Asymmetric hydrogenation of o-alkoxy-substituted arylenamides

Article abstract of DOI:10.1021/jo049723h

A series of (2-alkoxyaryl)glycinols have been prepared in up to 97.8% ee by asymmetric hydrogenation with cationic rhodium Me-BPE or Me-DuPhos complexes. Others have shown that the presence of ortho substituents on related α-arylenamides causes a decrease in enantioselectivity. However, in this study it was found that o-alkoxy α-arylenamides were reduced with high enantioselectivity irrespective of substituent size.

Full text of DOI:10.1021/jo049723h

Asym m etr ic Hyd r ogen a tion of o-Alk oxy-Su bstitu ted Ar ylen a m id es
J ulie Cong-Dung Le and Brian L. Pagenkopf*
Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, Texas 78712
pagenkopf@mail.utexas.edu
Received February 16, 2004
A series of (2-alkoxyaryl)glycinols have been prepared in up to 97.8% ee by asymmetric
hydrogenation with cationic rhodium Me-BPE or Me-DuPhos complexes. Others have shown that
the presence of ortho substituents on related R-arylenamides causes a decrease in enantioselectivity.
However, in this study it was found that o-alkoxy R-arylenamides were reduced with high
enantioselectivity irrespective of substituent size.
The value of â-amino alcohols as chiral ligands in
asymmetric catalysis,1 as resolving agents in asymmetric
synthesis,2 and as building blocks of many important
biologically active compounds3 is well-documented. As a
consequence, the development of efficient synthetic meth-
ods for the preparation of these compounds in optically
pure form is of considerable interest. Recently, we
required a scaleable and efficient route to a family of
optically active (2-hydroxyphenyl)glycinols and (2-alkoxy-
phenyl)glycinols. Such amino alcohols can in principle be
obtained by several methods, including asymmetric ami-
nohydroxylation of styrenes4 or reduction of the corre-
sponding R-amino acids or esters.5 The development of
synthetic strategies for accessing arylglycines has been
spurred in part by interest in vancomycin antibiotics, and
noteworthy approaches include cuprate or Friedel-Crafts
coupling to bromoglycinates,6 amination (or the equiva-
lent) of R-aryl enolates,7 and TiCl4-promoted Friedel-
Crafts reaction of phenols with chiral N,O-hemiacetals.8
Given the commercial unavailability of starting materials
or the need for chiral auxiliaries by these methods, we
sought to access the desired amino alcohols by asym-
metric hydrogenation.
Recently, Zhang and co-workers reported a practical
and highly enantioselective synthesis of â-amino alcohols
by rhodium-catalyzed asymmetric hydrogenation of
R-arylenamides with a MOM-protected â-hydroxy group.9
Despite the ostensible utility of that published procedure,
we are unaware of its application to the asymmetric
hydrogenation of arylenamides bearing o-hydroxy or
o-alkoxy substituents. Herein, we wish to report a highly
enantioselective asymmetric hydrogenation of new aryl
o-alkoxy-substituted enamides catalyzed by a cationic
rhodium Me-DuPhos or Me-BPE catalyst system (Scheme
1).10,11
Arylenamides bearing o-hydroxy substituents can be
prepared in gram quantities from readily available of
o-hydroxyacetophenone derivatives by adoption of the
protocols described independently by the groups of Zhang9a
and Burk12 (Scheme 2). Protection of the phenol 1a -k
(K2CO3, acetone, alkyl halide) and R-ketone oxidation
