Very mild, enantioselective synthesis of propargylamines catalyzed by copper(I)-bisimine complexes

Article abstract of DOI:10.1021/jo052481g

The stereoselective addition of aryl- and alkylacetylene derivatives to imines was studied. The reaction is catalyzed by copper complexes of enantiomerically pure bisimines, readily prepared in very high yields from the commercially available binaphthyl d

Full text of DOI:10.1021/jo052481g

Very Mild, Enantioselective Synthesis of Propargylamines Catalyzed
by Copper(I)-Bisimine Complexes
Federica Colombo,† Maurizio Benaglia,*,† Simonetta Orlandi,† Fabio Usuelli,† and
Giuseppe Celentano‡
Centro di Eccellenza CISI and Dipartimento di Chimica Organica e Industriale, and Istituto di Chimica
Organica della Facolta´ di Farmacia, UniVersita` degli Studi di Milano, Via Golgi 19 -20133- Milano, Italy
maurizio.benaglia@unimi.it
ReceiVed December 1, 2005
The stereoselective addition of aryl- and alkylacetylene derivatives to imines was studied. The reaction
is catalyzed by copper complexes of enantiomerically pure bisimines, readily prepared in very high yields
from the commercially available binaphthyl diamine. A very simple experimental procedure allowed to
obtain at room temperature optically active propargylamines in high yields and enantioselectivity.
Interestingly, bisimine/copper(I) complexes were able to promote the direct, enantioselective, catalytic
addition to imines of alkylacetylenes. The effects of catalyst loading and other reaction parameters on
the stereochemical outcome of the transformation were investigated. The extremely convenient
methodology, the mild reaction conditions, and the possibility of a modular approach for developing
new and more efficient bisimine-based chiral ligands make the present methodology very attractive.
Introduction
an important method.4 In this context, the development of an
efficient catalytic enantioselective version of this reaction is a
very appealing synthetic alternative.5
While several catalytic methods are known to promote the
addition of acetylenes to aldehydes in very high yields and
enantioselectivities,6 only very recently a limited number of
different organometallic systems have been reported to catalyze
the addition of acetylenes to imines to afford enantiomerically
enriched propargylamines. Hoveyda and co-workers used a Zr-
(IV) complex in the presence of a chiral amino acid-based
The enantioselective addition of acetylenic reagents to imines
or other related aza-carbonyl derivatives to give optically active
propargylamines is a valuable tool in the construction of highly
functionalized structures.1 Optically active propargylamines are
synthetically versatile intermediates for the construction of many
biologically active nitrogen compounds2 and key intermediates
for the synthesis of polyfunctional amino derivatives.3
Among the several synthetic methodologies available for the
preparation of these useful structures, the addition of an
organometallic reagent to chiral imine derivatives still represents
(4) For the addition of organometallic reagents to chiral imines, see:
Bloch, R. Chem. ReV. 1998, 98, 1407. Enders, D.; Reinhold, U. Tetrahe-
dron: Asymmetry 1997, 8, 1895. See also: Frantz, D. E.; Fassler, R.;
Oetiker, J.; Carreira, E. M. Angew. Chem., Int. Ed. 2002, 41, 3054. Frantz,
D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 1999, 121, 11245 and
references cited therein.
(5) For a few selected examples of interesting methodologies affording
racemic compounds, see also: Fischer, C.; Carreira, E. M. Org. Lett. 2001,
3, 4319. Fischer, C.; Carreira, E. M. Org. Lett. 2004, 6, 1497. Wei, C.; Li,
Z.; Li, C. J. Org. Lett. 2003, 5, 4473. Sakaguchi, S.; Mizuta, T.; Furuwan,
M.; Kubo, T.; Ishii, Y. Chem. Commun. 2004, 1638-1639.
(6) Reviews: Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org.
Chem. 2004, 4095. Pu, L.; Yu, H. B. Chem. ReV. 2001, 101, 757. Frantz,
D. E.; Fassler, R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem. Res. 2000,
33, 373.
* Corresponding Author. Tel.: +39.02.50314171. Fax: +39.02.50314159.
† Centro di Eccellenza CISI and Dipartimento di Chimica Organica e
Industriale.
‡ Instituto di Chimica Organica della Facolta´ di Farmacia.
(1) Review: Pu, L.; Yu, H. B. Chem. ReV. 2001, 101, 757. For a review
of the asymmetric synthesis of propargylamines, see: Blanchet, J.; Bonin,
M.; Micouin, L. Org. Prep. Proced. Int. 2002, 34, 459.
(2) Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.; VanDuyne, G.; Clardy,
J. J. Am. Chem. Soc. 1990, 112, 3715. Huffman, M. A.; Yasuda, N.;
DeCamp, A. E.; Grabowski, E. J. J. Org. Chem. 1995, 60, 1590.
(3) Nilsson, B.; Vargas, H. M.; Ringdahl, B.; Hacksell, U. J. Med. Chem.
1992, 35, 285. Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem.
1995, 60, 4999.
