Enantioselective, Copper(I)-Catalyzed Three-Component Reaction for the Preparation of Propargylamines

Article abstract of DOI:10.1002/anie.200352578

The one-pot reaction of alkynes, aldehydes, and secondary amines in the presence of CuBr/quinap as the catalytic system provides various enantiomerically enriched propargylamines in good yields (up to 99%) and good selectivities (up to 96% ee) [Eq. (1)].

Full text of DOI:10.1002/anie.200352578

Angewandte
Chemie
C–H Activation
Enantioselective, Copper(i)-Catalyzed Three-
Component Reaction for the Preparation of
Propargylamines**
Nina Gommermann, Christopher Koradin,
Kurt Polborn, and Paul Knochel*
The catalytic enantioselective formation of new CÀC bonds is
[
1]
an important class of reactions. Especially attractive are
multicomponent reactions which allow the formation of
several bonds including new CÀC bonds in a one-pot
[
2]
[3]
procedure. For achieving optimum atom economy and
avoiding the production of stoichiometric amounts of metal
[
4]
[5]
salts as by-products, we and others have examined the use
of an alkyne as the precursor for the nucleophilic reaction
component. Alkynes of type 1 can be deprotonated catalyti-
cally in situ by means of cesium salts and reacted subsequently
[
6]
with aldehydes and ketones, leading to propargyl alcohols.
Recently, we have shown that various enamines react with
terminal alkynes in the presence of copper(i) salts and quinap
[
7]
[4]
(
2), providing propargylamines in up to 90% ee.
In order to avoid the generation of sensitive enamines and
to extend the scope of this propargylamine synthesis to
nonenolizable aldehydes (i.e. aldehydes from which enamines
cannot be prepared), we have examined a new three-
[
8]
component reaction between an alkyne 1, an aldehyde 3,
and a secondary amine 4. We have found that propargyl-
amines of type 5 are formed in toluene at room temperature
in the presence of CuBr (5 mol%), (R)-quinap ((R)-2)
(
(
5.5 mol%), and molecular sieves 4 Š in excellent yields
up to 99%) and good enantioselectivities (up to 96% ee;
Scheme 1 and Table 1).
The reaction is usually complete within 12 to 48 h for the
racemic reaction without ligand and within one to six days for
the enantioselective reaction with high yields in most cases.
1
The alkyne can bear either an aryl substituent (R = Ph) or an
1
alkyl substituent (R = Bu; entries 1 and 2 in Table 1). The
resulting propargylamines 5a and 5b were obtained in 98 and
8
5% yield and 86 and 82% ee, respectively. Branched
aliphatic aldehydes like isobutyraldehyde lead to the
expected propargylamines 5c and 5d in 60 and 99% yield
and 84 and 83% ee, respectively (entries 3and 4). The use of
[*] Prof. Dr. P. Knochel, Dipl.-Chem. N. Gommermann, Dr. C. Koradin,
Dr. K. Polborn
Department Chemie
Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
[
**] We thank Chemetall GmbH (Frankfurt), Degussa (Frankfurt), and
BASF AG (Ludwigshafen) for generous gifts of chemicals. N.G.
thanks the DFG for a fellowship in the context of SPP 1118
“Sekundäre Wechselwirkungen als Steuerungsprinzip zur gerich-
teten Funktionalisierung reaktionsträger Substrate”.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 5763 –5766
DOI: 10.1002/anie.200352578
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5763