(1) (a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833-856. (b)
Butsugan, Y.; Ariki, S.; Watanabe, M. Ferrocenes; VCH: Weinheim,
Germany, 1995; pp 143-169. (c) Takehara, J .; Hashiguichi, S.; Fujii,
A.; Inoue, S.-i.; Ikariya, T.; Noyori, R. Chem. Commun. 1996, 233-
234. (d) Peper, V.; Martens, J . Chem Ber. 1996, 129, 691-695.
(2) (a) Sawayama, T.; Tsukamoto, M.; Sasagawa, T.; Naruto, S.;
Matsumoto, J .; Uno, H. Chem. Pharm. Bull. 1989, 37, 1382-1383. (b)
Kawai, M.; Omori, Y.; Yamamura, H.; Butsugan, Y. Tetrahedron:
Asymmetry 1992, 3, 1019-1020.
(3) (a) Roemer, D.; Buescher, H. H.; Hill, R. C.; Pless, J .; Bauer, W.;
Cardinaux, F.; Closse, A.; Hauser, D.; Huguenin, R. Nature 1977, 268,
547-549. (b) TenBrink, R. E. J . Org. Chem. 1987, 52, 418-422. (c)
Fincham, C. I.; Higginbottom, M.; Hill, D. R.; Horwell, D. C.; O’Toole,
J . C.; Ratcliffe, G. S.; Rees, D. C.; Robert, E. J . Med. Chem. 1992, 35,
1472-1474. (d) Wu, S. Y.; Takeya, R.; Eto, M.; Tomizawa, C. J . Pestic.
Sci. 1987, 12, 221-227.
(7) (a) Evans, D. A.; Evrard, D. A.; Rychnovsky, S. D.; Fru¨h, T.;
Whittingham, W. G.; DeVries, K. M. Tetrahedron Lett. 1992, 33, 1189-
1192. (b) Evans, D. A.; Nelson, S. G. J . Am. Chem. Soc. 1997, 119,
6452-6453. (c) Vicario, J . L.; Bad´ıa, D.; Dominguez, E.; Crespo, A.;
Carrillo, L.; Anakabe, E. Tetrahedron Lett. 1999, 40, 7123-7126.
(8) Ge, C.-S.; Chen, Y.-J .; Wang, D. Synlett 2002, 37-42.
(9) (a) Zhu, G.; Casalnuovo, A. L.; Zhang, X. J . Org. Chem. 1998,
63, 8100-8101. (b) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029-
3069.
(10) Abbreviations: BICP, 2,2-bis(diphenylphosphino)-1,1-dicyclo-
pentane; BPE, 1,2-bis(2,5-dimethylphospholano)ethane; TangPhos,
1,1′-di-tert-butyl-[2,2′]-diphospholanyl; DuPhos, 1,2-bis(2,5-dialkylphos-
pholane)benzene; Butiphane, 2,3-bis(2,5-diethylphospholan-1-yl)benzo-
[b]thiophene; DIOP, 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphe-
nylphosphino)butane; Walphos, 1-[2-(2′-diphenylphosphinophenyl)ferro-
cenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine; J osiphos, 1-[(2-
dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine; Tania-
phos, 1-diphenylphosphino-2-[R-(N,N-dimethylamino)-o-(diphenylphos-
phinohenyl)methyl]ferrocene; Mandyphos, 2,2′-bis(R-N,N-dimethyl-
aminophenylmethyl)-1,1′-bis(dicyclohexylphosphino)ferrocene.
(11) For the syntheses of these complexes see: Burk, M. J .; Feaster,
J . E.; Nugent, W. A.; Harlow, R. L. J . Am. Chem. Soc. 1993, 115,
10125-10138.
(4) (a) O’Brien, P.; Osborne, S. A.; Parker, D. D. J . Chem. Soc.,
Perkin Trans. 1 1998, 2519-2526. (b) Li, G.; Chang, H.-T.; Sharpless,
K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 451-454. (c) Rudolph,
J .; Sennhenn, P. C.; Vlaar, C. P.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2810-2813. (d) Rubin, A. E.; Sharpless, K. B.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2637-2640.
(5) (a) Gage, J . R.; Evans, D. A. Org. Synth. 1990, 68, 77-82. (b)
Abiko, A.; Masamune, S. Tetrahedron Lett. 1992, 33, 5517-5518. (c)
McKennon, M. J .; Meyers, A. I.; Drauz, K.; Schwarm, M. J . Org. Chem.
1993, 58, 3568-3571. (d) Nicola´s, E.; Rusell, K. C.; Hruby, V. J . J .
Org. Chem. 1993, 58, 766-770.
(6) Williams, R. M.; Hendrix, J . A. J . Org. Chem. 1990, 55, 3723-
3728.
10.1021/jo049723h CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/14/2004
J . Org. Chem. 2004, 69, 4177-4180
4177