10.1021/jo052481g CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/09/2006
2064
J. Org. Chem. 2006, 71, 2064-2070

Asymmetric Synthesis of Chiral Propargylamines
ligand.7 Li developed a Cu(I) complex of pyridyl-bisoxazoline8
that was able to promote the direct alkyne-imine addition in
toluene and in water. Knochel and co-workers9 described the
addition of functionalized alkynes to enamines catalyzed by Cu-
(I)-Quinap complexes. More recently, Carreira and co-workers
developed a new atropisomeric P,N ligand (Pinap), structurally
related to Quinap, that showed a similar reactivity and stereo-
chemical efficiency in promoting the CuBr-catalyzed three-
component reaction10 among dibenzylamine, an aldehyde, and
various acetylenes.11 Finally, Jiang and Si12 reported the zinc
acetylide addition to reactive ketoimines in the presence of a
chiral amino alcohol under mild reaction conditions.13
SCHEME 1. Chiral Bisimine/Cu(I) Complex-Promoted
Enantioselective Addition of Phenylacetylene to
N-Phenylbenzaldehyde Imine 10
Our group has recently started a program devoted to the
development of new catalytic systems, readily prepared from
commercially available and cheap chiral reagents, easy to
handle, in very simple experimental procedures. Following our
interest in developing new copper(I)-catalyzed reactions,14 we
were attracted by the copper complexes of bisimines derived
from enantiopure biaryl diamine, recently employed with success
by Suga et al.15 and by Scott et al.16 in the synthesis of aziridines
and cyclopropanes.17 We thought that Cu(I), chiral, bisimine-
based catalysts could represent readily available candidates as
catalytic systems to actively promote the direct addition of
acetylene derivatives to imines, without the need of any
addictive or further reagent transformation. The fact that the
catalyst would be less expensive than Quinap or Pybox added
further appeal to the new catalytic system.
Here we report that the stereoselective addition of phenyl-
acetylene and alkylacetylenes to imines may be catalyzed by
copper(I) complexes of enantiomerically pure bisimines, readily
prepared in one step in very high yields from commercially
available enantiomerically pure binaphthyl diamine,18 to afford
propargylamines often in quantitative yields and enantioselec-
tivities up to 85%.19
Results and Discussion
(7) Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. Org. Lett. 2003, 5,
3273. See also: Akullian, L. C.; Hoveyda, A. H.; Snapper, M. L. Angew.
Chem., Int. Ed. 2003, 42, 4244.
(8) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638. Wei, C.; Mague,
J. T.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5749.
(9) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2002,
41, 2535. Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew.
Chem., Int. Ed. 2003, 42, 5763.
(10) Wei, C.; Li, Z.; Li, C.-J. Synlett 2004, 1472.
(11) Knopfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.;
Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971.
(12) Jiang, B.; Si, Y.-G. Angew. Chem., Int. Ed. 2004, 43, 216.
(13) For other recent reports on the asymmetric catalyzed addition of
acetylenic reagents to imines, see: Rosa, J. N.; Santos, A. G.; Alfonso, C.
A. M. J. Mol. Catal. A: Chem. 2004, 214, 161. Gommermann, N.; Knochel,
P. Chem. Commun. 2005, 4175. See also: Park, S. B.; Alper, H. Chem.
Commun. 2005, 1315.
(14) Puglisi, A.; Benaglia, M.; Annunziata, R.; Bologna, A. Tetrahedron
Lett. 2003, 44, 2947.
(15) Suga, H.; Kakehi, A.; Ito, S.; Ibata, T.; Fudo, T.; Watanabe, Y.;
Kinoshita, Y. Bull. Chem. Soc. Jpn. 2003, 76, 189.
(16) Sanders, C. J.; Gillespie, K. M.; Bell, D.; Scott, P. J. Am. Chem.
Soc. 2000, 122, 7132. Sanders, C. J.; Gillespie, K. M.; Scott, P.
Tetrahedron: Asymmetry 2001, 12, 1055. Gillespie, K. M.; Sanders, C. J.;
O’Shaughnessy, P.; Westmoreland, I.; Thickitt, C. P.; Scott, P. J. Org. Chem.
2002, 67, 3450-3458. O’Shaughnessy, P.; Scott, P. Tetrahedron: Asym-
metry 2003, 14, 1979. O’Shaughnessy, P.; Knight, P. D.; Morton, C.;
Gillespie, K. M.; Scott, P. Chem. Commun. 2003, 1770. O’Shaughnessy,
P.; Gillespie, K. M.; Knight, P. D.; Munslow, I. J.; Scott, P. Dalton Trans.
2004, 2251.
Synthesis of the Ligands. The synthesis of all the ligands
followed the same general strategy, starting from the com-
mercially available (R)-binaphthyl diamine that was reacted with
different aromatic and heteroaromatic aldehydes to afford the
corresponding enantiomerically pure bisimines 1-8 in good
yields (Scheme 1). In a typical procedure, a 0.5 M solution of
the chiral diamine (1 mol/equiv) and the aromatic aldehyde (2.2
mol/equiv) was refluxed in dry toluene for 24-72 h in the
presence of molecular sieves. The reaction mixture, cooled to
room temperature, was filtered, and the solvent was evaporated
under reduced pressure to give the expected bisimine in more
than 90% yield, that was shown to be pure enough by 1H NMR
to be used as such.
Analytically pure samples could be obtained by crystalliza-
tion, typically in ethanol (see Experimental Section). The ligand
9 was prepared according to the literature procedure.20
Cu(I)-Catalyzed Asymmetric Phenylacetylene Addition to
Imines. The ligands were tested in the copper(I)-trifluo-
romethanesulfonate-catalyzed reaction between N-phenylben-
zaldehyde imine 10 and phenylacetylene to afford the optically
(18) Benaglia, M.; Negri, D.; Dell’Anna, G. Tetrahedron Lett. 2004, 45,
8705-8708.
(17) For other recent uses of binaphthyl diamine-based imines as ligands
in asymmetric catalysis, see also: Zhou, X.; Huang, J.; Ko, P.; Cheung,
K.; Che, C.-M. J. Chem. Soc., Dalton Trans. 1999, 3303. Suga, H.; Kakehi,
A.; Ito, S.; Sugimoto, H. Bull. Chem. Soc. Jpn. 2003, 76, 327. Suga, H.;
Kakehi, A.; Mitsuda, M. Bull. Chem. Soc. Jpn. 2004, 77, 561. Suga, H.;
Kitamura, T.; Kakehi, A.; Baba, T. Chem. Commun. 2004, 1414 and
references cited therein. Suga, H.; Nakajima, T.; Itoh, K.; Kakehi, A. Org.