Communications
trimethylsilylacetylene leads to a further increase of enantio-
selectivity with these branched aldehydes, affording the
propargylamines 5e–g in 72–99% yield and 92–96% ee.
Aromatic aldehydes can also be used. The presence of
either an electron-donating or an electron-withdrawing sub-
stituent in para position has only a moderate influence on the
enantioselectivity of the reaction (entries 8–10). However, the
yield of the product 5j (R = CF ) is strongly reduced (43%)
3
Scheme 1. Enantioselective three-component reaction for the synthesis
of proparylamines. RT=room temperature.
compared to that of 5i (R = OMe; 76%) due to a dramatic
decrease in reactivity. Steric effects are more important and
the presence of an ortho substituent in the aldehyde (2-
methylbenzaldehyde) leads to a dramatic decrease of the
selectivity (5k: 84%, 3 2%ee; cf. entries 8 and 11). Hetero-
cyclic aldehydes like 3-formylbenzothio-
phene and 3-furfural are also compatible
Table 1: Enantioselective, copper(i)-catalyzed three-component synthesis of propargylamines 5.
and allow the preparation of the corre-
sponding propargylic products 5l and 5n in
yields of 80% (78% ee) and 55% (64% ee),
respectively.
1
2
3
[a]
[b]
Entry
R
R
R
5
Yield [%]
Sel. [% ee]
Remarkably, this reaction is highly dia-
stereoselective if a chiral amine or aldehyde
is used. Thus, the reaction of the prolinol
derivative 6 with aromatic or aliphatic
aldehydes and phenylacetylene produces
the desired propargylamines 7a and 7b in
yields of 87 and 97% and good diastereo-
1
2
Ph
nBu
iBu
iBu
Bn
Bn
5a: R=Ph
5b: R=nBu
98
85
86
82
3
4
5
Ph
p-BrC H4
SiMe3
iPr
iPr
iPr
Bn
Bn
Bn
5c: R=Ph
5d: R=p-BrC H4
5e: R=SiMe3
60
99
87
84
83
92
[9]
6
6
selectivities of 96:4 and 93:7, respectively.
[
[
c]
c]
By using the racemic aldehyde 8, the
corresponding propargylamine 9 can also
be obtained in good diastereoselectivity
6
7
SiMe3
c-Hex
Bn
Bn
99
72
92
(92:8) (Scheme 2). The relative configura-
tion of 9 has been determined by X-ray
[
10]
structure analysis.
Preliminary mechanistic investigations
Eq. (1)] show that the enantioselective
[
c]
SiMe3
1-ethylpropyl
96
[
reaction displays a strong positive nonlinear
effect (Figure 1). This suggests that
a
dimeric Cu/quinap complex is the catalyti-
cally active species and is in good agreement
with the previously reported crystal struc-
ture of the [CuBr{(R)-quinap}] complex.
2
The heterochiral complex [Cu Br {(R)/(S)-
2 2
8
9
1
Ph
Ph
Ph
Ph
allyl
allyl
allyl
5h: R=H
5i: R=OMe
91
76
43
70
60
63
[
11]
p-MeO-C H4
p-CF -C H
6
0
1
5j: R=CF3
3
6
4
quinap}] seems to react at a much slower
rate than the corresponding homochiral
complex [Cu Br {(R)/(R)-quinap}]. This
1
Ph
o-CH -C H
4
allyl
84
32
3
6
2
2
explains the strong positive amplification.
Thus, a ligand having an enantiomeric
excess of 10% leads to the formation of
the propargylamine 5 g in 68% ee. A lower
conversion rate and product yield is
observed when the ligand has lower ee.
1
1
2
3
Ph
c-Hex
allyl
allyl
5l: R=Ph
5m: R=c-Hex
80
61
78
74
A
tentative reaction mechanism is
[
11]
described in Scheme 3. The dimeric
chiral copper complex 10 complexes the
alkyne 1, leading to the side-on complex 11.
The complexation of 11 with the intermedi-
ate aminal 12 (obtained by the reaction of
the amine 4 with the aldehyde 3) provides
the complex 13. Deprotonation of the
[
d]
1
4
Ph
allyl
55
64
[
a] Yield of analytically pure product. [b] Enantiomeric excess determined by HPLC with a Chiracel OD-H
column (n-heptane:iPrOH). [c] The ee value was determined after desilylation. [d] The ee value was
determined after deprotection to give the monodeallylated derivative.
5
764
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Angew. Chem. Int. Ed. 2003, 42, 5763 –5766