Cong-Dung Le and Pagenkopf
TABLE 1. Asym m etr ic Hyd r ogen a tion of
o-Meth oxylp h en yl En a m id e a n d Com p a r ison w ith
SCHEME 1
Non su bstitu ted En a m id e
SCHEME 2
(TMSOTf, Et3N; m-CPBA) gave 2a -k in 75-80% yield
for the three steps. MOM protection followed by reduction
of the ketone oximes with iron powder in acetic anhydride
and DMF gave an inseparable mixture of Z/E enamide
isomers 4a -k .
For the initial catalyst screening, we selected a sub-
strate with the phenol protected as its methyl ether, 4a
(Table 1). The reductions were generally carried out at
room temperature with 1 mol % of rhodium catalyst in
dry, degassed methanol under 170 psi of hydrogen for
24-36 h.
Four different ferrocenyl ligands and p-TolBINAP were
examined, but the enantioselectivities observed with
these were disappointing (entries 1-5). Switching to
DIOP (entry 6) gave a promising 74% ee. Hydrogenation
with Me-DuPhos gave a useful 94.2% ee, but two DuPhos
analogues, Et-Butiphane (entry 7) and Rhophos (entry
8), were slightly less effective (80 and 89% ee, respec-
tively). TangPhos (entry 10) gave an impressive 94.7%
ee, but the best results were attained with Me-BPE (entry
11, 97.8% ee). Note that in the absence of ortho substitu-
tion, DIOP and Rhophos gave noticeably higher ee values
(entries 6 and 8).
We found that preparing the Me-BPE catalyst in situ
(by mixing 1.1 equiv of (S,S)-Me-BPE and 1.0 equiv of
[(COD)2Rh]+OTf- prior to introduction of enamide) gave
slightly lower enantiomeric excess than when the dis-
crete, isolated rhodium-ligand complex was employed
(94% ee vs 98% ee). Varying the hydrogen pressure from
30 to 210 psi did not substantially affect any of the
observed ee values with the ortho-substituted enamides
(except for entry 10). Complete conversion was observed
in all cases.
Also included in Table 1 are the ee values measured
for hydrogenation of the parent unsubstituted enamide,
and similar enantioselectivity was obtained with this
series of ligands.9 The high enantiomeric excess observed
from hydrogenation of the ortho-substituted enamides is
significant because it has been reported that in reduction
of enamides lacking the 2-O-MOM group that replacing
a
Reactions were carried out with in situ generated Rh catalysts.
b
Reactions were carried out with 1 mol % isolated Rh catalysts.
c Opposite enantiomer predominated. Hydrogenation was done
d
in methanol at ca. 40 °C under 200 psi of H2. e Sodium carbonate
is used as a base and hydrogenation was done in methanol at room
temperature under 14 psi of H2. f Hydrogenation was done in THF
g
at room temperature under 20 psi of H2. The ee values were
determined by chiral HPLC (Whelk-O1) with i-PrOH and hexanes.
Complete conversion was observed in all cases (97-98% yield).
(12) Burk, M. J .; Casy, G.; J ohnson, N. B. J . Org. Chem. 1998, 63,
6084-6085.
4178 J . Org. Chem., Vol. 69, No. 12, 2004

