3634
J . Org. Chem. 2001, 66, 3634-3635
Ta ble 1. Sem ih yd r ogen a tion of Hyd r oxya lk yn e 1a
ver su s Am in oa lk yn e 4a a
Con tr olled Sem ih yd r ogen a tion of
Am in oa lk yn es Usin g Eth ylen ed ia m in e a s a
P oison of Lin d la r ’s Ca ta lyst
Kevin R. Campos,* Dongwei Cai, Michel J ournet,
J ason J . Kowal, Robert D. Larsen, and Paul J . Reider
Department of Process Research, Merck & Co., Inc., P.O.
Box 2000, Rahway, New J ersey 07065
time (h)
1a : 1b : 1c : 1d b
4a : 4b : 4c : 4d b
1
2
4
8
18
39 : 57 : 3.5 : 0.5
22 : 72 : 5.5 : 0.5
4 : 89 : 6.4 : 0.6
2 : 90.4 : 7 : 0.6
0 : 91.3 : 8 : 0.7
0 : 88 : 8.1 : 3.8
kevin•campos@merck.com
0 : 70.1 : 17.8 : 12.1
0 : 30.7 : 36.3 : 33.0
0 : 10.0 : 40.1 : 49.9
0 : 0 : 0 : 100
Received J anuary 10, 2001
In tr od u ction
a
All reactions were carried out in DMF (0.5 M in substrate) at
Lindlar’s catalyst is the most ubiquitous reagent
employed for the stereoselective reduction of alkynes to
(Z)-alkenes with low levels of Z/E isomerization and
overreduction.1 Although alkynes containing diverse
functionality have been successfully reduced in this
reaction,2 most substrates containing amines are pro-
tected before a half-reduction is performed.3 We report
that a primary amine functionality in the vicinity of an
alkyne accelerates the rate of overreduction using Lind-
lar’s catalyst to the point where the reaction is no longer
chemoselective; however, addition of approximately 1
equiv of ethylenediamine (EDA) to the hydrogenation
mixture affords a well-controlled reduction that produces
e0.5% of the overreduced impurity.
b
rt. Ratio of products determined by HPLC analysis. See Sup-
porting Information for details.
chemoselectivity between the Lindlar reduction of hy-
droxyalkyne (1a ) and its aminoalkyne counterpart (4a ,
Table 1). With low catalyst loading (10 wt %) in DMF,4
the hydrogenation of 1a with Lindlar’s catalyst proceeded
to completion in 18 h to afford (Z)-hydroxyalkene 1b with
typical levels (8%) of the trans isomer (1c) and 0.7% of
the overreduced product (1d ). In contrast, under the same
conditions, the half-reduction of 4a was complete in less
than 1 h with significant isomerization to the (E)-
aminoalkene 4c and overreduction to the aminoalkane
4d .5,6 Moreover, the overreduction was completely un-
controlled, continuing until 4d was the sole product of
the reaction. The increased rate of reaction of 4a versus
that of 1a could be attributed to preassociation of the
amine functionality in 4a to the catalyst surface.7 This
accelerated reaction rate would also be observed for the
product 5b, causing overreduction to be a significant side
reaction.8
Closer investigation of the hydrogenation of 4a at lower
catalyst loadings (4 wt %) revealed that overreduction
was only significant AFTER the alkyne was completely
consumed.9 Although it is theoretically possible to stop
the hydrogenation at a point where 4a is consumed and
4d has not been formed in significant quantity, this
solution is irreproducible, unreliable, and poorly con-
Resu lts a n d Discu ssion
(4) Typical solvents for Lindlar’s half-reduction (ethyl acetate,
heptane, toluene, or acetone) afforded more overreduction and Z/E
isomerization.
In our pursuits to synthesize (Z)-aminoalkene 4b (n )
3), we discovered a dramatic difference in rate and
(5) Significant overreduction has been observed with other sub-
strates containing unprotected amines. (a) Lindel, T.; Hochguertel, M.
