Copper reagents: A new and efficient solution for the selective addition of metallated propargylic amines to aldehydes

Article abstract of DOI:10.1021/ol034893m

(Matrix presented) Anti α-amino-homopropargylic alcohols are prepared by addition of metallated propargylic amines to aldehydes. Among the four organometallic (Ll, Zn, Ti, Cu) derivatives used, the most effective are the copper reagents.

Full text of DOI:10.1021/ol034893m

ORGANIC
LETTERS
2003
Vol. 5, No. 14
2567-2569
Copper Reagents: A New and Efficient
Solution for the Selective Addition of
Metallated Propargylic Amines to
Aldehydes
Frederic Bernaud, Emmanuel Vrancken, and Pierre Mangeney*
UMR 7611-Laboratoire de Chimie Organique, UniVersite´ Pierre et Marie Curie,
4 Place Jussieu, F-75252, Paris, Cedex 05, France
mangeney@moka.ccr.jussieu.fr
Received May 21, 2003
ABSTRACT
Anti r-amino-homopropargylic alcohols are prepared by addition of metallated propargylic amines to aldehydes. Among the four organometallic
(LI, Zn, Ti, Cu) derivatives used, the most effective are the copper reagents.
The addition of alkoxy-subsituted allenylmetal reagents to
aldehydes is widely used for the preparation of anti-R-alkoxy
homopropargylic alcohols.1 Surprisingly, the same reaction,
using aza-substituted allenylmetal reagents, to give R-amino-
homopropargylic alcohols, an interesting class of compounds
considering their potential in synthesis,2 is almost omitted.
Indeed, to the best of our knowledge, there are only two
reports, by Epsztein, on the synthesis of such amino alcohols
by addition of metallated propargylamines amino alcohols
where the anti stereomers were the major products. Unfor-
tunately, no precise anti/syn ratio was given. Therefore, we
decided to reexamine the scope and the generality of this
reaction (Scheme 1). The starting propargylic amine 1 was
prepared according to Scheme 2.3 In our hand, use of n-BuLi
or LDA was found to be ineffective, in THF, in promoting
deprotonation on the propargylic position. This was quan-
titatively achieved using sec-Buli in THF, as shown by a
deuteriolysis experiment that gave a mixture of deuterated
propargylic and allenic amines 2 and 3 (2/3 ) 65/35) in
quantitative yield (Scheme 2). The stereochemistry of the
addition of the lithium derivative to aldehydes (Scheme 3)
was then studied. The results obtained are shown in Table 1
(entries 1-7). The first point to note is that, in any case
(even after transmetallation), no allenic derivatives were
obtained, the only observed compounds being the propargylic
amino alcohols 5a-g. The configuration of anti-5a was
1
determined by X-ray analysis4 and by H NMR (NOE) of
Scheme 1
* Corresponding author. Phone: 01 44 27 55 68. Fax: 01 44 27 75 67.
(1) Scheidt, K. A.; Bannister, T. D.; Tasaka, A.; Wendt, M. D.; Savall,
B. D.; Fegley, G. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 6981-
6990 and references therein. For addition to imines see: Poisson, J. F.;
Normant, J. F. Org. Lett. 2001, 3, 1889-1891.
(2) Fleming, J. J.; Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc. 2003,
125, 2028-2029.
(3) Ireland, R. E.; Anderson, R. C.; Badoud, R.; Fitzsimmons, B. J.;
McGarvey, G. J.; Thaisrivongs, S.; Wilcox, C. S. J. Am. Chem. Soc. 1983,
105, 1988.
10.1021/ol034893m CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/17/2003

