Copper-catalyzed coupling of pyridines and quinolines with alkynes: A one-step, asymmetric route to functionalized heterocycles

Article abstract of DOI:10.1021/jo702293h

(Chemical Equation Presented) A copper (I)-catalyzed, asymmetric method to directly functionalize pyridines, quinolines, and isoquinolines with terminal alkynes is described. The reaction is readily diversified to incorporate a range of pyridine-based het

Full text of DOI:10.1021/jo702293h

Copper-Catalyzed Coupling of Pyridines and Quinolines with
Alkynes: A One-Step, Asymmetric Route to Functionalized
Heterocycles
Daniel A. Black, Ramsay E. Beveridge, and Bruce A. Arndtsen*
Department of Chemistry, McGill UniVersity, 801 Sherbrooke Street West, Montreal,
Quebec H3A 2K6, Canada
bruce.arndtsen@mcgill.ca
ReceiVed October 23, 2007
A copper (I)-catalyzed, asymmetric method to directly functionalize pyridines, quinolines, and isoquinolines
with terminal alkynes is described. The reaction is readily diversified to incorporate a range of pyridine-
based heterocycles and electron-rich or electron-poor alkynes. This provides a straightforward alternative
to nucleophilic or cross-coupling approaches to directly derivatize these heterocycles, and yields useful
propargylcarbamates.
Introduction
have been developed to functionalize nitrogen-containing
aromatic heterocycles. These include electrophilic aromatic
substitution or metalation methodologies, as well as the now
common use of metal-catalyzed cross-coupling reactions.6 The
latter are typically performed on presynthesized halogenated or
metalated pyridine derivatives, or with N-activated heterocycles
(e.g., catalytic arylation of pyridine N-oxides, or alkynylation
of N-alkyl quinolinium salts).7,8 Alternatively, the reductive
functionalization of pyridine can be achieved by the addition
of nucleophiles to in situ generated N-acyl pyridinium salts.9
These products can be subsequently oxidized to form the
The ability to efficiently functionalize heterocycles such as
pyridines and their derivatives (e.g., quinoline, isoquinoline, etc.)
remains an important issue in synthetic chemistry. This is driven
in part by the prevalence of these structures in biologically
relevant molecules1,2 as well as components in polymers,3
ligands,4 and various functional materials.5 A range of methods
(1) (a) Pozharskii, A. F.; Soldartenko, A. T.; Katritzky, A. Heterocycles
in Life and Society, Wiley: New York, 1997. (b) Que´guiner, G.; Marsais,
F.; Sniekus, V.; Epsztajn, J. AdV. Heterocycl. Chem. 1991, 52, 187.
(2) For recent examples: (a) Davies, I. W.; Marcoux, J. F.; Reider, P. J.
Org. Lett. 2001, 3, 209. (b) Roppe, J. R.; Wang, B.; Huang, D.; Tehrani,
L.; Kamenecka, T.; Schweiger, E. J.; Anderson, J. J.; Brodkin, J.; Jiang,
X.; Cramer, M.; Chung, J.; Reyes-Manalo, G.; Munoz, B.; Cosford, N. D.
P. Bioorg. Med. Chem. Lett. 2004, 14, 3993. (c) Nu´n˜ez, M. J.; Guadan˜o,
A.; Jime´nez, I. A.; Ravelo, A. G.; Gonza´lez-Coloma, A.; Bazzocchi, I. L.
J. Nat. Prod. 2004, 67, 14. (d) Kitamura, A.; Tanaka, J.; Ohtani, I. I.; Higa,
T. Tetrahedron 1999, 55, 2487. (e) Tsukamoto, S.; Takahashi, M.;
Matsunaga, S.; Fusetani, N.; van Soest, R. W. M. J. Nat. Prod. 2000, 63,
682.
(3) (a) Zheng, J. Y; Feng, X. M.; Bai, W. B.; Qin, J. G.; Zhan, C. M.
