A convenient procedure for the preparation of α-aminoallenes using a three-component reaction of aldehyde, carbamate and propargylsilane

Article abstract of DOI:10.1016/S0040-4039(02)00056-4

A three-component reaction is described using an aldehyde, a carbamate and trimethylpropargylsilane in the presence of a Lewis acid for the production in moderate to good yield of α-allenyl amines. The reaction is applicable to aromatic or aliphatic aldehydes. The obtained α-aminoallenes are transformed into Δ³-pyrrolidines or amino acids by using the reactivity of the cumulene function.

Full text of DOI:10.1016/S0040-4039(02)00056-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1453–1456
A convenient procedure for the preparation of a-aminoallenes
using a three-component reaction of aldehyde, carbamate and
propargylsilane
Manuella Billet, Ange`le Schoenfelder, Philippe Klotz and Andre´ Mann*
Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR 7081, 74 route du Rhin, BP 24 F-67401 Illkirch, France
Received 9 November 2001; accepted 4 January 2002
Abstract—A three-component reaction is described using an aldehyde, a carbamate and trimethylpropargylsilane in the presence
of a Lewis acid for the production in moderate to good yield of a-allenyl amines. The reaction is applicable to aromatic or
aliphatic aldehydes. The obtained a-aminoallenes are transformed into D3-pyrrolidines or amino acids by using the reactivity of
the cumulene function. © 2002 Elsevier Science Ltd. All rights reserved.
The search for rapid and ‘low tech’ procedures for the
construction of functionalized compounds from com-
mercial sources is a stimulating trend in the daily
practice of organic chemistry.1–3 One way to approach
this objective is to use multi-component reactions, such
as the ones developed in the past by Ugi,4 Passerini,5
Bignelli,6 or recently by Petasis.7 The obvious advan-
tages of these processes are the production of molecular
diversity from cheap reaction partners. As we were
involved in the utilization of silicon reagents for the
preparation of azaheterocycles,8,9 we and others have
made use of a three-component reaction for the prepara-
tion of homoallylamines. Indeed a mixture of an alde-
hyde, an allylsilane and a carbamate in the presence of
a Lewis acid furnished homoallylamines in excellent
yields.10–14 A transient acyliminium ion is supposed to be
the reactive species in this reaction. As both propargyl-
and allylsilanes react via an SE2% process in the presence
of electrophiles, we decided to experiment with the
behavior by using propargylsilane in place of allylsilane
in the above three-component reaction. We speculated
that if, as expected, g-attack would occur on the interme-
diate acyliminium,15 this new three-component mixture
would offer a direct access to a-aminoallenes (Scheme 1).
Allenylamines are not only valuable functionalized inter-
mediates for organic synthesis (see below), but have also
been identified as potent irreversible substrates for pyri-
doxal-phosphate dependent enzymes.16,17 Usually a-
allenylamines are obtained by a tedious elaboration
from the corresponding propargylamine using Crabbe’s
procedure,18–20 but to the best of our knowledge no
general one-step process has been reported. In this letter
we report our preliminary results on a new synthesis
of a-aminoallenes using
a three-component reac-
tion, and their transformation into D3-pyrrolidines
or amino acids. In a first experiment, trimethylpropar-
gylsilane, benzyl carbamate and benzaldehyde (1a) were
NHCBz
SiMe3
R
(see ref .11-14)
(This work)
O
+
NHCBz
R-CHO
NH2-CBz
R
N
H
O
Ph
SiMe3
•
R
1a-6a
1b-6b
acyl-iminium
CBz = CO2CH2Ph
Scheme 1. Three-component reactions with allyl- and propargylsilane.
* Corresponding author. Tel.: +33 (0)3 90 24 42 27; fax: +33 (0)3 90 24 43 10; e-mail: andre.mann@pharma.u-strasbg.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00056-4