Tetrahedron Lett. 1998, 39, 2541-2544. (b) Sagi, G.; Oetvoes, L.; Ikeda,
S.; Andrei, G.; Snoeck, R.; De Clerq, E. J . Med. Chem. 1994, 37, 1307-
1311. (c) Merino, P.; Castillo, E.; Franco, S.; Merchan, F. L.; Tejero, T.
Tetrahedron: Asymmetry 1998, 9,1759-1769. (d) Cliff, M. D.; Pyne,
S. G. J . Org. Chem. 1997, 62, 1023-1032.
(6) Hydrogenation of 4a as the HCl salt was unsuccessful, affording
only 20% conversion; however, hydrogenation of 4a NBoc derivative
was clean with <1% overreduced product and minor Z/E isomerization.
(7) The preassociation of an amine to a catalyst surface (Pd/C) has
been previously reported to account for surprising selectivities in olefin
hydrogenations. See: Thompson, H. W.; Wong, J . K. J . Org. Chem.
1985, 50, 4270-4276.
(8) On the basis of this model, highly polar, aprotic solvents such
as DMF would reduce the reaction rate, whereas less polar solvents
such as heptane or ethyl acetate would favor substrate/catalyst
interactions, leading to increased reaction rates. This is in accord with
our experimental data (ref 4).
(9) With only 4 wt % catalyst, the hydrogenation was complete in
less than 2 h. At the end of the reaction, the ratio of 4b:4c:4d was
94:4:2; however, by the time that the ratio had been determined by
HPLC (25 min), the ratio had already changed to 91:5:4.
(1) Lindlar, H.; Dubuis, R. Organic Syntheses; Wiley: New York,
1973; Collect. Vol. V, pp 880-883.
(2) (a) Evans, D. A.; Fitch, D. M. Angew. Chem., Int. Ed. 2000, 39,
2536-2540. (b) Nicolaou, K. C.; Xu, J .-Y., Kim, S.; Ohshima, T.;
Hosokawa, S.; Pfefferkorn, J . J . Am. Chem. Soc. 1997, 119, 11353-
11354. (c) Rzasa, R. M.; Shea, H. A.; Romo, D. J . Am. Chem. Soc. 1998,
120, 591-592. (d) Noyori, R.; Suzuki, M. Angew. Chem., Int. Ed. Engl.
1984, 23, 847-850. (e) Yanagisawa, A.; Habaue, S.; Yamamoto, H.
Tetrahedron 1992, 48, 1969-1980. (f) Zhou, W.-S.; Shen, Z.-W. J .
Chem. Soc., Perkin Trans. 1 1991, 2827-2830.
(3) (a) Fujita, M.; Chiba, K.; Nakano, J .; Tominaga, Y.; Matsumoto,
J . Chem. Pharm. Bull. 1998, 46, 631-638. (b) Li, S.; Kosemura, S.;
Yamamura, S. Tetrahedron Lett. 1994, 35, 8217-8220. (c) Walters,
M. A.; Hoern, A. B. J . Org. Chem. 1994, 59, 2645-2647. (d) Knight,
D. W.; Little, P. B. Tetrahedron Lett. 1998, 39, 5105-5108. (e)
Koskinen, A. M. P.; Paul, J . M. Tetrahedron Lett. 1992, 33, 6853-
6856. (f) Altenbach, H.-J .; Himmeldirk, K. Tetrahedron: Asymmetry
1995, 6, 1077-1080. (g) Hamprecht, D.; J osten, J .; Steglich, W.
Tetrahedron 1996, 52, 10883-10902. (h) Examples containing nitrogen
in a pyridine ring do not appear to require protection. See: Taylor, E.
C.; Yoon, C. J . Org. Chem. 1994, 59, 7096-7098. Teubner, A.; Gerlach,
H. Leibigs Ann. Chem. 1993, 161-165.
10.1021/jo015514a CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/21/2001