-amino esters via highly regioselective amination of allylic carbonates

Article abstract of DOI:10.1021/ol8006919

(Chemical Equation Presented) The allylic amination of acetates and carbonates affords dehydro-β-aminoesters, which are useful precursors of biologically active compounds. The uncatalyzed reaction proceeds via a S _N2′ mechanism. On the other hand, under palladium-catalyzed conditions, the reaction shows a strong solvent-dependent regiocontrol, affording exclusively one of the two possible regioisomers with complete transfer of chirality from the substrates to the products.

Full text of DOI:10.1021/ol8006919

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2425-2428
Synthesis of Dehydro-ꢀ-amino esters
via Highly Regioselective Amination of
Allylic Carbonates
Fides Benfatti, Giuliana Cardillo,* Luca Gentilucci, Elisa Mosconi, and
Alessandra Tolomelli*
Department of Chemistry ”G. Ciamician”, UniVersity of Bologna, Via Selmi 2,
40126 Bologna, Italy
giuliana.cardillo@unibo.it; alessandra.tolomelli@unibo.it
Received March 26, 2008
ABSTRACT
The allylic amination of acetates and carbonates affords dehydro-ꢀ-aminoesters, which are useful precursors of biologically active compounds.
The uncatalyzed reaction proceeds via a SN2′ mechanism. On the other hand, under palladium-catalyzed conditions, the reaction shows a
strong solvent-dependent regiocontrol, affording exclusively one of the two possible regioisomers with complete transfer of chirality from the
substrates to the products.
Allylic compounds are privileged substrates in organic
synthesis, allowing the substitution reaction to be performed
with a variety of nucleophiles.1 The substitution with amines
is a very efficient method for C-N bond formation.2 One
of the most interesting aspects of this chemistry is the control
of the regio- and the stereoselectivity on the allylic moiety.
The reaction may be carried out in the absence of catalyst
or under Pd-catalyzed conditions. Depending on the nature
of the nucleophile, the substitution can occur via SN2 or
through an SN2′ process.1b–d For symmetrically substituted
compounds, the step of formation of the metal complex is
irrelevant for the regioselectivity of the overall reaction. On
the contrary, for substrates bearing different substituents at
the two allylic termini, interest increases when the regiose-
lectivity can be controlled.3 Excellent results have been
obtained under metal catalysis by choosing the proper
enantiopure ligand.4 On the other hand, several examples
showing a solvent effect on the regioselectivity have been
reported.5 In particular, solvent-dependent regiocontrol has
been recently reported in Baylis-Hillman adduct amination6
* Department of Chemistry ”G. Ciamician”, University of Bologna, Via
Selmi 2, 40126 Bologna, Italy. Fax: +39 051 2099456.
(3) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545–
4554. (b) Cook, G. R.; Yu, H.; Sankaranarayanan, S.; Shanker, S. S. J. Am.
Chem. Soc. 2003, 125, 5115–5120. (c) Dong, Y.; Teesdale-Spittle, P.;
Hoberg, J. O. Tetrahedron Lett. 2005, 46, 353–355.
(1) (a) Magid, R. M. Tetrahedron 1980, 36, 1901–1930. (b) Trost, B. M.;
Van Vraken, D. L. Chem. ReV. 1996, 96, 395–442. (c) Pfaltz, A.; Lautens,
M. ComprehensiVe Asymmetric Catal. 1999, 2, 833–884. (d) Trost, B. M.;
Crawley, M. L. Chem. ReV. 2003, 103, 2921–2943. (e) Kar, A.; Argade,
N. P. Synthesis 2005, 18, 2995–3002. (f) Helmchen, G. Asymmetric Synth.
2007, 95, 95–99.
(4) (a) Lipowsky, G.; Helmchen, G. Chem. Commun. 2004, 116–117.
