A new copper-catalyzed [3 + 2] cycloaddition: Enantioselective coupling of terminal alkynes with azomethine imines to generate five-membered nitrogen heterocycles

Article abstract of DOI:10.1021/ja036922u

A copper-catalyzed method for the regioselective 1,3-dipolar cycloaddition of azomethine imines to terminal alkynes has been developed. Through the use of a chiral phosphaferrocene-oxazoline ligand, a wide range of substrates can be coupled to generate us

Full text of DOI:10.1021/ja036922u

Published on Web 08/16/2003
A New Copper-Catalyzed [3 + 2] Cycloaddition: Enantioselective Coupling of
Terminal Alkynes with Azomethine Imines To Generate Five-Membered
Nitrogen Heterocycles
Ryo Shintani and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received June 26, 2003; E-mail: gcf@mit.edu
1,3-Dipolar cycloadditions are powerful methods for constructing
a variety of five-membered heterocycles in a convergent manner
from relatively simple precursors.1,2 Recently, several examples of
Cu(I)-catalyzed 1,3-dipolar cycloadditions to terminal alkyness
presumably proceeding via a copper acetylideshave been described
(Figure 1).3,4 In addition to achieving heterocycle formation under
milder conditions, copper-catalyzed processes can overcome the
poor regioselectivity observed in some of the corresponding thermal
cycloadditions (e.g., eq 1),3 as well as provide interesting new
opportunities for asymmetric catalysis.4b,5
Figure 1. Examples of copper-catalyzed [3 + 2] cycloadditions.
Table 1. 1,3-Dipolar Cycloaddition of an Azomethine Imine to an
Alkyne: Effect of Copper and Ligands on Yield and
Enantioselectivitya
To date, such copper-catalyzed cycloadditions have been reported
entry
catalyst
yield (%)b
ee (%)
for just two families of dipoles, azides and nitrones, furnishing 1,2,3-
triazoles3 and â-lactams,4 respectively (Figure 1). In this Com-
munication, we considerably expand the scope of this useful mode
of reactivity, demonstrating that 1,3-dipolar cycloadditions of
azomethine imines to alkynes can be catalyzed by Cu(I); at the
same time, we achieve effective asymmetric catalysis of this new
process (eq 2).
1
2
3
4
5
6
7
none
5% CuI
<2
88
<2
98
98
100
100
5% CuI/5.5% (S)-BINAP
5% CuI/5.5% 5
5% CuI/5.5% 6a
5% CuI/5.5% 6b
5% CuI/5.5% 7
19
90
58
80
a All data are the average of two runs. b Isolated yield.
In 1968, Dorn and Otto established that 3-oxopyrazolidin-1-ium-
2-ides such as 1, which are derived from the reaction of pyrazolidin-
3-one with an aldehyde, are stable, easily handled compounds.6
Cycloadditions of these dipoles even with highly electron-deficient
alkynes (e.g., dimethyl acetylenedicarboxylate) are often conducted
at elevated temperatures and, in the case of unsymmetrical alkynes,
generally furnish mixtures of regioisomeric heterocycles.6,7 The
products of such cycloadditions have a variety of applications,
including as antibacterial agents (e.g., LY186826).8,9
In an initial investigation, we examined the reaction of azo-
methine imine 2 with ethyl propiolate (3) (Table 1). At room
temperature in the absence of a copper catalyst, essentially none
of the target heterocycle (4) is generated (entry 1). In contrast, in
the presence of 5% CuI, the desired 1,3-dipolar cycloaddition
proceeds cleanly, affording the product as a single regioisomer (88%
yield; entry 2).