Scheme 2a
Table 1. Additions of Metallated Derivatives to Aldehydes
entry
M
R
product anti/ syna yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Li
t-Bu
5a
5b
5c
5d
5e
5f
5g
5a
5b
5c
5d
5d
5e
5f
5g
5d
5d
5b
5c
5e
5f
67/33
65/35
62/38
65/35
50/50
63/37
75/25
>95/5
>95/5
85/15
90/10
93/7
68/32
88/12
76/24d
50/50
>95/5
>95/5
>95/5
95/5
73
78
82
84
82
79
65
81
81
81
86
88
79
83
85
85
86
81
82
79
83
74
c-hexyl
n-hexyl
i-Pr
Ph
propenyl
hexynyl
t-Bu
c-hexyl
n-hexyl
i-Prc
i-Pr
Ph
propenyl
heptynyl
ZnBr
Ti(OiPr)3 i-Pr
CuCN
i-Pr
a Reactions conditions: (a) propargyl bromide, K2CO3, CH3CN,
purification, and then MeLi, TMSCl, THF, 0 °C. (b) sec-BuLi (1.1
equiv), THF, -80 to -40 °C. (c) D2O. (d) ZnBr2 (1.1 equiv), -80
°C or room temperature. (e) CuCN, 2LiCl (1.4 equiv), -80 °C to
-30 °C. (f) Ti(OiPr)4 (1.1 equiv), -78 °C.
c-hexyl
n-hexyl
Ph
propenyl
heptynyl
95/5
93/7d
5g
a Determined by 1H NMR of the crude product. b Isolated product. c Fast
addition of the aldehyde. d Unseparable mixture.
the corresponding oxazolidinones derived from anti-5b and
anti-5c.5 As shown in the table, with the lithium derivative,
probably via the allenyl zinc reagent 4.7 The addition of this
zinc derivative to aldehydes was found to be more anti
selective than the addition of the lithium derivative (Table,
entries 8-15). This selectivity was sensitive to steric effects,
the best results being obtained with bulky aldehydes (entries
8, 9, and 12). Furthermore, better results were obtained by
a slow addition of the aldehyde (via syringe pump) into the
zinc derivative (compare entries 11 and 12). Such observation
is in favor of a kinetic control for the reaction. It is interesting
to note that deprotonation by sec-BuLi and transmetallation
by ZnBr2 of anti-5b gave the amino alcohol completely
unchanged after several hours of stirring, even at room
temperature. The observed anti stereochemistry is in ac-
cordance with the classical Yamamoto-Chodkiewicz’s cyclic
transition state commonly involved for analoguous reactions
where the formation of the anti-amino alcohol is favored by
steric interactions (Scheme 4). 8 Nevertheless, poor selectivi-
ties were obtained with benzaldehyde, crotonaldehyde, and
octynal (entries 13-15), and we decided to explore the
possiblity of using the titanium derivative,9 which was
obtained by transmetallation of the lithium derivative by
titanium tetraisopropoxyde. Unfortunately, and curiously, the
addition of this titanium reagent to isobutyraldehyde was
totally unselective (entry 16).
Scheme 3
the anti-amino alcohols were isolated in good yields but with
poor (or no) selectivity. A transmetallation of the lithiated
intermediate by ZnBr2 afforded the zinc derivative, which
was quantitatively deuterated into the propargylamine 2,
6
(7) Structure of these organometallic reagents is under study but is
probably allenic: see ref 8.
(8) Epzstein, R. The Formation and Transformations of Allenic and
R-Acetylenic Carbanions. In ComprehensiVe Carbanions Chemistry; Buncel,
E., Durst, T., Eds.; Elsevier: Amsterdam, 1984; Vol. B, pp 107-175.
Yamamoto, H. Propargyl and Allenyl Organometallics. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: London,
1991; Vol. 2, pp 81-98.
(4) Crystallographic data for the structural analysis have been deposited
with the crystallographic Data Center as deposition no. CCDC209061.
(5) Barret, A. G. M.; Seefeld, M. A.; White, J. P. J. Org. Chem 1996,
61, 2677-2685. Bergmeier, S. C.; Stanchina, D. M. Tetrahedron Lett. 1995,
36, 4533-4536.
(6) We have checked that the nature of the zinc salt (ZnI2 or ZnBr2) did
not affect the selectivity.
(9) Anies, C.; Lallemand, J. Y.; Pancrazi, A. Tetrahedron Lett. 1996,
37, 5519-5522 and references therein.
2568
Org. Lett., Vol. 5, No. 14, 2003

22) were obtained with very good stereoselectivity even for
benzaldehyde (entry 20). Noteworthy are the results obtained
with crotonaldehyde and octynal (entries 21 and 22). With
these unsaturated aldehydes, no product resulting from a
conjugate addition was observed11 and again a significant
increase of the selectivity was obtained (compare entries 14
and 15 and entries 21 and 22). In conclusion, we have shown
that the addition of lithium or titanium reagents, derived from
propargylic amines, to aldehydes occurs with poor selectivity.
With the zinc derivative, a significant enhancement of the
anti selectivity, leading to good results, is obtained except
with benzaldehyde, crotonaldehyde, and octynal. With the
copper derivative, which is obviously a reagent of choice
for such reactions, the anti-amino alcohols are obtained with
good selectivity, regardless of the nature of the aldehyde.
We are currently studying the structure (allenyl-propargyl)
of these organometallic reagents, their configurational stabil-
ity, and the possible extension to the proparglic ether
analogues.
Scheme 4
We then turned our attention to copper derivatives for
which preparation was never reported.10 This new copper
derivative was prepared by transmetallation of the lithium
derivative with CuCN, 2LiCl. Deuteriolysis afforded exclu-
sively, and quantitatively, the propargylamine 2 (Scheme 2).
We were very pleased to observe that the addition to
aldehydes occurred cleanly, without the formation of any
allenic derivatives. The anti-amino alcohols (entries 17-
Acknowledgment. We thank Carine Duhayon for the
crystal structure determination and Prof. Fabrice Chemla and
Prof. Jean Normant for many interesting discussions.
(10) For the use of propargyl-allenyl copper reagents, see: Lam, H. W.;
Pattenden, G Angew. Chem., Int. Ed. 2002, 41, 508-511. Rozema, M. J.;
Knochel, P. Tetrahedron Lett. 1991, 32, 1855-1858. Bednarski, P. J.;
Nelson, S. D. J. Med. Chem. 1989, 32, 203-213. de Graaf, W.; Boersma,
J.; van Koten, G. J. Organomet. Chem. 1989, 378, 115-124. Ruitenberg,
K.; Vermeer, P. J. Organomet. Chem. 1983, 256, 175-180. Ruitenberg,
K.; Kleijn, H.; Meijer, J.; Oostveen, E. A.; Vermeer, P. J. Organomet. Chem.
1982, 224, 399-405. Michelot, D.; Linstrumelle, G. Tetrahedron Lett. 1976,
275-276. Commerc¸on, A.; Normant, J.; Villieras, J. J. Organomet. Chem.
1975, 93, 415-421. Ganem, B. Tetrahedron Lett. 1974, 4467-4470.
Supporting Information Available: Spectral and ana-
lytical data and experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL034893M
(11) With heptynal, a small amount (10%) of an undetermined product
was obtained.
Org. Lett., Vol. 5, No. 14, 2003
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