Lett. 2005, 7, 1431 and references cited therein.
(19) We have recently found that the arylacetylene addition to imines is
promoted also by chiral diamine/Cu(I) complexes. See: Orlandi, S.;
Colombo, F.; Benaglia, M. Synthesis 2005, 1689-1691. The bisimine/Cu-
(I) catalysts usually performed better than diamine/Cu(I) complexes in terms
of yields and stereoselectivities.
(20) Reetz, M. T.; Haderlein, G.; Angermund, K. J. Am. Chem. Soc.
2000, 122, 996. Following the reported procedure, in our hands, product 9
was obtained in 51% yield after chromatographic purification.
J. Org. Chem, Vol. 71, No. 5, 2006 2065

Colombo et al.
TABLE 1. Cu(I)-Catalyzed Asymmetric Phenylacetylene Addition
to Imine 10a
TABLE 2. Optimization of the Cu(I)-Catalyzed Phenylacetylene
Addition to Imine 10a
entry
ligand
yieldb (%)
eec (%)
entry
ligand
temp (°C)
solvent
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
7
8
9
98
97
98
98
77
67
98
-
77
63
81
77
73
23
65
-
1
2
3
4
5
3
3
3
3
1
1
3
3
3
3
1
25
25
25
25
25
25
25
25
25
0
toluene
DCM
THF
98
91
11
7
71
83
7
83
98
37
21
81
41
n.d.
n.d.
21
5
n.d.
82
82
83
75
n-hexane
n-hexane
NO2CH3
MeOH
toluene
toluene
toluene
toluene
6
7
8d
9e
10
11
81
7
a Reaction conditions: 72 h, 25 °C, toluene, 10 mol % of catalyst.
b Isolated yield after chromatographic purification. c Determined by HPLC
on chiral stationary phase.
0
a Reaction conditions: 72 h, 10 mol % of catalyst. b Isolated yield after
chromatographic purification. c Determined by HPLC on chiral stationary
phase. d Reaction conditions: 24 h, 10 mol % of catalyst. e Reaction
conditions: 48 h, 10 mol % of catalyst.
active propargylamine 11. In a typical experimental procedure,
to a 2 mL toluene solution of the chiral ligand (0.02 mmol),
kept at room temperature under nitrogen, copper(I)-trifluo-
romethanesulfonate (0.02 mmol) was added. After stirring for
10 min, imine 10 (0.2 mmol) and phenylacetylene (0.3 mmol)
were added. The reaction mixture was allowed to stir for 72 h
at room temperature, then it was filtered onto a Celite cake and
purified by flash chromatography. It is noteworthy that at the
end of reaction, after filtration onto a Celite cake, the recovered
crude reaction mixture did not show any trace of phenylacety-
lene addition to the bisimine ligand, but only product 11 and,
in some cases, nonreacted starting material 10. The results are
reported in Table 1.
Benzaldehyde-derived bisimine 1 afforded the propargylamine
with 77% ee, the same enantioselectivity being obtained with
the more sterically crowded mesityl derivative 4 (Table 1, entries
1 and 4). However, by employing a ligand more sterically
demanding at the 2,6-phenyl positions as bisimine 2, the
enantiomeric excess drops to 63% (Table 1, entry 2). The best
results were obtained with the pentafluorobenzaldehyde-derived
binaphthyl bisimine 3, which promoted the addition of phenyl-
acetylene to imine 10, in quantitative yield and 81% ee (Table
1, entry 3).
The presence of a hydroxy group does not seem to have any
appreciable influence on the stereoselectivity (Table 1, entry 5,
73% ee).21 However, surprisingly enough, ligand 6 bearing a
methoxy group promoted the reaction in a very low ee (23%,
Table 1, entry 6). The use of bisimines derived from heteroaro-
matic aldehydes strongly depended on the presence of the latter
of a coordinating atom. Indeed, a possible weak coordinating
element like a thiophene ring does not show any appreciable
effect (ligand 7, 65 vs 77% ee, Table 1, entry 7 vs entry 1).22
However, as expected, the stronger coordinating pyridine rings
inactivated the catalyst, and the reaction did not occur (Table
1, entry 8). Finally, for this copper(I)-promoted transformation,
the benzophenone-derived bisimine 9 showed a good catalytic
activity but a poor stereocontrol ability.
the chiral ligands. The chiral-copper complex guarantees high
chemical efficiency as well as good enantioselectivity (up to
81%). It is important to note that a single crystallization of the
product 11 allows the increase of the enantiomeric excess of
the propargylamine from 81% to more than 99%23 (see
Experimental Section).
Having identified bisimine 3 as the ligand of choice, the
dependence of the catalyst behavior on solvent and temperature
was investigated (Table 2).
Toluene proved to be the best performing solvent; other
solvents were tested, like dichloromethane or hexane, but they
proved to be less effective for the enantioselectivity of the
reaction (Table 2, entries 2, 4, and 5 vs entry 1). Polar solvents,
like tetrahydrofuran, acetonitrile, methanol, or N,N-dimethyl-
formamide, were not good reaction solvents both for enantio-
selectivity and chemical efficiency.
In toluene, ligand 3 worked well and, after 12 h, afforded
the product 11 in 83% yield and in quantitative yield after 40
h, always maintaining a comparable level of stereoselectivity
(Table 2, entries 8 and 9).24 Also, the temperature played a
crucial role, because the phenylacetylene addition did not
proceed for temperatures lower than room temperature. For
instance, at 0 °C the reaction rate was slowed and no change in
the enantioselectivity was observed.25
The dependence of the results on the nature of the copper
salt was then studied (Table 3).