Eur. Polym. J. 2005, 41, 2770. (b) DuBois, C. J.; Abboud, K. A.; Reynolds,
J. R. J. Phys. Chem. B 2004, 108, 8550. (c) Jenekhe, S. A.; Lu, L.; Alam,
M. M. Macromolecules 2001, 34, 7315. (d) Huang, W. Y.; Yun, H.; Lin,
H. S.; Kwei, T. K.; Okamoto, Y. Macromolecules 1999, 32, 8089. (e) Kim,
J. L.; Cho, H. N.; Kim, J. K.; Hong, S. I. Macromolecules 1999, 32, 2065.
(4) (a) von Zelewsky, A. Coord. Chem. ReV. 1999, 190, 811. (b) Albrecht,
M.; van Koten, G. Angew. Chem., Int. Ed. 2001, 40, 3750. (c) Belda, O.;
Moberg, C. Coord. Chem. ReV. 2005, 249, 727. (d) Desimoni, G.; Faita,
G.; Quadrelli, P. Chem. ReV. 2003, 103, 3119. (e) Chelucci, G.; Thummel,
R. P. Chem. ReV. 2002, 102, 3129.
(5) (a) Shifrina, Z. B.; Rajadurai, M. S.; Firsova, N. V.; Bronstein, L.
M.; Huang, X.; Rusanov, A. L.; Muellen, K. Macromolecules 2005, 38,
9920. (b) Gandubert, V. J.; Lennox, R. B. Langmuir 2006, 22, 4589. (c)
Zhang, Z.; Imae, T.; Sato, H.; Watanabe, A.; Ozaki, Y. Langmuir 2001,
17, 4564.
(6) (a) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2000. For recent examples,
see: (b) Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed. 2006,
45, 1282. (c) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S.
L. J. Am. Chem. Soc. 2005, 127, 4685. (d) Thompson, A. E.; Hughes, G.;
Batsanov, A. S.; Bryce, M. R.; Parry, P. R.; Tarbit, B. J. Org. Chem. 2005,
70, 388.
(7) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005,
127, 18020.
(8) Taylor, A. M.; Schreiber, S. L. Org. Lett. 2006, 8, 143.
(9) (a) Comins, D. L.; Joseph, S. P. ComprehensiVe Heterocyclic
Chemistry II, Elsevier: Oxford, 1996; p 37. (b) Comins, D. L.; O’Connor,
S. AdV. Heterocycl. Chem. 1988, 44, 199. (c) Sliwa, W. Heterocycles 1986,
24, 181.
10.1021/jo702293h CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/24/2008
1906
J. Org. Chem. 2008, 73, 1906-1910

Cu-Catalyzed Direct Coupling of Alkynes with Pyridine
SCHEME 1. Proposed Mechanism for the Catalytic
Addition of Terminal Alkynes to Pyridine
FIGURE 1. Imines and pyridine in catalytic carbon-carbon bond
formation.
substituted pyridine, reduced to form piperdines, or are them-
selves valuable building blocks in natural product synthesis.
We and others have recently reported that imines can
participate in metal-catalyzed coupling reactions with a range
of cross-coupling reagents (e.g., organostannanes, organoindium
compounds, or terminal alkynes).10,11 Notably, these reactions
do not require the initial halogenation of the precursor, nor
strong nucleophiles or bases, providing a mild and straightfor-
ward route to R-substituted amides. In light of the resonance
structure similarity between imines and nitrogen-containing
heterocycles such as pyridine (Figure 1), we became intrigued
with the potential that pyridine itself might participate in similar
metal-catalyzed carbon-carbon bond-forming reactions, such
as alkynylation to form cyclic propargylamides. Toward this
end, we have preliminarily communicated one example of the
simple copper-catalyzed coupling of phenylacetylene with
pyridine in the presence of an acid chloride, to rapidly generate
a propargylamide.10b While the addition of stoichiometric
alkynyl-metal nucleophiles to in situ generated N-acyl pyri-
dinium salts is well established,12 as is the catalytic alkynylation
of N-alkylated quinolines to form tertiary propargylamines,8 this
represented what was to our knowledge the first example of
the direct coupling of alkynes with pyridine using simple copper
salts as catalysts. More recently, the use of stoichiometric zinc
salts to mediate this reaction has been reported.14 In addition,
Ma and co-workers have demonstrated that this copper-catalyzed
reaction can be performed with high levels of enantioselectivity
using chiral bisoxazoline ligands, although the scope of this
reaction is limited to the use of electron-deficient 3-carbonyl
substituted alkynes.13
TABLE 1. Copper-Catalyzed Coupling of Pyridine,
Chloroformates, and Alkynesa
entry
cat.