Angewandte
Chemie
coordinated alkyne and the elimination of H O gives complex
2
1
4, an end-on copper acetylide with a coordinated iminium
ion. The addition of the acetylide to the iminium salt in the
coordination sphere of the chiral copper(i) complex leads to
the chiral propargylamine 5 and regenerates the catalyst 10.
In summary, we have shown that a wide range of chiral
propargylamines can be prepared in a one-pot three-compo-
nent reaction in good yield and good enantioselectivity.
Further applications in natural-product synthesis and mech-
anistic studies of this reaction are currently underway in our
laboratories.
Scheme 2. Diastereoselective three-component reactions.
Experimental Section
(
À)-5a: A dry and argon-flushed 10-mL flask equipped with a
magnetic stirrer and a septum was charged with copper(i) bromide
3.6 mg, 0.0250 mmol) and (R)-quinap (12.1 mg, 0.0275 mmol).
(
Anhydrous toluene (2 mL) was added, the mixture was stirred at
room temperature for 30 min. Molecular sieves (4 Š, 0.3 g) and n-
decane (30 mg, as internal standard) were added, followed by
phenylacteylene (51 mg, 0.5 mmol), 3-methylbutanal (43 mg,
0.5 mmol), and dibenzylamine (99 mg, 0.5 mmol). The reaction
mixture was stirred for 70 h at room temperature. The molecular
sieves were removed by filtration and washed with diethyl ether. The
crude product was concentrated in vacuo and purified by chromatog-
raphy on silica gel (pentane:diethyl ether= 98:2) yielding the
propargylamine ((À)-5a) as a colorless oil (180 mg, 98%, 86% ee).
Received: August 6, 2003[Z52578]
Published Online: November 11, 2003
Keywords: alkynes · asymmetric catalysis · CÀH activation ·
.
multicomponent reactions · propargylamines
Figure 1. Nonlinear effects in the three-component reaction leading to
[1] a) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley,
Weinheim, 1994; b) G. Helmchen, R. W. Hoffmann, J. Mulzer, E.
Schaumann, Houben-Weyl: Stereoselective Synthesis, Thieme,
Stuttgart 1996; c) E. N. Jacobsen, A. Pfaltz, H. Yamamoto,
Comprehensive Asymmetric Catalysis, Springer, Berlin 1999;
d) R. A. Aitken, S. N. KilØnyi, Asymmetric Synthesis,
Blackie A&P, London, 1992.
5
g [Eq. (1)]. %ee : enatiomeric excess of the ligand, %ee5g: enantio-
l
meric excess of the product.
[
2] For recently described three-component reactions, see:
a) S. Kamijo, Y. Yamamoto, J. Am. Chem. Soc. 2002, 124,
11940; S. Kamijo, T. Jin, Y. Yamamoto, J. Am. Chem.
Soc. 2001, 123, 9453; b) F. Bertozzi, M. Gustafsson, R.
Olsson, Org. Lett. 2002, 4, 4333; c) G. W. Kabalka, Z. Wu,
Y. Ju, Org. Lett. 2002, 4, 3415; d) T.-P. Loh, S.-L. Chen,
Org. Lett. 2002, 4, 3647; e) A. Dömling, I. Ugi, Angew.
Chem. 2000, 112, 3300; Angew. Chem. Int. Ed. 2000, 39,
3168; f) B. List, P. Pojarliev, W. T. Biller, H. J. Martin, J.
Am. Chem. Soc. 2002, 124, 827; g) U. Bora, A. Saikia,
R. C. Boruah, Org. Lett. 2003, 5, 435; h) R. Dhawan,
R. D. Dghaym, B. A. Arndtsen, J. Am. Chem. Soc. 2003,
125, 1474; i) C. Cao, Y. Shi, A. L. Odom, J. Am. Chem.
Soc. 2003, 125, 2880; j) S. J. Patel, T. F. Jamison, Angew.
Chem. 2003, 115, 1402, Angew. Chem. Int. Ed. 2003, 42,
1364; k) J. R. Porter, J. F. Traverse, A. H. Hoveyda, M. L.
Snapper, J. Am. Chem. Soc. 2001, 123, 10409.
[
3] a) B. M. Trost, Angew. Chem. 1995, 107, 285; Angew.
Chem. Int. Ed. Engl. 1995, 34, 259; b) B. M. Trost, Science
1991, 254, 1471.
[
4] a) C. Koradin, K. Polborn, P. Knochel, Angew. Chem.
2002, 114, 2651; Angew. Chem. Int. Ed. 2002, 41, 2535;
Scheme 3. Tentative mechanism of the three-component reaction.
Angew. Chem. Int. Ed. 2003, 42, 5763 –5766
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ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5765