The phenylacetylene addition seems to be a ligand-accelerated
reaction, because copper(I)-trifluoromethanesulfonate as such
promoted the reaction in toluene after 72 h at 25 °C in only
15% yield (Table 3, entry 2 vs entry 1). However, in dichlo-
romethane (DCM), a catalytic amount, 10 mol %, of CuOTf
was able to catalyze the formation of 11 in 90% yield; the lower
enantioselectivity of the reaction promoted by the ligand 3/Cu-
(I) complex in DCM compared to that of the reaction in toluene
(41 vs 81% ee, Table 2, entries 1 and 2) may be explained in
terms of different solubility profiles. Other salts were completely
The results of this initial screening are very interesting in
light of the extremely simple experimental procedure, the very
mild reaction conditions, and the easy synthesis in one step of
(23) In the case of product 11, it was possible to obtain a basically
enantiomerically pure compound after a single crystallization step even
starting from a sample with 65% ee.
(24) Other ligands were less efficient; for example, with ligand 1, after
48 h, less than 60% conversion was observed. Furthermore, because with
other substrates and different acetylenic reagents different reaction rates
were observed, for the sake of comparison, a 72 h reaction time was kept
in all the experiments.
(21) The use of other, even more hindered, ligands like a chiral bisimine
derived from 2-hydroxy-3-t-butyl-benzaldehyde did not allow the improve-
ment of the enantioselectivity, which was always in a 70-80% ee range.
See also ref 29.
(22) On the contrary, in a chiral bisimine/metal catalyzed allylation of
imines, we have recently discovered a positive effect of the thiophene ring
on the stereoselectivity of the process. See: Colombo, F.; Benaglia, M.;
Cozzi, F.; Cinquini, M. manuscript in preparation.
(25) At 0 °C, other ligands, like 2, 5, and 6, did not promote the reaction
at all.
2066 J. Org. Chem., Vol. 71, No. 5, 2006

Asymmetric Synthesis of Chiral Propargylamines
TABLE 3. Different Copper Salts Employed in the
Cu(I)-Catalyzed Asymmetric Synthesis of 11a
entry
ligand
copper salt
yieldb (%)
eec (%)
81
1
2
3d
4
5
6
7
3
CuOTf
CuOTf
CuOTf
CuCl
CuCl
CuPF6
CuPF6
98
15
90
<5
<5
47
3
3
<5
27
39
a Reaction conditions: toluene, 25 °C, 72 h, 10 mol % of catalyst.
b Isolated yield after chromatographic purification. c Determined by HPLC
on chiral stationary phase. d Reaction in DCM.
TABLE 4. Effect of Catalyst Loading in the Cu(I)-Catalyzed
Phenylacetylene Addition to Imine 10a
entry
mol % cat.
cat. concn
yieldb (%)
eec (%)
1
2
3
4
10
5
1
5
1
10
5
10
5
1.5 × 10-2
1.5 × 10-2
1.5 × 10-2
1.5 × 10-3
1.5 × 10-3
1.5 × 10-2
1.5 × 10-3
1.5 × 10-2
1.5 × 10-3
M
98
87
77
98
71
98
75
77
51
81
77
71
75
85
77
71
63
69
M
M
M
M
M
M
M
M
5
6d
7d
8e
9e
FIGURE 1. Catalytic cycle for the phenylacetylene addition to imines.
performance of the same catalysts, employed at 10 mol % of
catalyst and at 10-2 M concentration, indicate there is not a
clear difference in the results obtained by two ligands with
different steric environments and at variable concentrations.
These data seem to indicate that the catalyst is not sensitive to
the reaction concentration parameters, suggesting that chiral
bisimine behavior is not dependent on a possible equilibrium
between monomeric and dimeric species.
a Reaction conditions: toluene, ligand 3, 25 °C, 72 h. b Isolated yield
after chromatographic purification. c Determined by HPLC on chiral station-
ary phase. d Ligand 1 was used. e Ligand 2 was used.
ineffective, as CuCl (Table 3, entries 4 and 5),26 or less efficient
both in terms of chemical yield and stereoselectivity (CuPF6,
Table 3, entries 6 and 7).
To better understand the nature of the catalytic system and
to propose a possible mechanism for the reaction, a few
experiments were performed. Scott et al. have already demon-
strated how the copper complexes of bisimines derived from
C2-symmetric biaryl diamine may exist both as either a
“monomeric” or a “dimeric” form, depending on the steric
requirements of the substituents in 2,6 positions of the aldehyde
aromatic ring.16 To understand if different catalytic species were
present in the reaction medium, the phenylacetylene addition
was performed with a different catalyst loading and in different
dilution conditions (Table 4).
By employing the pentafluorobenzaldehyde derivative, ligand
3, the reaction was promoted by 10, 5, and 1 mol % of catalyst.
It is noteworthy that the chiral bisimine-copper(I) complex
catalyzed the phenylacetylene addition also at a lower catalyst
loading, with marginal loss of enantioselectivity. By running
the reaction at 10-3 M catalyst concentration, similar results
were observed, with the product being obtained with 75% ee
for the 5 mol % catalyst-promoted reaction and even with 85%
ee for the reaction performed with only 1 mol % of the chiral
catalyst (Table 4, entries 2-5).
To get further insight into the structure of the catalytic species,
the isolation and characterization of the chiral bisimine/copper
1
complex was attempted. The H NMR spectrum of a mixture
of an equimolar amount of copper-trifluoromethanesulfonate and
chiral ligand 3 in toluene-d8 accounts for the formation of a
single species (see Experimental Section). Although, as already
pointed out by Scott et al.,16 the NMR spectra in solution of
the free ligand and the complex are very similar; nevertheless,
1
the H NMR of the complex presented clear differences from
that of the free ligand. Also, the complexation of the more
hindered ligand 5 afforded a catalyst whose NMR both in CDCl3
and in CD(CN)3 clearly illustrated the formation of a new
species, even if in this case the shift of the imine signal is less
evident.