Hydrogenation of o-Alkoxy-Substituted Arylenamides
TABLE 2. Asym m etr ic Hyd r ogen a tion of
P h en ylen a m id es w ith Differ en t P h en olic P r otective
Gr ou p s
TABLE 3. Asym m etr ic Hyd r ogen a tion of Ar om a tic
En a m id es
% eeb (5) for two ligands
entrya
R
(R,R)-Me-BPE
(R,R)-Me-DuPhos
1
2
3
4
Me (a )
CH2CH2Cl (b)
Bn (c)
97.8
96.9
97.2
93.9
94.2
93.8
95.4
92.8
PMB (d )
a
Reactions were carried out in methanol at room temperature
b
with 1 mol % of Rh isolated catalysts and 170 psi of H2. The ee
values were determined by chiral HPLC (Whelk-O1) with i-PrOH
and hexanes.
an o-hydrogen with a bromo or methyl group acutely
reduced the observed enantioselectivities (89% and 75%
ee, respectively, vs 98% ee).13
With future synthetic applications for these (2-hydroxy-
phenyl)glycinols in mind, we explored the hydrogenation
of enamides with different phenolic protective groups
(Table 2). Surprisingly, the ee values attained with either
Me-DuPhos-Rh or Me-BPE-Rh catalysts proved to be
remarkably consistent regardless of the size of the
protective group. Methyl, 2-chloroethyl, and benzyl ethers
all gave nearly identical ee values. The more rigid Me-
DuPhos ligand was generally slightly less effective than
the related Me-BPE. From the hydrogenation of aryl-
enamides bearing benzyl and p-methoxybenzyl (PMB)
protecting groups an insignificant amount of debenzyla-
tion products were formed (∼3%) when in situ generated
Rh catalysts were employed.
a
Reactions were carried out in methanol at room temperature
b
with 1 mol % of Rh isolated catalysts and 170 psi of H2. The ee
values were determined by chiral HPLC (Whelk-O1) with i-PrOH
and hexanes.
The influence of substituents at the meta and para
positions was also examined (Table 3). Gratifyingly, the
enantioselectivity proved to be unaffected by additional
aryl substituents or protective group size. Compatible
substrate modifications include the addition of a 5-methyl
(entry 1, 95% ee), a 5-chloro (entry 2, 94% ee), or a 5-tert-
butyl group (entry 4, 94% ee). A 2-naphthyl enamide and
a 4-methoxy were each reduced in 93% ee. No substantial
electronic effects were observed in these reductions,
although the electronic variation within the series of
substrates tested was only moderate (e.g., 5-chloro vs
4-methoxy, Table 3, entries 2 and 7). The substrate in
entry 1 was reduced in the greatest ee by Me-DuPhos,
whereas in all other cases Me-BPE was the most effec-
tive.
Exp er im en ta l Section
Gen er a l P r oced u r e for Hyd r ogen a tion : With in Situ
Gen er a ted Ca ta lyst. [Rh(COD)2]OTf (4.7 mg, 0.01 mmol) and
ligand (0.011 mmol) were added to a test tube in a drybox,
the tube was sealed with a rubber septum, and degassed
MeOH (3 mL) was introduced. After the mixture was stirred
for 10 min, a solution of substrate 4a -k (1 mmol) in MeOH
(3 mL) was added. The flask was placed in an argon-filled high-
pressure stainless steel bomb, the rubber septum was removed,
and the bomb was sealed and charged with H2 [three cycles of
vacuum (20 psi) and hydrogen (20 psig)]. The final fill of H2
was raised to the indicated pressure. After 12-48 h at room
temperature the hydrogen was released, and the reaction
mixture was filtered through a short silica gel plug to remove
the catalyst. Solvent was removed with a rotary evaporator
under vacuum, and the yellow solid was purified by flash
chromatography on silica gel with 20% hexanes/EtOAc to give
the desired product as a white powder (97-98% yield).
Enantiomeric excesses were measured by chiral HPLC ((S,S)-
Poly Whelk-01 column; particle size: 5.0 µm; column dimen-
sions: 25 cm × 0.46 cm).
In summary, a new series of chiral orthogonally N,O-
diprotected ortho-substituted arylglycinols has been pre-
pared in high enantiomeric excess by asymmetric hydro-
genation of arylenamides with commercially available
cationic (R,R)-Me-BPE-Rh and (R,R)-Me-DuPhos-Rh com-
plexes. With these substrates the size of a substituent
at the ortho position was found to have little effect on
the asymmetric induction. The use of these arylglycinols
for the preparation of novel chiral scaffolds with applica-
tions in asymmetric catalysis will be reported elsewhere.
With Isola ted Ca ta lyst. The rhodium-ligand complex was
added to a test tube in a drybox, and subsequently treated as
described above.
Ack n ow led gm en t. J .C.-D.L. is grateful to the Gates
Millennium Scholars for a graduate fellowship. We
thank the Robert A. Welch Foundation, donors of the
(13) Burk, M. J .; Wang, Y. M.; Lee, J . R. J . Am. Chem. Soc. 1996,
118, 5142-5143.
J . Org. Chem, Vol. 69, No. 12, 2004 4179

Cong-Dung Le and Pagenkopf
American Chemical Society Petroleum Research fund,
the Texas Advanced Research Program 003658-0455-
2001, and the DOD Prostate Cancer Research Program
DAMD17-01-1-0109 for partial financial support of this
research. We thank J ohn E. Feaster of DuPont Central
Research & Development for providing generous samples
of (R,R)-Me-DuPhos and (R,R)-Me-BPE rhodium com-
plexes, Prof. Xumu Zhang for TangPhos ligand, and
Solvias for ferrocenyl and Butiphane ligands and rhod-
ium complexes.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal protocols and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O049723H
4180 J . Org. Chem., Vol. 69, No. 12, 2004