CuI
R1
R2
Ph
n-C4H9
Ph
Ph
Ph
% yield 1
1
2
3
4
5
Ph
Ph
Ph
Ph
EtO
PhO
73
33
31
-
82
88
62
83
72
64
78
CuI
CuOTfb
Zn(OTf)2
CuI
6
CuI
Ph
7
CuI
(9-fluorenyl) CH2O
Ph
8
9
10
11
CuI
CuI
CuI
CuI
EtO
EtO
PhO
PhO
n-C4H9
TMS
CH2Cl
CO2Et
a 0.50 mmol heterocycle, 0.60 mmol acid chloride, 0.50 mmol alkyne,
0.70 mmol NEtiPr2, and 10 mol % catalyst in 2 mL CH3CN. b CuOTf‚C6H6.
provides a versatile catalytic route to enantioenriched alkynyl-
ated heterocycles.
Results and Discussion
Our approach to this reaction is based upon the postulate that
pyridines can be activated by acid chlorides toward a copper-
catalyzed coupling with terminal alkynes in a fashion similar
to that with imines, as shown in Scheme 1. As we have
previously communicated, pyridine undergoes a clean coupling
with phenylacetylene and benzoyl chloride in the presence of a
copper iodide catalyst to generate 1 (Table 1, entry 1).10b While
effective, attempts to couple other terminal alkynes with pyridine
in the presence of benzoyl chloride resulted in very poor yields
(Table 1, entry 2). Other metal salts were also found to be
ineffective as catalysts (Table 1, entries 3, 4). Considering the
electrophilicity of chloroformates, we examined the possibility
that they might both interact more strongly with pyridine and
better activate the heterocycle toward reaction. As shown in
entries 5-8, a number of common nitrogen protecting group
reagents (TROC, FmocCl) can participate in the coupling of
pyridine with phenylacetylene, in this case providing access to
synthetically useful N-protected cyclic amines. The yields of
these reactions are similar if not better than those with acid
chlorides. In addition, the use of chloroformates can allow the
use of a range of functionalized alkynes as the carbon-carbon
bond-forming partner with pyridine, including both electron-
rich (e.g., entry 9) and electron-poor (entries 10, 11) substrates.
This copper-catalyzed multicomponent coupling is straight-
forward to perform (mixing of the three reagents with catalyst
We report herein the full details, scope, and limitations of
this copper-catalyzed one-step functionalization of pyridines and
related nitrogen-containing heterocycles with various simple
alkynes. In addition, performing the coupling with chiral ligands
(10) (a) Davis, J. L.; Dhawan, R.; Arndtsen, B. A. Angew. Chem., Int.
Ed. 2004, 43, 590. (b) Black, D. A.; Arndtsen, B. A. Org. Lett. 2004, 6,
1107. (c) Black, D. A.; Arndtsen, B. A. Org. Lett. 2006, 8, 1991. (d) Black,
D. A.; Arndtsen, B. A. J. Org. Chem. 2005, 70, 5133.
(11) For the direct alkynylation of imines and related iminium salts,
see: (a) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638. (b) Fischer,
C.; Carreira, E. M. Org. Lett. 2001, 3, 4319. (c) Li, C.-J.; Wei, C. Chem.
Commun. 2002, 268. (d) Koradin, C.; Polborn, K.; Knochel, P. Angew.
Chem., Int. Ed. 2002, 41, 2535. (e) Brannock, K. C.; Burpitt, R. D.; Thweatt,
J. G. J. Org. Chem. 1963, 28, 1462. (f) Wei, C.; Li, C.-J. J. Am. Chem.
Soc. 2003, 125, 9584. (g) Youngman, M. A.; Dax, S. L. Tetrahedron Lett.
1997, 38, 6347. (h) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem.
Soc. 1999, 121, 11245. (i) Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L.
Org. Lett. 2003, 5, 3273. (j) Ukaji, Y.; Kenmoku, Y.; Inomata, K.
Tetrahedron: Asymmetry 1996, 7, 53.