On the basis of the collected results, a tentative mechanism
is suggested in Figure 1.
The chiral ligand/copper complex coordinates the imine 10
and the phenylcetylene.9 After the intramolecular addition of
the alkyne to the imine has occurred, the propargylamine, a
product of the reaction, is released, regenerating by decom-
plexation the catalytic species, which is then ready to coordinate
with new molecules of imine and alkyne to start again the
catalytic cycle.27
A similar trend was observed with other ligands, characterized
by different steric requirements. The use of a copper complex
of ligand 1 at a 10-3 M concentration afforded the product in
75% yield and 71% ee, while ligand 2 allowed to obtain the
product in 51% yield and 69% ee. The comparison with the
Cu(I)-Catalyzed Asymmetric Aryl- and Alkylacetylene
Additions to Various Imines. The methodology was then
(27) Any attempt to obtain crystals of the chiral bisimine/copper(I)
complex was unsuccessful. For the proposed reaction mechanism, we do
have NMR evidence of Cu(I)-imine coordination. Then the formation of
a Cu-alkynide, as suggested by one of the referees, is a possibility.
However, on the basis of our own investigation, at the moment we are not
in the position to indicate the structure of the real active catalytic species
and to assign the geometry at the copper ion.
(26) CuBr was reported to be a poor catalyst for the reaction also by Li
et al.,8 who showed that the Pybox/CuBr complex worked as active chiral
catalyst but with less efficiency than Cu(OTf). Knochel et al.9 and Carreira
et al.11 do use CuBr as the Cu(I) source, but it is complexed with Quinap
or other related biaryl P,N ligands, and the reaction is believed to proceed
through a different mechanism that involves an enamine formation.
J. Org. Chem, Vol. 71, No. 5, 2006 2067

Colombo et al.
SCHEME 2. Cu(I)-Promoted Addition of Phenylcetylene to
Differently Substituted Imines
SCHEME 3. Cu(I)-Promoted Addition of Phenylcetylene to
Differently Substituted Imines
TABLE 5. Cu(I)-Catalyzed Phenylacetylene Addition to Imines
TABLE 6. Cu(I)-Catalyzed Phenylacetylene Addition to Imines
12-20a
30-34a
entry
ligand
imine
R group
product
yieldb (%)
eec (%)
entry ligand imine R′ group product yieldb (%) eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1
3
5
1
3
5
3
3
3
3
3
3
3
12
12
12
13
13
13
14
15
16
17
18
19
20
4-OMe
4-OMe
4-OMe
2-OMe
2-OMe
2-OMe
2-Cl
2,6-diCl
4-F
4-Cl
21
21
21
22
22
22
23
24
25
26
27
28
29
55
77
75
97
73
21
91
<10
98
91
98
98
71
73
45
55
77
51
n.d.
80
n.d.
71
73
75
15
73
1
2
3
4
5
6
7
8
9
1
3
5
1
3
3
1
3
3
30
30
30
31
31
32
33
33
34
4-OMe
4-OMe
4-OMe
2-OMe
2-OMe
4-Cl
4-F
4-F
3,5-diCl
35
35
35
36
36
37
38
38
39
91
55
53
25
81
98
71
75
98
31
41
27
51
71
25
41
61
27
a Reaction conditions: toluene, 25 °C, 72 h, 10 mol % of catalyst.
b Isolated yield after chromatographic purification. c Determined by HPLC
on chiral stationary phase.
4-Br
4-NO2
4-Me
a Reaction conditions: toluene, 25 °C, 72 h, 10 mol % of catalyst.
b Isolated yield after chromatographic purification. c Determined by HPLC
on chiral stationary phase.
oxidative degradation and thus obtain the N-unprotected pro-
pargylamine. Unfortunately, none of the chiral ligands tested
in the usual conditions showed a good ability to stereocontrol
the phenylacetylene addition to 30, affording the product 35 in
the best case with 41% ee (Table 6, entries 1-3). It must be
noted also that, in the work of Li et al., by using a Pybox/
copper(I) catalytic system, the enantioselective addition of
phenylacetylene to imine 30 was not reported.8 However, better
results were obtained with the N-2-methoxyphenyl derivative
31; by employing ligand 3, the phenylacetylene addition was
promoted in 81% yield and 71% ee (Table 6, entry 5). The result
is extremely interesting from a synthetic point of view, because
also the 2-methoxyphenyl group is removable29 and product 36
represents a direct precursor of an enantiomerically enriched
propargylamine with a free NH2 group. By comparison of the
analytical data of 36 with those reported by Hoveyda et al.,29 it
was possible to assign the (R) absolute configuration to the chiral
propargylamines obtained with our methodology by employing
chiral ligands derived from (R)-binaphthyl diamine.30
Also in the case of N-4-fluorophenylimine 33, ligand 3,
derived from pentafluorobenzaldehyde, performed better than
ligand 1, obtained from benzaldehyde, affording the propargyl-
amine 38 in 75% yield and 61% ee (Table 6, entries 7 and 8).
Finally, the addition of different acetylenic reagents was
studied (Scheme 4).
As can be seen from the reported data, the methodology seems
to work with differently substituted arylacetylenes. For example,
ligand 1 promoted the 4-bromo-phenylacetylene addition to
extended to differently substituted imines (Scheme 2). The
catalytic system worked with imines 12-20, obtained by the
reaction of aniline with several aromatic aldehydes, affording
products 21-29 in fair to excellent yields and with enantio-
selectivities up to 80% (Table 5).