attention to asymmetric catalysis. Unfortunately, the addition of
(S)-BINAP shuts down the reaction (<2% yield; entry 3). Although
bidentate phosphines appear to generally inhibit catalysis by
copper,10 bidentate nitrogen-based ligands do not. Thus, cycload-
dition proceeds smoothly in the presence of bisoxazoline 5, although
the desired heterocycle (4) is produced with very modest enantio-
selectivity (19% ee; entry 4).11,12 Fortunately, copper catalysis is
also effective in the presence of a P,N ligand, phosphaferrocene-
oxazoline 6a,13 leading to cycloaddition in excellent yield and with
high stereoselection (98% yield, 90% ee; entry 5). Increasing the
steric demand of the substituent on the oxazoline (i-Pr f t-Bu)
results in a decrease in ee (90% ee f 58% ee; entry 5 vs entry 6),
as does a change in the planar chirality of the phosphaferrocene
subunit (90% ee f 80% ee; entry 5 vs entry 7). Thus, the
investigation outlined in Table 1 describes two critical discover-
Having established the viability of copper-catalyzed [3 + 2]
cycloadditions of azomethine imines to alkynes, we turned our
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J. AM. CHEM. SOC. 2003, 125, 10778-10779
10.1021/ja036922u CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reaction Scope: The Azomethine Imine Componenta
In summary, we have developed a new copper-catalyzed 1,3-
dipolar cycloaddition of terminal alkynes, presumably relying upon
the transient formation of a copper acetylide to enhance the
reactivity of the dipolarophile. By employing a phosphaferrocene-
oxazoline as a chiral bidentate ligand, we have efficiently coupled
a wide range of azomethine imines and alkynes to generate useful
heterocycles in very good enantiomeric excess. Future studies will
explore further expansion of the scope of copper-catalyzed cy-
cloaddition reactions.
entry
R
yield (%)b
ee (%)
1
2
3
4
5
6
7
Ph
98
99
99
99
98
92
94
90
81
86
95
94
82
96
o-FC6H4
m-BrC6H4
p-CF3C6H4
1-cyclohexenyl
n-pentyl
Acknowledgment. Support has been provided by the National
Institutes of Health (NIGMS, R01-GM066960), Merck, and No-
vartis. We thank Ivory D. Hills and Dr. William M. Davis for an
X-ray crystallographic study.
Cy
a All data are the average of two runs. b Isolated yield.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
Table 3. Reaction Scope: The Alkyne Componenta
References
(1) For reviews of 1,3-dipolar cycloadditions, see: (a) Synthetic Applications
of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural
Products; Padwa, A., Pearson, W. H., Eds.; Wiley: New York, 2003;
Vol. 59. (b) Karlsson, S.; Hogberg, H.-E. Org. Prep. Proced. Int. 2001,
33, 103-172. (c) Gothelf, K. V.; Jørgensen, K. A. Chem. ReV. 1998, 98,
863-909.
(2) For a review of catalytic asymmetric cycloadditions, see: Maruoka, K.
In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: New York, 1999; pp 467-491.
(3) For reactions of azides, see: (a) Rostovtsev, V. V.; Green, L. G.; Fokin,
V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596-2599.
(b) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057-3064.
(4) For reactions of nitrones, see: (a) Kinugasa, M.; Hashimoto, S. J. Chem.
Soc., Chem. Commun. 1972, 466-467. (b) Miura, M.; Enna, M.; Okuro,
K.; Nomura, M. J. Org. Chem. 1995, 60, 4999-5004.
(5) (a) Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 4572-4573.
(b) Shintani, R.; Fu, G. C. Angew. Chem., Int. Ed., in press.
(6) (a) Dorn, H.; Otto, A. Chem. Ber. 1968, 101, 3287-3301. (b) Dorn, H.;
Otto, A. Angew. Chem., Int. Ed. Engl. 1968, 7, 214-215.
(7) For a few examples, see: (a) Svete, J.; Preseren, A.; Stanovnik, B.; Golic,
L.; Golic-Grdadolnik, S. J. Heterocycl. Chem. 1997, 34, 1323-1328. (b)
Chuang, T.-H.; Sharpless, K. B. HelV. Chim. Acta 2000, 83, 1734-1743.
(c) Turk, C.; Svete, J.; Stanovnik, B.; Golic, L.; Golic-Grdadolnik, S.;
Golobic, A.; Selic, L. HelV. Chim. Acta 2001, 84, 146-156. (d) Panfil,
I.; Urbanczyk-Lipkowska, Z.; Suwinska, K.; Solecka, J.; Chmielewski,
M. Tetrahedron 2002, 58, 1199-1212.
(8) For a review of the chemistry of pyrazolidinones, see: Claramunt, R.
M.; Elguero, J. Org. Prep. Proced. Int. 1991, 23, 273-320.