(12) (a) Agawa, T.; Miller, S. I. J. Am. Chem. Soc. 1961, 83, 449. (b)
Yamaguchi, R.; Nakazono, Y.; Kawanisi, M. Tetrahedron Lett. 1983, 24,
1801. (c) Natsume, M.; Ogawa, M. Heterocycles 1983, 20, 601. (d) Lee, P.
H.; Park, J. J. Korean Chem. Soc. 1996, 40, 2.
(13) Sun, Z.; Yu, S.; Ding, Z.; Ma, D. J. Am. Chem. Soc. 2007, 129,
9300.
(14) Lee, K. Y.; Lee, M. J.; Kim, J. N. Bull. Korean Chem. Soc. 2005,
26, 665.
J. Org. Chem, Vol. 73, No. 5, 2008 1907

Black et al.
TABLE 2. Ligands in Catalytic Enantioselective Alkynylationa
TABLE 3. Enantioselective Alkynylation of Nitrogen Heterocyclesa
entry
heterocycle
ligand
% yieldb
ee (%)
1
2
3
4
5
6
7
8
9
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
quinoline
quinoline
quinoline
quinoline
quinoline
quinoline
(R)-Tol-BINAP
n.d.
n.d.
n.d.
-
2
0
1
-
0
49
43
53
41
75
66
81
(R)-iPr-PYBOX
(R)-tBu-BOX
(R)-MONOPHOS
(R)-MOP
(R)-QUINAP
72
17
86
91
84
86
75
92
(R)-QUINAP
2a
2b
2c
2d
2e
10
11
12
a 0.10 mmol heterocycle, 0.12 mmol chloroformate, 0.11 mmol alkyne,
i
12 mol % ligand, 10 mol % CuCl, and 0.15 mmol Pr2NEt in CH3CN/
CH2Cl2 (5 mL). b n.d. ) not determined.
and base for 20 min) and regioselectively generates the 1,2-
addition product: cyclic propargylcarbamates. The latter are of
broad utility as chiral building blocks in the synthesis of various
alkaloids and other biologically relevant molecules.15 In addition,
since this reaction is mediated by copper salts, it suggests the
potential for asymmetric catalysis. The enantioselective synthesis
of dihydropyridine derivatives has attracted significant attention,
including several very recent catalytic examples. This includes
the catalytic addition of nucleophilic organolithium reagents16
and silyl-nitriles17 or -enolates,18 and the copper-catalyzed
alkynylation of N-alkyl isoquinolinium salts.8 In addition, as
previously mentioned, the addition of 3-carbonyl-substituted
alkynes to N-acylpyridinium salts can proceed with high
enantioselectivity employing bis(oxazoline) ligands,13 although
other alkyne substrates (e.g., simple phenylacetylene, alkyl-
substituted alkynes, propargyl esters, etc.) yielded near racemic
products.
a 0.10 mmol heterocycle, 0.11 mmol chloroformate, 0.10 mmol alkyne,
5.5 mol % ligand, 5 mol % CuCl, and 0.14 mmol iPr2NEt in CH3CN/CH2Cl2
(5 mL).
As shown in Table 2, the use of several commercially
available chiral phosphorus- and nitrogen-donor ligands in this
reaction unfortunately resulted in low to zero enantioselectivity
with phenylacetylene, similar to previous reports.13,19 Neverthe-
less, we were encouraged by the results with (R)-QUINAP,
which yielded the functionalized pyridine derivative in moderate
ee (49%, entry 6).20 Similar selectivity was observed in the
alkynylation of quinoline (entry 7), although in higher yield.
Building upon this ligand class, further improvement of the
enantioselectivity can be obtained with the PINAP derivatives
2a-c, (up to 75% ee). A feature of the PINAP series of ligands
is their modularity, where the substituents can be changed and
the ligand subsequently resolved as column-separable diaster-
eomers.21 As such, two new variants of this ligand (2d and 2e)
were prepared, in analogy to literature procedures. In the case
(15) (a) Porco, J. A., Jr.; Schoenen, F. J.; Stout, T. J.; Clardy, J.;
Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 7410. (b) Nicolaou, K. C.;
Hwang, C.-K.; Smith, A. L.; Wendeborn, S. V. J. Am. Chem. Soc. 1990,
112, 7416. (c) Yoon, T.; Shair, M. D.; Danishefsky, S. J.; Shulte, G. K. J.