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M. Billet et al. / Tetrahedron Letters 43 (2002) 1453–1456
mixed in acetonitrile at 0°C, BF3·OEt2 was added drop-
wise; after 30 min reaction time at 0°C, a TLC control
revealed that all the starting material was consumed.
Indeed a fast reaction took place, the new compound
formed was isolated by column chromatography on
with allylsilane. However, as propargylsilanes are gen-
erally reported to be less reactive as the allylsilanes,23
these results were not obvious at all and constituted
good surprises. In order to check for the generality of
the reaction, several aliphatic or aromatic aldehydes
were submitted to the three-component reaction. We
report our results in Table 1. The reaction proceeds
with either kind of aldehyde (the yields were not opti-
mized). It seems that the reaction gave slightly better
yields with aliphatic rather than aromatic aldehydes
(compare entries 1–2 with 3–6). Anyway, the merits of
this reaction for the preparation of a-aminoallenes are
the following: the aldehyde substrates are commercially
available, benzylcarbamate is a cheap nitrogen equiva-
lent and the reaction conditions are easy to implement.
Our finding is a good example of what a ‘low-tech’
chemical transformation can be. Finally we describe a
very easy way to transform various aldehydes (1a–6a)
to a-aminoallenes (1b–6b).
1
silica gel, and the H (300 MHz) and 13C (50 MHz)
NMR spectra exhibited the characteristic signals for an
allenyl group.21,22 A small amount of the corresponding
propargyl adduct could also be isolated. However, we
found that if the reaction time is shortened to 10 min,
this by-product was not detected. This result which is
not unexpected at all, but has never been observed
constitutes a fast and good yielding process for the
obtention of a-aminoallen. It is noteworthy that no
traces of the corresponding allenyl or propargyl alco-
hols were detected, suggesting that the propargylsilane
reacts faster with the iminium than with the corre-
sponding aldehyde. Fortunately the formation of water
during the initial step of the reaction (iminium step)
does not interfere at all with the subsequent elec-
trophilic substitution step. These two observations have
already been made in the three-component reaction
Next we turn our interest to the transformation of the
allenes (1b–6b). The unique chemistry of the propa-1,2-
Table 1. Results from aldehydes (1a–6a) in the three-component reaction, and their transformation in pyrrolidines
Entry
Aldehyde
amino-allene
pyrrolidine
NHCbz
•
CHO
N
1
2
Cbz
1c (80%)
1b (63%)
1a
NHCbz
CHO
•
N
Cbz
Cl
Cl
Cl
2b (68%)
2c (73%)
2a
NHCbz
•
CHO
3
N
Cbz
3c (79%)
3b (69%)
3a
4a
NHCbz
CHO
•
N
Cbz
4
4b (74%)
4c (79%)
NHCbz
PO(OEt)2
N
•
5
CHO
(EtO)2OP
5b (77%)
Cbz
(EtO)2OP
5a
5c (84%)
NHCbz
•
6
N
Cbz
CHO
6a
6c (69%)
6b (82%)