(b) Lipowsky, G.; Miller, N.; Helmchen, G. Angew. Chem., Int. Ed. 2004,
43, 4595–4597. (c) Zheng, W. H.; Sun, N.; Hou, X.-L. Org. Lett. 2005, 7,
5151–5154. (d) Trost, B. M.; Fandrick, D. R.; Brodmann, T.; Stiles, D. T.
Angew. Chem., Int. Ed. 2007, 46, 6123–6125.
(2) (a) Magriotis, P. A. Angew. Chem., Int. Ed. 2001, 40, 4377–4379.
(b) Hultzsch, K. C. AdV. Synth. Cat. 2005, 347, 367–391. (c) Xu, L.-W.;
Xia, C. G. Eur. J. Org. Chem. 2005, 633–639. (d) Watson, I. D. G.; Yu,
L.; Yudin, A. K. Acc. Chem. Res. 2006, 39, 194–206. (e) Beccalli, E. M.;
Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. ReV. 2007, 107, 5318–
5365.
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Kasai, N.; Murai, S.; Ikeda, I. J. Am. Chem. Soc. 1992, 114, 8417–8424.
(b) Saitoh, A.; Misawa, M.; Morimoto, T. Tetrahedron: Asymmetry 1999,
10, 1025–1028. (c) Bouquillon, S.; Muzart, J. Eur. J. Org. Chem. 2001,
3301–3305.
10.1021/ol8006919 CCC: $40.75
Published on Web 05/17/2008
2008 American Chemical Society

and excellent enantioselective allylic alkylation has been
performed by Trost using the (S,S)-Ln ligand.7 To the best
of our knowledge, less effort has been devoted to substrates
bearing substituents on the CR, Cꢀ, and Cγ position of the
allylic system.8 In pursuing our work on the allylic amina-
tion,9 we report herein our preliminary results on the solvent-
dependent regiocontrol in amination reaction10 of racemic
or enantiomerically pure acetate 1a and carbonates 2a-c
(Figure 1). The reaction, carried out in the absence of catalyst
or pathway B (Scheme 1). The regioselective nucleophilic
Scheme 1. Pathways A and B
displacement may afford the dehydro-ꢀ-amino esters 3a-c
and 4a-c, respectively.
In our initial experiments, (()-1a and benzylamine were
refluxed in CH2Cl2, affording (()-3a in 65% yield although
in a very long reaction time (Table 1, entry 1). On changing
Figure 1. Starting materials for amination reactions.
Table 1. Uncatalyzed Amination of 1a and 2a-c
and under palladium-catalyzed conditions, led to dehydro-
ꢀ-amino esters 3 and 4,11 which are interesting precursors
of unsaturated ꢀ-amino acids12 and R-alkylidene-ꢀ-lactams.13
The optically active amino acetate 1a was synthesized by
kinetic enzymatic resolution of the corresponding alcohol
catalyzed by Pseudomonas Cepacia Lipase.14 Carbonates
2a-c have been obtained from the corresponding (S)-
alcohols by treatment with LiHMDS and methyl chlorofor-
mate in dry THF.
solventa
time (h)
3b c/4
,
entry
substrate
The amination reactions were carried out with benzylamine
as nucleophile in different solvents, following pathway A
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(()-1a
(()-1a
(R)-1a
(R)-1a
(()-2a
(()-2a
(S)-2a
(S)-2a
(()-2b
(()-2b
(S)-2b
(()-2c
(()-2c
(S)-2c
CH2Cl2
THF
THF
CH3CN
THF
CH3CN
THF
CH3CN
THF
CH3CN
THF
THF
CH3CN
THF
96
42
42
50
24
40
24
40
24
40
24
24
40
24
>99/1
>99/1
>99/1
90/10
>99/1
>99/1
>99/1
>99/1
>99/1
95/5
(6) (a) Rajesh, S.; Banerij, B.; Iqbal, J. J. Org. Chem. 2002, 67, 7852–
7857. (b) Watson, I. G.; Yudin, A. K. J. Am. Chem. Soc. 2005, 127, 17516–
17529.