Org. Chem. 1994, 59, 3752. (d) Nilsson, B. M.; Hacksell, U. J. Heterocycl.
Chem. 1989, 26, 269. (e) Arcadi, A.; Cacchi, S.; Cascia, L.; Fabrizi, G.;
Marinelli, F. Org. Lett. 2001, 3, 2501. (f) Harvey, D. F.; Sigano, D. M. J.
Org. Chem. 1996, 61, 2268. (g) Tabei, J.; Nomura, R.; Masuda, T.
Macromolecules 2002, 35, 5405. (h) Gao, G.; Sanda, F.; Masuda, T.
Macromolecules 2003, 36, 3932.
(16) (a) Amiot, F.; Cointeaux, L.; Silve, E. J.; Alexakis, A. Tetrahedron
2004, 60, 8221. (b) Cointeaux, L.; Alexakis, A. Tetrahedron: Asymmetry
2005, 16, 925.
(17) (a) Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2000, 122, 6327. (b) Funabashi, K.; Ratni, H.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 10784. (c) Ichikawa, E.; Suzuki,
M.; Yabu, K.; Albert, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2004, 126, 11808.
(18) Taylor, M. S.; Tokunaga, N.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2005, 44, 6700.
(19) CuCl was employed rather than CuI as catalyst due to its higher
solubility in this solvent mixture at low temperature.
(20) This ligand has been successfully employed by Knochel in the
asymmetric alkynylation of N-alkyliminium salts. For example: Gommer-
mann, N.; Koradin, C.; Polborn, K.; Knochel P. Angew. Chem., Int. Ed.
2003, 42, 5763.
1908 J. Org. Chem., Vol. 73, No. 5, 2008

Cu-Catalyzed Direct Coupling of Alkynes with Pyridine
2.12-2.19 (t, 2H), 1.27-1.48 (m, 5H), 0.82-0.94 (t, 3H). 13C NMR
(75.5 MHz, 60 °C, CDCl3): δ 125.3, 121.7, 119.7, 105.1, 83.9,
77.9, 62.5, 44.0, 30.8, 21.9, 18.6, 14.5, 13.5. HRMS (M + Na) for
C14H19NO2, calculated: 256.1316, found: 256.1306.
of ligand 2e, this allows the coupling to proceed in up to 81%
enantioselectivity (entry 12).
The scope of this copper-catalyzed coupling of alkynes,
heterocycles, and chloroformates is shown in Table 3. Perhaps
most notably, a number of nitrogen-containing heterocycles can
be alkynylated via this route, provided they contain a CdN
π-bonded resonance structure, including quinoline, isoquinoline,
and pyridine. In addition, functionalized heterocycles can also
participate in this reaction, such as those with either electron-
withdrawing or -donating groups. Interestingly, even the
halogenated heterocycles lead to alkynylation exclusively at the
ortho position to the nitrogen, rather than cross-coupling at the
halogenated carbon (1i,j). Finally, a range of alkynes can be
employed in this chemistry, including various functionalized,
electron-rich and electron-poor alkynes. Each of these multi-
component reactions proceeds in high yield and reasonable
selectivity. Overall, this provides a relatively general approach
to construct enantioenriched propargylcarbamate derivatives.
General Procedure for the Synthesis of Enantioenriched
Alkynylated Heterocycles. Under a nitrogen atmosphere, the
heterocycle (0.10 mmol) and ethyl chloroformate (0.11 mmol) were
mixed in 2 mL of CH2Cl2. Copper (I) chloride (0.35 mg, 5.00 µmol)
and 2e (2.2 mg, 5.50 µmol) were mixed in 2 mL of 1:1 CH3CN/
CH2Cl2. These solutions were mixed with the alkyne (0.10 mmol)
in 1 mL of CH2Cl2, and the mixture cooled to -78 °C. EtNiPr2
(0.14 mmol) in 1 mL of CH2Cl2 was added over 30 min. The
reaction was stirred 14 h, warmed to ambient temperature, and
concentrated in vacuo; the product was isolated by column
chromatography with ethyl acetate/hexanes. Enantioselectivity was
determined using a Daicel ChiralPak OD-H or AD-H column 250
mm × 4.6 mm i.d. with hexane/2-propanol.