(9) The pyrazolidinone ring serves as a surrogate for the â-lactam unit that is
a common feature of many antibiotics. For an overview of the chemistry
and biology of LY186826, see: (a) Ternansky, R. J.; Holmes, R. A. Drugs
Future 1990, 15, 149-157. (b) Ternansky, R. J.; Draheim, S. E. In Recent
AdVances in the Chemistry of â-Lactam Antibiotics; Bentley, P. H.,
Southgate, R. H., Eds.; Royal Society of Chemistry: London, 1989; pp
139-156. (c) Jungheim, L. N.; Sigmund, S. K. J. Org. Chem. 1987, 52,
4007-4013. In contrast to LY186826, which is a [3.3.0]-fused (w car-
bapenem analogue) pyrazolidinone, monocyclic (w monobactam analogue)
or [4.3.0]-fused (w carbacephem analogue) pyrazolidinones do not show
biological activity.
entry
R
yield (%)b
ee (%)
1
2
3
4
5
6
CO2Et
COMe
98
98
100
77
90
100
73
90
90
94
88
86
84
88
74
CONMePh
p-EtO2CC6H4
p-CF3C6H4
2-pyridyl
Ph
7c,d
8c,e
n-pentyl
63
a All data are the average of two runs. b Isolated yield. c The reaction
was conducted at 45 °C. The yield and the ee are those of the major
regioisomer. d Regioselectivity: 5.6/1. e Regioselectivity: 6.6/1.
ies: Cu(I) can efficiently catalyze regioselective14 1,3-dipolar
cycloadditions of azomethine imines to alkynes, and, in the presence
of an appropriate chiral ligand, a highly enantioselective reaction
can be achieved.
We have determined that the scope of the Cu(I)/phosphafer-
rocene-oxazoline-catalyzed asymmetric cycloaddition is fairly
broad. With respect to the imine portion of the dipole, the process
tolerates aromatic (Table 2, entries 1-4), alkenyl (entry 5), and
alkyl (entries 6 and 7) groups on carbon, furnishing the products
in excellent yields and with very good enantioselectivities.15 With
respect to variations in the pyrazolidinone ring of the dipole, the
cycloaddition proceeds cleanly and with high ee for a range of
substitution patterns (eq 3).
(10) For example, the addition of CHIRAPHOS, DUPHOS, or JOSIPHOS leads
to a low yield of heterocycle 4.
(11) (a) For a review of applications of C2-symmetric bisoxazolines in
asymmetric catalysis, see: Ghosh, A. K.; Mathivanan, P.; Cappiello, J.
Tetrahedron: Asymmetry 1998, 9, 1-45. (b) For some leading references
to enantioselective copper-catalyzed reactions, see: Rovis, T.; Evans, D.
A. Prog. Inorg. Chem. 2001, 50, 1-150.
(12) The 1,3-dipolar cycloaddition also proceeds cleanly in the presence of
(-)-sparteine and a pybox ligand, albeit in lower ee.
With regard to the alkyne, the best yields and enantioselectivities
are obtained when this coupling partner is electron-poor (Table 3).
Thus, if the alkyne bears a carbonyl (entries 1-3), an electron-
deficient aromatic (entries 4 and 5), or a heteroaromatic group (entry
6), the ee of the cycloaddition is high. Simple aryl- or alkyl-
substituted alkynes are also suitable substrates for Cu(I)/phospha-
ferrocene-oxazoline-catalyzed asymmetric cycloaddition, although
gentle heating is necessary for a reasonable reaction rate, and an
erosion in regioselectivity is observed (∼6:1; entries 7 and 8).16
To the best of our knowledge, these are, however, the first examples
of an unactivated alkyne undergoing cycloaddition with this family
of dipoles.
(13) For previous reports, see: (a) Shintani, R.; Lo, M. M.-C.; Fu, G. C. Org.
Lett. 2000, 2, 3695-3697. (b) Shintani, R.; Fu, G. C. Org. Lett. 2002, 4,
3699-3702. (c) Reference 5b.
(14) Unless otherwise noted, we detect none of the other regioisomer in these
copper-catalyzed dipolar cycloadditions.
(15) Notes (Table 2, entry 1): (1) Use of other solvents leads to somewhat
lower ee (THF, toluene, and anisole), slow reaction (MeCN), or many
side products (EtOH). (2) The ee shows little dependence on reaction
temperature. (3) Replacement of Cy2NMe with i-Pr2NEt has minimal
impact (93% yield, 88% ee with i-Pr2NEt). (4) CuBr, CuCl, and Cu(OTf)
furnish comparable yield, but lower ee. (5) When the cycloaddition is
conducted on a 4.0 mmol scale, the desired product is isolated in 97%
yield (1.06 g) and with 84% ee. Ligand 6a is recovered in 78% yield.
(16) Higher regioselectivitysat the expense of reaction ratescan be obtained
by conducting the cycloadditions at room temperature.
JA036922U
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J. AM. CHEM. SOC. VOL. 125, NO. 36, 2003 10779