(7) (a) Trost, B. M.; Fandrick, D. R. Aldrichimica Acta 2007, 40, 59–
72. (b) Trost, B. M.; Brennan, M. K. Org. Lett. 2007, 9, 3961–3964.
(8) Nemoto, T.; Fukuyama, T.; Yamamoto, E.; Tamura, S.; Fukuda, T.;
Matsumoto, T.; Akimoto, Y.; Hamada, Y. Org. Lett. 2007, 9, 927–930.
(9) (a) Cardillo, G.; Fabbroni, S.; Gentilucci, L.; Perciaccante, R.;
Tolomelli, A. AdV. Synth. Cat. 2005, 6, 833–838. (b) Cardillo, G.; Fabbroni,
S.; Gentilucci, L.; Perciaccante, R.; Piccinelli, F.; Tolomelli, A. Org. Lett.
2005, 4, 533–536.
>99/1
>99/1
88/12
>99/1d
(10) Ricci, A. Modern Amination Methods; Wiley-VCH: Weinheim,
Germany, 2000.
(11) (a) Wasek, T.; Olczak, J.; Janecki, T. Synlett 2006, 10, 1507–1510,
and references cited therein. (b) Perlmutter, P.; Tabone, M. J. Org. Chem.
1995, 60, 6515–6522.
a Reactions were carried out in refluxing solvent. b Regioisomeric ratio
was determined by 1H NMR. Configuration of the double bond in 3 4/1
Z/E. c Yield of compounds purified by flash chromatography on silica gel
>90% (65% only for entry 1). d A 12% racemization of the benzylic position
was observed by HPLC on chiral column.
(12) (a) Cardillo, G.; Tomasini, C. Chem. Soc. ReV. 1996, 25, 117–128.
(b) Abdel-Magid, A. F.; Cohen, J. H.; Maryanoff, C. A. Curr. Med. Chem.
1999, 6, 955–969. (c) Juaristi, E., Ed. EnantioselectiVe Synthesis of b-amino
acids, 2nd ed.; Wiley-VCH: New York, 2005.
(13) (a) Alcaide, B.; Plumet, J.; Rodriguez-Lopez, J.; Sanchez-Cantalejo,
Y. M. Tetrahedron Lett. 1990, 31, 2493–2496. (b) Buchholz, R.; Hoffmann,
H.; Martin, R. HelV. Chim. Acta 1991, 74, 1213–1220. (c) Toyofuku, M.;
Fujiwara, S.-I.; Shin-ike, T.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc.
2005, 127, 9706–9707. (d) Benfatti, F.; Cardillo, G.; Fabbroni, S.; Gentilucci,
L.; Perciaccante, R.; Tolomelli, A. ArkiVoc 2005, VI, 136–152.
(14) Benfatti, F.; Cardillo, G.; Gentilucci, L.; Mosconi, E.; Tolomelli,
A. Tetrahedron: Asymmetry 2007, 2227–2232.
the solvent to THF, faster quantitative conversion to (()-3a
was observed (entry 2).
Following the same protocol on enantiomerically enriched
(R)-1a, optically active 3a was obtained as exclusive
2426
Org. Lett., Vol. 10, No. 12, 2008

regioisomer in THF, whereas a 90/10 regioisomeric mixture
of 3a/4a was observed carrying out the reaction in acetonitrile
(entries 3-4). Complete conversion of the starting material
to 3a in reduced reaction time was observed in both solvents
starting from the carbonate 2a (entries 5-6).
On repeating the reaction on (S)-2a, the chirality of the
starting carbonate was completely transferred to the dehy-
droamino ester 3a (99% ee determined by chiral HPLC on
the pure isolated Z-3a, entries 7,8). Similar results have been
obtained for compounds 2b and 2c (entries 9-13), although
(S)-2c afforded enriched 3c with a partial racemization of
the benzylic position (entry 14).