Ethyl-2-(phenylethynyl)quinoline-1(2H)-carboxylate (1a). The
above procedure was followed with quinoline, ethyl chloroformate,
and phenylacetylene. Isolated yield: 86%. Enantiomeric excess:
81%. Enantioselectivity was determined using a Daicel ChiralCel
OD-H column 250 mm × 4.6 mm i.d. with hexane/2-propanol )
95:5, flow rate 0.5 mL/min, UV 254 nm, tr(minor) ) 11.13 min, tr(major)
) 12.34 min. 1H NMR (300 MHz, CDCl3): δ 7.63 (d, 1H, J ) 6.8
Hz), 7.33-7.07 (m, 9H), 6.60-6.52 (m, 1H), 6.15-6.06 (m, 2H),
4.42-4.22 (m, 2H), 1.37 (t, 3H, J ) 9.2 Hz). 13C NMR (75.0 MHz,
CDCl3): δ 154.1, 134.6, 132.0, 128.5, 128.3, 128.0, 126.8, 126.2,
125.4, 124.6, 124.6, 122.8, 85.9, 83.7, 62.8, 44.9, 14.7. HRMS
calculated for C20H18NO2+: 304.1332; found: 304.1330.
Conclusions
In conclusion, we have reported a general and simple copper-
catalyzed method to directly couple pyridines and related
heterocycles with a diverse range of alkynes. Considering the
efficiency of this catalytic coupling, the availability of each of
the building blocks, and the lack of any prederivatization steps,
this provides a straightforward method to assemble enantioen-
riched dihydropyridine derivatives. Experiments directed toward
the application of this approach to activate heterocycles toward
other metal-catalyzed, asymmetric carbon-carbon bond-forming
reactions are in progress.
Ethyl-2-((trimethylsilyl)ethynyl)quinoline-1(2H)-carboxy-
late (1b). The above procedure was followed with quinoline, ethyl
chloroformate, and trimethylsilylacetylene. Isolated yield: 72%.
Enantiomeric excess: 84%. Enantioselectivity was determined using
a Daicel ChiralCel OD-H column 250 mm × 4.6 mm i.d. with
hexane/2-propanol ) 99:1, flow rate 0.5 mL/min, UV 254 nm,
1
tr(minor) ) 15.40 min, tr(major) ) 16.26 min. H NMR (500 MHz,
Experimental Section
CDCl3): δ 7.62 (br, 1H), 7.28-7.20 (m, 1H), 7.13-7.05 (m, 2H),
6.51 (d, 1H, J ) 6.4 Hz), 6.04-5.97 (m, 1H), 5.88 (d, 1H, J ) 5.3
Hz), 4.37-4.21 (m, 2H), 1.35 (t, 3H, J ) 5.6 Hz), 0.05 (s, 9H).
13C NMR (125 MHz, CDCl3): δ 154.0, 134.6, 127.9, 126.8, 126.7,
126.0, 125.5, 124.5, 102.0, 88.5, 62.7, 44.9, 14.7, 0.0. HRMS
calculated for C17H22NO2Si+: 300.1414; found: 300.1409.
Synthesis of 2d. A procedure analogous to that reported for
ligands 2a-c was followed.21 Trifluoromethanesulfonic acid 1-(4-
chlorophthalazin-1-yl)-7-methoxynaphthalen-2-yl ester (1.30 g, 2.77
mmol) and (R)-1-amino-2-benzyl-1,3-diphenylpropan-2-ol (4.40 g,
13.9 mmol) were mixed neat in a screw-capped vial. The suspension
was stirred for 24 h at 120 °C. After cooling to ambient temperature,
30 mL of methylene chloride was added, and the suspension was
filtered. The filtrate was concentrated under reduced pressure. The
product was isolated by column chromatography using toluene/
EtOAc (10:1 to 5:1) as eluent, as a mixture of diastereomers. The
product, 1-(4-((R)-2-benzyl-2-hydroxy-1,3-diphenylpropylamino)-
phthalazin-1-yl)-7-methoxy-naphthalen-2-yl-trifluoromethane-
sulfonate (1.28 g, 1.62 mmol, 59% yield), was dried on a vacuum
line for 24 h and then used in the next step.