For imine 12, derived from 4-methoxybenzaldehyde, ligand
1 performed better than the usual ligand of choice, ligand 3,
affording the product 21 with 73% ee (Table 5, entries 1 and
2). This behavior was confirmed also in the case of phenyl-
acetylene addition to imine 13, a derivative of 2-methoxyben-
zaldehyde, which in the presence of ligand 1 produced the
propargylamine 22 in basically quantitative yield and 77% ee
(Table 5, entry 4).
With other derivatives, ligand 3 performed constantly better;
for example, it promoted the addition to imine 14 to give the
corresponding o-chloro-substituted product 23 in 80% ee (Table
5, entry 7).28 While the sterically hindered imine 15 did not
react, the 4-halogen derivatives, 16-18, reacted very well and
afforded the corresponding products, 25-27, in yields always
higher than 90% and with enantioselectivities between 70 and
75%. While the presence of a methyl group does not seem to
have an effect on the outcome of the reaction (73% ee, Table
5, entry 13), a nitro group heavily interferes, depressing the
enantioselectivity of the process (15% ee) but not the chemical
efficiency of the catalyst (Table 5, entry 12).
The phenylacetylene addition to different benzaldimines
derived from variously substituted anilines was also studied
(Scheme 3).
The N-4-methoxyphenyl imine 30 is a substrate of great
interest, because it is possible to remove the aryl group by
(29) For the degradation of N-2-methoxyphenyl anilines, see ref 7.
(30) The assigned absolute configuration has been confirmed also by
the comparison of the analytical data of compound 11 with those reported
by Li et al.8 Product 11 was isolated as a white solid: mp 56-57 °C; [R]23
D
+71.3° (c 1.03, CH2Cl2) for a sample of 77% ee, determined by HPLC
analysis on a Chiracel OD column with a hexane/2-propanol, 95:5, mixture
as eluent (flow rate, 1 mL/min); tR of the major enantiomer, 12.79 min; tR
of the minor enantiomer, 16.1 min. After crystallization, the product, with
(28) Imines derived from heteroaromatic aldehydes reacted sluggishly
and with low enantioselectivity; imines derived from cinnamic aldehyde
and aliphatic aldehydes did not react at all, as well as N-alkyl imines.
N-phenyl imine of ethylglyoxalate was completely consumed after only 12
h of reaction, but any attempt to isolate a well-defined product was
unsuccessful.
95% ee (determined by HPLC), is a white solid: mp 91-92 °C; [R]23
D
+124° (c 0.32, CH2Cl2). These results match with those reported in the
recent paper by Li et al. (ref 8), where the absolute configuration of N-[1-
(3-bromophenyl)-3-phenyl-2-propynyl]-aniline was determined by X-ray
crystallography.
2068 J. Org. Chem., Vol. 71, No. 5, 2006

Asymmetric Synthesis of Chiral Propargylamines
SCHEME 4. Cu(I)-Promoted Addition of Aryl- and
Alkylacetylene Derivatives to Substituted Imines
SCHEME 5. Synthetic Transformations of Chiral Propargyl
Amines
TABLE 7. Cu(I)-Catalyzed Aryl- and Alkylacetylene Additions to
Iminesa
yieldb
(%)
eec
(%)
entry
ligand
R′ group
R′′ group
Ph
product
1
2
3
4
5
3
1
1
1
1
3
3
3
3
1
3
3
3
4-H
4-H
4-H
4-H
2-OMe
4-H
4-H
4-H
4-H
4-H
4-H
2-OMe
4-H
11
11
40
41
42
43
44
44
44
44
45
46
47
98
98
98
77
97
73
91
81
37
63
51
25
35
81
77
75
33
57
71
73
71
65
61
21
31
27
Ph
4-BrPh
3,5-diNO2Ph
4-BrPh
C4H9
C8H17
C8H17
C8H17
C8H17
COOMe
COOMe
TMS
6
7
8d
9e
10
11
12
13
formations. For example, as already mentioned, the N-2-
methoxyphenyl group undergoes an oxidative cleavage to afford
enantiomerically enriched propargylamines,7 direct precursors
for the preparation of amino acids. Propargylamine 11 may be
reduced selectively to the corresponding highly functionalized
allylic amine 48 or may be completely hydrogenated to the
saturated compound 49, without loss of stereochemical integrity
(Scheme 5).
The nitrogen atom of amine 11 may be protected as the
N-acetyl compound 50, which was converted to the â-amino
ketone 51 in a not-optimized 35% yield, after chromatographic
purification.32 Also, the adduct 51 is a very attractive building
block for the preparation of enantiomerically enriched, func-
tionalized molecules, among which chiral 1,3-hydroxy-amino
derivatives occupy a pre-eminent role.
a Reaction conditions: toluene, 25 °C, 72 h, 10 mol % of catalyst.
b Isolated yield after chromatographic purification. c Determined by HPLC
on chiral stationary phase. d A 5 mol % of catalyst was employed. e A 1
mol % of catalyst was employed.
imine 10 in quantitative yield and 75% enantioselectivity,
comparable to that obtained in the phenylacetylene addition to
imine 10 (Table 7, entries 2 and 3). The addition of 4-bromo-
phenylacetylene to N-2-methoxyphenyl-benzaldehyde imine 31
occurred in good yield and 57% ee. Once again, the presence
of the nitro group on one of the reagents determined a marked
drop in the stereoselectivity of the process, as demonstrated by
the reaction of the 3,5-dinitro-phenylacetylene with imine 10
(33% ee, Table 7, entry 4).