The regiochemistry of the products accounts for a nucleo-
philic displacement occurring via SN2′ mechanism. Because
a syn attack is to be predicted for neutral nucleophiles,15
starting from (R)-acetate 1a, the (S) configuration was
attributed to the dehydro-ꢀ-amino ester 3a, whereas from
(S)-carbonates 2a-c, the (R) configuration was assigned to
products 3a-c.
amination was performed in the presence of PPh3.17
A
significant increase of regioselectivity was observed for the
reaction carried out in CH3CN, where 4a was formed as the
exclusive regioisomer (entry 5).
Because both the oxidative addition leading to palladium
complex and the nucleophilic attack normally occur stereo-
selectively with inversion of configuration at the reacting
allylic carbon atom, the overall process proceeds with
retention of configuration.18 Therefore, starting from (S)-
2a, the (R) configuration was assigned to 3a, also confirmed
by the observed optical rotation, and the (S) configuration
was assigned to 4a. Thus, starting from (S)-2a carbonate,
selected conditions gave access to the two different optically
active dehydroamino esters (R)-3a or (S)-4a through a solvent
dependent regioselective control.
On the basis of these results, 2b and 2c were reacted in
CH3CN (Table 3, entries 1 and 2) giving 4b and 4c in
With these results in hand, we treated racemic or (S)-2a
allylic carbonate16 with benzylamine in the presence of
Pd2(dba)3CHCl3 catalyst, either in THF or CH3CN. Selected
results are reported in Table 2.
Table 3. Pd-Catalyzed Amination of 2b-c in CH3CN
Table 2. Solvent Effect in Pd-Catalyzed Amination of 2a
entry
substrate
solventa
CH3CN
CH3CN
CH3CN+ PPh3
CH3CN+ PPh3
3/4b c (%)
,
1
2
3
4
(S)-2b
(S)-2c
(()-2b
(()-2c
15/85d
11/89d
5/95
5/95
a Reactions were carried out in refluxing solvent (solution 0.1 M of 2).
b Regioisomeric ratio was determined by 1H NMR. Configuration of the
double bond in 3 4/1 Z/E. c Yield of compounds purified by flash
chromatography on silica gel >90%. d 90% ee from HPLC on chiral column,
starting from (S)-2 having 90% ee.
,
entry
substrate
solventa
THF
CH3CN
THF
CH3CN
CH3CN + PPh3
3a/4ab c (%)
1
2
3
4
5
(()-2a
(()-2a
(S)-2a
(S)-2a
(S)-2a
93/7
20/80
90/10d
20/80d
99/1d
a Reactions were carried out in refluxing solvent (solution 0.1 M of 2).
b Regioisomeric ratio was determined by 1H NMR. Configuration of the
double bond in 3a 4/1 Z/E. c Yield of compounds purified by flash
chromatography on silica gel >90%. d A 90% ee from HPLC on chiral
column, starting from (S)-2a having 90% ee.
satisfactory regioselectivity (>85/15), which was strongly
improved when PPh3 was added to the reaction mixture, in
agreement with the above-reported results on the isopropyl
derivative (entries 3 and 4). The dehydro-ꢀ-amino esters were
then converted to (4S)-R-alkylidene-ꢀ-lactams to obtain
compounds of interest in our research group.19 To this
purpose, (S)-4a-b were easily quantitatively transformed
into the corresponding (Z)-ꢀ-lactam (S)-5a-b by treatment
with LiHMDS in anhydrous THF at -20 °C (Scheme 2).
The Z configuration of the double bond was attributed on
the basis of vinyl proton 1H NMR chemical shift (5.33-5.36
ppm)12b,20 and confirmed by NOE experiments.
The data reported show that the reaction carried out in
THF at reflux gave compound 3a in 93/7 regioisomeric ratio
(entry 1).