A solution of Ni(dppe)Cl2 (0.082 g, 0.16 mmol) in 3 mL of DMF
was mixed with a solution of diphenylphosphine (0.620 g, 3.32
mmol) in 2 mL of DMF, under a nitrogen atmosphere. This red
solution was heated at 120 °C for 1 h. After cooling under nitrogen,
a solution of the above product (1.28 g, 1.62 mmol) in 1.5 mL of
DMF was added, followed by addition of DABCO (0.73 g, 6.50
mmol) in 3 mL of DMF. The solution was then heated at 120 °C
for 36 h. The mixture was then concentrated under reduced pressure.
The green/black residue was then purified by column chromatog-
raphy in toluene/EtOAc (pure toluene to 4:1) as eluent, as a mixture
of diastereomers. Separation of the diastereomers was performed
subsequently by column chromatography in toluene/EtOAc (12:
1). From this, 290 mg (23%) of ligand 2d was isolated.
General Procedure for the Synthesis of Racemic 2-Alkynyl-
1,2-dihydropyridines. Under a nitrogen atmosphere, pyridine (0.50
mmol) and acid chloride/chloroformate (0.60 mmol) were mixed
in 1 mL of CH3CN. To this was added the alkyne (0.50 mmol)
and catalyst (10 mol %, CuI, CuOTf‚C6H6, or Zn(OTf)2) in 1 mL
of CH3CN. NEtiPr2 was then added dropwise over 1 min, and the
reaction was stirred for 20 min at ambient temperature. The solvent
was then removed, and the product isolated by column chroma-
tography with ethyl acetate/hexanes.
Ethyl 2-(phenylethynyl)pyridine-1(2H)-carboxylate (Table 1,
entry 5). The above procedure was followed with pyridine, ethyl
chloroformate, and phenylacetylene. Isolated yield: 82%. 1H NMR
(300 MHz, 60 °C, CDCl3): δ 7.32-7.41 (m, 2H), 7.21-7.28 (m,
3H), 6.8 (d, 1H), 6.0 (m, 1H), 5.79 (d, 1H), 5.65 (t, 1H), 5.36 (t,
1H), 4.32 (q, 2H), 1.37 (t, 3H). 13C NMR (67.9 MHz, 60 °C,
CDCl3): δ 153.4, 131.9, 128.1, 125.2, 122.9, 122.5, 122.3 118.6,
105.1, 86.8, 82.2, 62.5, 44.2, 14.4. HRMS (M + H) for C16H15-
NO2, calculated: 254.1183, found: 254.1176.
Ethyl 2-(hex-1-ynyl)pyridine-1(2H)-carboxylate (Table 1,
entry 8). The above procedure was followed with pyridine, ethyl
1
chloroformate, and 1-hexyne. Isolated yield: 83%. H NMR (300
MHz, 60 °C, CDCl3): δ 6.72-6.77 (d, 1H), 5.87-5.95 (q, 1H),
5.49-5.58 (br, m, 2H), 5.25-5.33 (t, 1H), 4.21-4.34 (q, 2H),
(21) (a) Kno¨pfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.;
Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971. (b) Aschwanden,
P.; Stephenson, C. R. J.; Carreira, E. M. Org. Lett. 2006, 8, 2437. (c)
Kno¨pfel, T. F.; Zarotti, P.; Ichikawa, T.; Carreira, E. M. J. Am. Chem. Soc.
2005, 127, 9682.
(22) Amberg, W.; Bennani. Y. L.; Chadha, R. K.; Crispino, G. A.; Davis,
W. D.; Hartung, J.; Jeong, K.-S.; Ogino, Y.; Shibata, T.; Sharpless, K. B.
J. Org. Chem. 1993, 58, 844.
(23) Peper, V.; Martens, J. Chem. Ber. 1996, 129, 691.
J. Org. Chem, Vol. 73, No. 5, 2008 1909

Black et al.