In a previous communication we reported the direct, enan-
tioselective, alkylacetylene-derivatives addition to imines.18
Indeed, the reaction between imine 10 and 1-hexyne afforded
the corresponding propargylamine 43 in 73% yield and 71%
ee. Analogously, the addition of 1-decyne to imine 10 gave 44
in 91% yield and 73% ee. Also, for alkylacetylene addition,
the reaction promoted by only 5 mol % of catalyst afforded
product 44 in very good yield (81%) and without appreciable
loss of enantioselectivity (71%, Table 7, entry 8 vs entry 7),
while in the presence of 1 mol % catalyst, a clear decrease of
chemical yield was observed (Table 7, entry 9). Also, in the
case of alkylacetylenes, ligand 3 seems to perform better than
ligand 1 both in chemical efficiency and stereoselectivity. It is
worth mentioning that, to our knowledge, only one other
example of direct, enantioselective, catalytic addition to imines
of alkylacetylenes is known.31
Conclusions
A highly stereoselective addition of aryl- and alkylacetylene
derivatives to imines was developed. The reaction is catalyzed
by copper complexes of enantiomerically pure bisimines, readily
prepared in one step and in very high yields from binaphthyl
diamine, commercially available in both enantiomeric forms.
A very simple experimental procedure allowed to obtain at room
temperature optically active propargylamines in up to >98%
yields and up to 85% ee. Interestingly, bisimines/copper(I)
complexes were also able to promote the direct, enantioselective,
catalytic addition of alkylacetylenes to imines.
It is worth mentioning that a multicomponent, stereoselective
reaction between an aldehyde, an amine, and arylacetylenes to
afford optically active propargylamines at room temperature has
been also developed.33 The extremely convenient methodology,
which involves the use of commercially available reagents, mild
reaction conditions, and the possibility of a modular approach
for developing new and more efficient bisimine-based chiral
ligands, make the present catalytic system very attractive.
Unfortunately, the methodology did not work well with
propargylic ester or trimethylsilyl acetylene, which reacted with
imine 10 to give the corresponding propargylamines 45 and 47
in 51 and 35% yields, respectively and, in both cases, with low
enantioselectivity (Table 7, entries 11 and 13).
The propargylamines easily prepared by this methodology
represent useful starting materials for further synthetic trans-
(32) Meyer, A.; Flammang, M.; Wermuth, C.-G. Synthesis 1976, 832.
(33) An asymmetric, multicomponent, copper-catalyzed synthesis of
chiral propargylamines was developed. See: Colombo, F.; Benaglia, M.;
Orlandi, S.; Usuelli, F. J. Mol. Catal. A: Chem. 2005, submitted.
(31) Only very recently have alkylacetylenes been employed in a direct
addition to imines (see ref 8). For other examples of the use of alkylacety-
lenes in other methodologies, see refs 9 and 7.
J. Org. Chem, Vol. 71, No. 5, 2006 2069

Colombo et al.
After 15 min at room temperature, the propenylamine 4835 was
isolated, while prolonged reaction times (1 h) afforded in quantita-
tive yield the saturated compound 49.
Experimental Section
General Procedure for the Synthesis of Ligands 1-8. To a
solution of chiral diamine (10 mmol) in dry toluene (20 mL) was
added aromatic aldehyde (20.2 mmol). The mixture was stirred in
the presence of molecular sieves for 40-72 h at 110 °C. The
reaction mixture was cooled to room temperature and filtered, and
the solvent was evaporated under vacuum to give the corresponding
imines in yields >90%. Eventually the bisimines may be crystallized
from ethanol.
1
N-(1,3-Diphenyl-2-propenyl)aniline 48. H NMR (CDCl3): δ
3
7.10-7.50 (m, 13H), 6.6-6.8 (m, 2H), 6.50 (d, JH,H ) 6.1 Hz,
3
3
1H), 5.80 (dd, JH,H ) 5.1, 6.1 Hz, 1H), 5.30 (d, JH,H ) 5.1 Hz,
1H), 4.1 (br s, 1H). [R]23 +87.1 (c 0.33, CH2Cl2).
D
N-(1,3-Diphenyl-2-propyl)aniline 49. 1H NMR (CDCl3): δ
3
7.15-7.40 (m, 12H), 6.7 (m, 1H), 6.60 (m, 2H), 4.40 (t, JH,H
)
5.5 Hz, 1H), 2.70 (m, 2H), 2.10 (m, 2H). 13C NMR: δ 147.1, 143.7,
141.2, 129.0, 128.5, 128.4, 127.0, 126.4, 126.2, 126.0, 176.7, 113.1,
57.7, 40.1, 32.6. Elem anal. Calcd for C21H21N (287.40): C, 87.36;
H, 7.36; N, 4.87. Found: C, 87.05; H, 7.55; N, 4.91. [R]23D +15.3
(c 0.33, CH2Cl2).
Ligand 1. Mp 119-124 °C; [R]23 +112.9 (c 0.23, CH2Cl2).
D
1H NMR (CDCl3): δ 8.24 (s, 2H), 7.98 (d, JH,H ) 5.1 Hz, 2H),
3
7.93 (d, 3JH,H ) 4.8 Hz, 2H), 7.44 (m, 2H), 7.42 (m, 2H), 7.37 (m,
3
1H), 7.36 (d, m, 2H), 7.34 (d, JH,H ) 5.1 Hz, 2H), 7.30 (m, 2H),
7.28 (m, 2H). 13C NMR: δ 160.7, 148.8, 136.3, 133.6, 131.6, 131.0,
129.1, 128.5, 128.4, 128.2, 127.9, 126.8, 126.4, 124.7, 119.3. Elem
anal. Calcd for C34H24N2 (460.57): C, 88.67; H, 5.25; N, 6.08.
Found: C, 89.01; H, 5.44; N, 6.01.