When (S)-2a was used as starting material, the chirality
was completely retained, affording 3a with the same enan-
tiomeric excess of the starting carbonate (entry 3). Complete
inversion of the regiochemistry occurred in CH3CN at reflux,
4a/3a being obtained in 80/20 regioisomeric ratio (entries 2
and 4). Similarly to that observed in THF, the reaction
performed in CH3CN on (S)-2a gave 4a in 90% ee (entry
4). To enhance the regioselectivity of the reaction, the
Finally, a preliminary study on the enantioselective variant
of this methodology by reaction of (()-2a with benzylamine
was performed using different chiral ligands and solvents.
In the presence of 5% amount of Pd and 8% amount of
(17) Amatore, C.; Jutand, A.; Meyer, G.; Mottier, L. Chem.-Eur. J.
1999, 5, 466–473.
(15) Fukui, K. Theory of Orientation and Stereoselection; Springler-
Verlag: Berlin, 1975; pp 58-76.
(16) Arcadi, A.; Bernocchi, E.; Cacchi, S.; Caglioti, L.; Marinelli, F.
Gazz. Chim. Ital. 1991, 121, 369–371.
(18) Moreno-Manas, M.; Morral, L.; Pleixats, R. J. Org. Chem. 1998,
63, 6160–6166.
(19) Benfatti, F.; Cardillo, G.; Gentilucci, L.; Tolomelli, A. Bioorg. Med.
Chem. Lett. 2007, 1946–1950.
Org. Lett., Vol. 10, No. 12, 2008
2427

Scheme 2
.
Synthesis of Alkylidene-ꢀ-lactams 5a-b
Scheme 3. Asymmetric Allylic Amination
enantiopure (R,R)-DACH-Phenyl Trost ligand, a strong effect
on the regioselectivity was observed. Compound 4a was
obtained as exclusive product in CH2Cl2, whereas it was
isolated in 80/20 regioisomeric ratio when the reaction was
performed in THF. In both cases, only a moderate 40% ee
was observed. Otherwise, decreasing the amount of Pd/ligand
(2%/6%) in THF, 4a was isolated in 30/70 regioisomeric
ratio and 61% ee, whereas the major isomer 3a was obtained
in racemic form through uncatalyzed SN2′ reaction (Scheme
3).
by Trost as excellent Pd-ligand in allylic carbonate
alkylation,7b (()-3a was exclusively isolated, whereas using
8% of (R)-BINAP, 89/11 ratio of (()-3a/4a was observed.
(S)-4a was obtained as predominant enantiomer in 20% ee.
These results suggest that the dynamic kinetic asymmetric
transformation (DYKAT)7a of 2 involves a complex sequence
of events that deserve further investigation.
Acknowledgment. We thank MIUR (PRIN 2006 prot.n.
2006030449_003), CNR-ISOF, and University of Bologna
(Strategic project ID 450) for financial support. Mr. Andrea
Garelli is gratefully acknowledged for the LC-ESI-MS
analysis
The (R) absolute configuration of the predominant enan-
tiomer of 4a was determined by comparison of the HPLC
retention times on chiral column and optical rotation values
[(R)-4a [R]D ) +4, 61% ee] with (S)-4a ([R]D ) -7, 87%
ee). The attribution was further confirmed by the comparison
of HPLC of the corresponding ꢀ-lactams (S)-5a and (R)-5a.
Carrying out the amination of (()-2a in THF in the
presence of (S,S)-DACH-Naphtyl ligand, recently reported
Supporting Information Available: Complete charac-
terizations and selected spectra for 2a-c, 3a-c, 4a-c, 5a-b.
HPLC spectra for (S)-5a and (R)-5a. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) (a) Otto, H. H.; Bergmann, H. J.; Mayrhofer, R. Arch. Pharm. 1986,
319, 203–216. (b) Anklam, S.; Liebscher, J. Tetrahedron 1998, 54, 6369–
6384.
OL8006919
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Org. Lett., Vol. 10, No. 12, 2008