1H NMR (300 MHz, CDCl3): δ 7.84 (d, 1H, J ) 7.6 Hz), 7.80
(d, 1H, J ) 8.4 Hz), 7.69 (d, 2H, J ) 7.6 Hz), 7.60-7.03 (m,
29H), 6.40 (d, 1H, J ) 7.8 Hz), 5.93 (d, 1H, J ) 7.8 Hz), 3.38 (s,
3H), 3.25-2.99 (m, 3H), 2.83 (br, 2H). 13C NMR (68.0 MHz,
CDCl3): δ 158.3, 152.8, 152.8, 152.5, 141.0, 140.9, 140.6, 138.4,
138.2, 138.0, 137.8, 137.5, 137.5, 136.9, 136.7, 134.9, 134.8, 134.2,
134.0,133.7, 133.4, 131.2, 131.1, 131.0, 129.8, 129.7, 129.5, 128.9,
128.7, 128.6, 128.4, 128.3, 128.0, 127.5, 126.9, 126.8, 126.5, 120.9,
119.7, 118.3, 105.7, 77.5, 62.0, 55.3, 44.9, 43.7. 31P NMR (81.0
MHz, CDCl3): δ -12.38. HRMS calculated for C53H45N3O2P+:
nitrogen, a solution of the above product (1.10 g, 1.99 mmol) in
1.5 mL of DMF was added, followed by addition of DABCO (0.90
g, 8.0 mmol) in 3 mL of DMF. The solution was then heated at
120 °C for 48 h. The mixture was then concentrated under reduced
pressure. The green/black residue was then purified by column
chromatography in toluene/EtOAc (pure toluene to 4:1) as eluent,
as a mixture of diastereomers. Separation of the diastereomers was
performed subsequently by column chromatography in toluene/
EtOAc (10:1). From this, 415 mg (35%) of ligand 2e was isolated.
1H NMR (300 MHz, CDCl3): δ 7.90 (m, 3H), 7.63 (t, 1H, J )
6.9 Hz), 7.57-7.09 (m, 19H), 6.48 (s, 1H), 5.82 (quint, 1H, J )
786.3244; found: 786.3241. [R]24 ) 182.0 (c ) 1.0, CHCl3).
D
6.9 Hz), 5.47 (br, 1H), 3.42 (s, 3H), 1.73 (d, 3H, J ) 6.8 Hz). 13
C
Synthesis of Ligand 2e. A procedure analogous to that reported
for ligands 2a-c was followed.21 Trifluoromethanesulfonic acid
1-(4-chlorophthalazin-1-yl)-7-methoxynaphthalen-2-yl ester (1.30
g, 2.77 mmol) and (R)-R-methyl-benzylamine (1.70 g, 14.0 mmol)
were mixed neat in a screw-capped vial. The suspension was stirred
for 14 h at 120 °C. After cooling to ambient temperature, the
product was isolated by column chromatography using hexanes/
ethyl acetate (65:35) as eluent, as a mixture of diastereomers. This
product, 7-methoxy-1-(4-((R)-1-phenylethylamino)phthalazin-1-yl)-
naphthalen-2-yl trifluoromethanesulfonate (1.10 g, 1.99 mmol,
72%), was dried on a vacuum line for 24 h and then used in the
next step.
NMR (68.0 MHz, CDCl3): δ 158.2, 152.4, 144.9, 134.7, 134.6,
134.2, 133.9, 133.6, 133.3, 131.0, 129.6, 129.4, 128.9, 128.7, 128.6,
128.5, 128.4, 128.3, 128.2, 128.2, 127.3, 126.9, 126.9, 126.8, 120.7,
119.5, 118.0, 105.6, 55.3, 50.7, 22.5. 31P NMR (81.0 MHz,
CDCl3): δ -12.07. HRMS calculated for C39H33N3OP+: 590.2356;
found: 590.2350. [R]24 ) 180.0 (c ) 1.0, CHCl3).
D
Acknowledgment. We thank NSERC (Canada), FQRNT
(Quebec), and CFI for their financial support.
Supporting Information Available: Spectral data on the
compounds in Tables 1-3, and ligands 2d and 2e. This material is
available free of charge via the Internet at: http://pubs.acs.org.
A solution of Ni(dppe)Cl2 (0.105 g, 0.020 mmol) in 3 mL of
DMF was mixed with a solution of diphenylphosphine (0.745 g,
4.0 mmol) in 2 mL of DMF, under a nitrogen atmosphere. This
red solution was heated at 120 °C for 1 h. After cooling under
JO702293H
1910 J. Org. Chem., Vol. 73, No. 5, 2008