Synthesis of â-Amino Ketone 51. To a solution of 130 mg of
amine 11 (0.46 mmol) in 5 mL of dry dichloromethane was added
at 0 °C triethylamine (0.77 mL, 0.55 mmol), followed by acetyl
chloride (0.4 mL, 0.56 mmol). The reaction mixture was allowed
to stir at 0 °C for 30 min, then it was quenched with water and the
organic phase was separated, dried over magnesium sulfate, and
evaporated under reduced pressure to give the N-acetyl derivative
50 in 90% yield (135 mg).
Complexation Experiments of Chiral Bisimines with Copper-
Trifluoromethanesulfonate. Cu(OTf) (0.01 mmol) was added to
a toluene-d8 solution (1 mL) of the chiral ligand (0.01 mmol) at rt,
1
under a nitrogen atmosphere. After stirring for 15 min, H NMR
spectra were obtained. After 12 h, the copper complexes showed
the same NMR spectra, with no appreciable differences.
Ligand 3. 1H NMR (C7D8): δ 8.50 (s, 2H), 7.78 (d, 3JH,H ) 9.0
A solution of 253 mg of 50 (0.78 mmol) in 1 mL of acetic acid
was poured into a solution of 0.5 mL of formic acid in 0.05 mL of
water. To the reaction mixture was added dropwise a 5% catalytic
amount of a 15% Hg(OAc)2 aqueous solution. The mixture was
stirred for 2 h, hydrolyzed with water, and extracted with diethyl
ether. The organic phase was separated, dried over magnesium
sulfate, and evaporated under reduced pressure to give a crude
reaction mixture that was purified by flash chromatography
(eluent: hexanes/ethyl acetate 6/4) to afford the ketone 5136 in 37%
3
3
Hz, 2H), 7.67 (d, JH,H ) 8.5 Hz, 2H), 7.35 (d, JH,H ) 8.3 Hz,
3
2H), 7.27 (d, JH,H ) 8.8 Hz, 2H), 7.19 (m, 2H), 7.09 (m, 2H).
1
Cu(OTf)/ligand 3 complex. H NMR (C7D8): δ 8.05 (s, 2H),
7.75 (d, 3JH,H ) 8.7 Hz, 2H), 7.68 (d, 3JH,H ) 8.5 Hz, 2H), 7.16-
7.00 (m, 8H).
General Procedure for the Enantioselective Addition of Aryl-
and Alkylacetylenes to Imines. In a typical experimental proce-
dure, Cu(OTf) (0.02 mmol) was added to a toluene solution (2 mL)
of the chiral ligand (0.02 mmol) at rt, under a nitrogen atmosphere.
After stirring for 10 min, imine 8 (0.2 mmol) and phenylacetylene
(0.3 mmol) were added. The reaction mixture was allowed to stir
for 72 h at rt and was then filtered through Celite and purified by
silica gel flash chromatography, if necessary (hexanes/ethyl acetate
mixtures as eluent).34
yield (103 mg), [R]23 -25.3 (c 0.43, CH2Cl2).
D
N-Acetyl-N′-(1,3-diphenyl-2-propynyl)aniline 50. 1H NMR
(CDCl3): δ 7.25-7.40 (m, 6H), 7.15-7.25 (m, 9H), 6.90 (br s,
1H), 1.80 (s, 3H). 13C NMR: δ 170.0, 139.9, 133.7, 131.6, 130.4,
129.1, 128.9, 128.7, 128.5, 128.4, 128.3, 128.1, 127.2, 122.6, 89.3,
86.0, 50.5. Elem anal. Calcd for C23H19NO (325.40): C, 84.89; H,
5.89; N, 4.30. Found: C, 85.11; H, 5.85; N, 4.10. [R]23D -65.3 (c
0.53, CH2Cl2).
N-[1-(4-Methoxyphenyl)-3-phenyl-2-propynyl]aniline 21. 1H
NMR (CDCl3): δ 7.55 (d, 3JH,H ) 7.5 Hz, 2H), 7.40 (m, 2H), 7.20-
7.30 (m, 5H), 6.90 (d, 3JH,H ) 6.5 Hz, 2H), 6.75 (m, 3H), 5.45 (s,
1H,), 3.8 (s, 3H). 13C NMR: δ 147.5, 130.2, 129.6, 129.1, 127.5,
127.0, 126.9, 123.9, 122.4, 119.8, 116.7, 111.1, 90.5, 87.1, 56.9,
46.4. Elem anal. Calcd for C22H19NO (313.39): C, 84.31; H, 6.11;
N, 4.47. Found: C, 84.01; H, 6.15; N, 4.55. HPLC analysis
(Chiralcel OD; flow rate, 0.8 mL/min; λ ) 230; hexane/i-PrOH,
95:5; tR, 17.0 min (minor) and 19.4 min (major)).
Acknowledgment. This work was supported by MIUR
(Progetto Nazionale Stereoselezione in Sintesi Organica. Metod-
ologie ed Applicazioni).
Supporting Information Available: Synthesis and character-
ization of ligands 2-9, synthesis and HPLC analysis details for
products 22, 23, 25, 38-44, and 47. This material is available free
of charge via the Internet at http://pubs.acs.org.
Hydrogenation of Chiral Propargylamines. 50 mg of N-[1,3-
diphenyl-2-propynyl]aniline 11 was dissolved in 10 mL of absolute
ethanol and hydrogenated in the presence of 5 mg of Pd(C)/CaCO3.
JO052481G
(35) Kodama, H.; Taji, T.; Ohta, T.; Furukawa, I. Tetrahedron: Asym-
metry 2000, 11, 4009.
(36) Blatt, A. H.; Gross, N. J. Org. Chem. 1964, 29, 3306.
(34) The enantiomerically enriched propargylamines 11, 21-29, 35-
39, and 41-44 all showed positive optical rotation values.
2070 J. Org. Chem., Vol. 71, No. 5, 2006