Communications
b) C. Koradin, N. Gommermann, K. Polborn, P. Knochel, Chem.
Eur. J. 2003, 9, 2797.
[
5] a) C. M. Wei, C. J. Li, J. Am. Chem. Soc. 2002, 124, 5638; b) N. K.
Anand, E. M. Carreira, J. Am. Chem. Soc. 2001, 123, 9687; c) E.
El-Sayed, N. K. Anand, E. M. Carreira, Org. Lett. 2001, 3, 3017;
d) D. E. Frantz, R. Faessler, C. S. Tomooka, E. M. Carreira, Acc.
Chem. Res. 2000, 33, 373; e) D. E. Frantz, R. Faessler, E. M.
Carreira, J. Am. Chem. Soc. 2000, 122, 1806; f) K. C. Brannock,
R. D. Burpitt, J. G. Thweatt, J. Org. Chem. 1963, 28, 1462; g) J. J.
McNally, M. A. Youngman, S. L. Dax, Tetrahedron Lett. 1998,
39, 967; M. A. Youngman, S. L. Dax, Tetrahedron Lett. 1997, 38,
6347.
[
[
[
6] a) D. Tzalis, P. Knochel, Angew. Chem. 1999, 111, 1547; Angew.
Chem. Int. Ed. 1999, 38, 1463; b) D. Tzalis, C. Koradin, P.
Knochel, Tetrahedron Lett. 1999, 40, 6193.
7] a) J. M. Valk, G. A. Whitlock, T. P. Layzell, J. M. Brown,
Tetrahedron: Asymmetry 1995, 6, 2593; b) E. Fernandez, K.
Maeda, M. W. Hooper, J. M. Brown, Chem. Eur. J. 2000, 6, 1840.
8] a) During the preparation of the manuscript, an analogous
racemic, gold-catalyzed reaction was reported: C. Wei, C.-J. Li, J.
Am. Chem. Soc. 2003, 125, 9584; b) for an analogous racemic,
iridium-catalyzed reaction see: S. Sakaguchi, T. Kubo, Y. Ishii,
Angew. Chem. 2001, 113, 2602; Angew. Chem. Int. Ed. 2001, 40,
2534; c) for solid-phase three-component reactions leading to
racemic propargylamines, see: J. J. McNally, M. A. Youngman,
S. L. Dax, Tetrahedron Lett. 1998, 39, 967; A. B. Dyatkin, R. A.
Rivero, Tetrahedron Lett. 1998, 39, 3647; d) for a microwave-
enhanced heterogeneous three-component reaction, see: G. W.
Kabalka, L. Wang, R. M. Pagni, Synlett 2001, 676.
[
9] The absolute configuration was determined by comparison to a
known compound (see the Supporting Information).
[
[
10] The crystal structure is shown in the Supporting Information.
CCDC 216200 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
11] An X-ray analysis of quinap–CuBr shows that the complex is
dimeric (see ref. [4]).
5
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Angew. Chem. Int. Ed. 2003, 42, 5763 –5766