M. Billet et al. / Tetrahedron Letters 43 (2002) 1453–1456
1455
R
N
Cbz
i
NHCbz
1c-6c
•
R
ii, iii, iv
3d R = PhCH2CH2
1b-6b
NHCbz
CO2Me
R
5d R= (EtO)2OPCH2CH2
Scheme 2. Reagents and conditions: (i) AgBF4, CH2Cl2, rt, 12 h; (ii) O3, CH2Cl2, Me2S; (iii) PCD then (iv) CH2N2.
dienyl system is amenable to a variety of useful struc-
tures. For instance it has been reported that activation
with Lewis acids produces an intramolecular cyclization
of the allene, a hydroamination, which yields the corre-
sponding pyrrolidines.24 When we tried that heterocy-
clization in the presence of AgBF4 in CH3CN on allenes
1b–6b, we obtained with excellent yields the corre-
sponding pyrrolidines 1c–6c.25–28 The synthetic poten-
tialities of these pyrrolidines towards the obtention of
polycondensed azaheterocycles are very large.29
6. Hu, E.; Sidler, D.; Dolling, U. J. Org. Chem. 1998, 63,
3454–3457 and references cited therein.
7. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997,
119, 445–446.
8. Ungureanu, I.; Klotz, P.; Schoenfelder, A.; Mann, A.
Chem. Commun. 2001, 958–959.
9. Ungureanu, I.; Klotz, P.; Schoenfelder, A.; Mann, A.
Tetrahedron Lett. 2001, 42, 6087–6091.
10. Meester, W. J. N.; Rutjes, F. P. J. T.; Hemkens, P. H. H.;
Hiemstra, H. Tetrahedron Lett. 1999, 40, 1601–1604.
11. Veenstra, S. J.; Schmid, P. Tetrahedron Lett. 1997, 38,
997–1000.
12. Panek, J. S.; Jain, N. F. J. Org. Chem. 1994, 59, 2674–
2675.
13. Roux, M.; Santelli, M.; Parrain, J. L. Org. Lett. 2000, 2,
1701–1704.
14. Billet, M.; Klotz, P.; Mann, A. Tetrahedron Lett. 2001,
42, 631–634.
15. Hiemstra, H.; Fortgens, H. P.; Speckamp, W. N. Tetra-
hedron Lett. 1984, 25, 3115–3118.
16. Casara, P.; Jund, K.; Bey, P. Tetrahedron Lett. 1984, 25,
1891–1894.
17. McCarthy, J. R.; Barney, C. L.; Matthews, D. P.; Bargar,
T. M. Tetrahedron Lett. 1987, 28, 2207–2210.
18. Crabbe, P.; Fillion, D.; Andre´, D.; Luche, J. L. Chem.
Commun. 1979, 859–860.
Other chemical transformations of allenes are of inter-
est, for instance the ozonolysis of the cumulene system.
This reaction first reported by Favorskii has been used
by Corey in the synthesis of a-hydroxyaldehydes.28 We
decided to extend this sequence to the synthesis of
amino acids in the following way: allenes 3b and 5b
were submitted to ozonolysis in the usual way and the
aldehydes obtained were directly oxidized to the corre-
sponding acids with PDC (Scheme 2). The crude was
treated by diazomethane to get the fully protected
a-amino acids 3d and 5d. Both compounds were
obtained, in 60–65% yields. Interestingly, compound 5d
is the fully protected ( ) AP5 (2-amino-5-phosphono-
pentanoic acid) a potent ligand for the metabotropic
glutamate receptor.30
19. Schuster, H. E.; Coppola, G. M. Allenes in Organic
Synthesis; Wiley and Sons: New York, 1984.
20. Dieter, R. K.; Nice, L. E. Tetrahedron Lett. 1999, 40,
4293–4296 and references cited therein.
Thus, in this work we have presented a rapid access to
a-aminoallenes in a one-pot procedure making use of a
three-component reaction. The reaction conditions are
mild, easy to perform and applicable to many alde-
hydes. We believe that this improvement in the synthe-
sis of aminoallenes, together with the transformation of
the cumulene function should encourage the utilization
of aminoallenes in organic synthesis.
21. Typical experimental procedure for the preparation of
1b–6b. A mixture of aldehyde (1 equiv.), benzyl carba-
mate (1 equiv.) and trimethyl-propargylsilane (1 equiv.)
was prepared in CH3CN (5 mL) under nitrogen. Then
BF3·OEt2 (1 equiv. as a commercial solution in ether) was
added dropwise at 0°C. The reaction mixture was
quenched 10 min later with NaHCO3 (5 mL of a satu-
rated aqueous solution). The organic material was
extracted with Et2O (2×10 mL), washed with saturated
brine (5 mL) and concentrated in vacuo to a residue that
was purified by chromatography on silica gel eluting with
Hex/Et2O: 1/9.
References
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1
22. Physical data for 3b: Rf=0.53 (Hex/Et2O: 1/9); H NMR
(300 MHz) l=1.85–1.97 (m, 2H), 2.66 (m, 2H), 4.18–4.22
(m, 1H), 4.80 (dd, J=2.7 and 6.6 Hz, 2H), 5.08 (s, 2H),
5.24 (q, J=6.6 Hz, 1H), 6.42 (d, J=7.6 Hz, 1H), 7.19–
7.31 (m, 10H). 13C NMR (75 MHz) l=32.5, 37.3, 49.8,
66.0, 77.0, 93.15, 126.1, 128.1, 128.7, 128.8, 137.9, 142.3,
156.1, 207.8.
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M. Billet et al. / Tetrahedron Letters 43 (2002) 1453–1456
1
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26. Typical procedure for the preparation of pyrrolidines
1c–6c. The aminoallene (1 equiv.) is dissolved in CH2Cl2
and AgBF4 (1 equiv.) is added at once to the mixture;
stirring was continued overnight and then the solvent
evaporated in vacuo. The residue was immediately
purified by chromatography on silica gel eluting with
Hex/Et2O: 1/9.
27. Physical data for 3c: H NMR (300 MHz) l=1.19–1.27
(m, 2H), 1.63–1.79 (m, 2H), 4.03–4.10 (dd, J=6.0 and 6.0
Hz, 2H), 5.01–5.13 (m, 2H), 5.48–5.64 (m, 2H), 5.76–5.79
(d, J=7.9 Hz, 2H), 7.32–7.39 (m, 10H). 13C NMR (50
MHz) l=32.1, 35.3, 48.6, 58.2, 69.9, 125.2, 126.3, 127.4,
128.3, 128.4, 128.7, 129.5, 137.3, 141.0, 156.0.
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