Primary amides. A general nitrogen source for catalytic asymmetric aminohydroxylation of olefins

Article abstract of DOI:10.1021/ol000098m

(equation presented) N-Bromo,N-lithio salts of primary carboxamides have been shown to be efficient nitrogen sources for catalytic asymmetric aminohydroxylation of olefins, behaving much like the parent N-bromoacetamide in these reactions. α-Chloro-N-brom

Full text of DOI:10.1021/ol000098m

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2221-2223
Primary Amides. A General Nitrogen
Source for Catalytic Asymmetric
Aminohydroxylation of Olefins
Zachary P. Demko, Michael Bartsch, and K. Barry Sharpless*
Department of Chemistry and the Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
sharples@scripps.edu
Received April 19, 2000
ABSTRACT
N-Bromo,N-lithio salts of primary carboxamides have been shown to be efficient nitrogen sources for catalytic asymmetric aminohydroxylation
of olefins, behaving much like the parent N-bromoacetamide in these reactions. r-Chloro-N-bromoacetamide is a particularly interesting nitrogen
source, as it is functionalized for further reaction, including easy deprotection by treatment with thiourea.
The asymmetric aminohydroxylation (AA) provides a direct
route to enantiomerically enriched vicinal amino alcohols, a
moiety which is widespread throughout the modern phar-
macopoeia.1 The AA has been successfully performed with
a variety of nitrogen sources, including sulfonamides,2,3
carbamates,4 and aminoheterocycles.5 N-Bromoacetamide has
also been demonstrated to act as a nitrogen source in the
AA process,6 but this is the only commercially available
N-bromocarboxamide, and traditional methods to halogenate
amides are limited in scope and facility.7 Here we report
the facile monobromination of a variety of primary amides
and their subsequent use as nitrogen sources in the AA
reaction.
Most N-halogenated oxidants used in the AA are prepared
in situ by N-chlorination with tert-butyl hypochlorite in the
presence of base;8 however, primary carboxamides do not
react under these conditions. Moreover, N-chloro, N-sodio-
carboxamides are much more prone to undergo Hoffmann
rearrangement9 in the presence of base than their N-bromo,
N-lithio counterparts. A largely unappreciated paper by
Gottardi10 reported dibromoisocyanuric acid (DBI) to be a
(1) The Merck Index, 12th ed.; Chapman & Hall: New York, 1996. Shaw,
G. In ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C.
W., Scriven, E. F. V., Eds.; Pergamon: New York, 1996; Vol. 7, pp 397-
429.
(2) Li, G.; Chang, H-.T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl.
1996, 35, 451-454. (b) Li, G.; Sharpless, K. B. Acta Chem. Scand. 1996,
50, 649-651.
(3) (a) Rudolph, J.; Sennhenn, P. C.; Vlaar, C. P.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2810-2813. (b) Reddy, K. L.; Dress, K.
R.; Sharpless, K. B. Tetrahedron Lett. 1998, 39, 3667-3670. (c) Kolb, H.
C.; Sharpless, K. B. In Transition Metals for Fine Chemicals and Organic
Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: New York, 1998; Vol.
2., pp 243-260. (d) Schlingloff, G.; Sharpless, K. B. In Asymmetric
Oxidation Reactions: A Practical Approach; Katsuki, T., Ed.; Oxford
University: Oxford, U.K.; in press.
(4) Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl.
1996, 35, 2813-2817.
(5) (a) Goossen, L. J.; Liu, H.; Dress, K. R.; Sharpless, K. B. Angew.
Chem., Int. Ed. 1999, 38, 1080-1083. (b) Dress, K. R.; Goossen, L. J.;
Liu, H.; Jerina, D. M.; Sharpless, K. B. Tetrahedron Lett. 1998, 39, 7669-
7672.
(6) Bruncko, M.; Schlingloff, G.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1483-1486.
(7) (a) Park, J. D.; Gerjovich, H. J.; Lycan, W. R.; Lacher, J. R. J. Am.
Chem. Soc. 1952, 74, 2189-2192. (b) Bachard, C.; Driguez, H.; Paton, J.
M.; Touchard, D.; Lessard, J. J. Org. Chem. 1974, 39, 3136-3138. (c)
Kajigaeshi, S.; Nakagawa, T.; Fujisaki, S. Chem. Lett. 1984, 2045-2046.
(8) The exceptions are the three commercially available halogenated
nitrogen salts, (N-chloro,N-sodio-p-toluenesulfonamide, N-chloro,N-sodio-
benzene sulfonamide, and N-bromoacetamide), and the recently reported
N-bromobenzamide (see: Song, C. E.; Oh, C. R.; Roh, E. J.; Lee, S.; Choi,
J. H. Tetrahedron Asymmetry 1999, 10, 671-674).
(9) Wallis, E. S.; Lane, J. F. Org. React. 1967, 3, 267-306.
(10) Gottardi, W. Monatsh. Chem. 1975, 106, 611-623.
10.1021/ol000098m CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/28/2000

As nitrogen sources, aliphatic carboxamides were found
to give the best results, with butyramide and acetamide
showing greater than 95% conversion of isopropyl cinnamate
to the corresponding â-hydroxyamide. Moderate steric
hindrance does not have a marked effect on yield, although
enantiomeric excess suffers slightly; e.g., see entry 2d.
Highly hindered carboxamides such as tert-butyl carbox-
amide and 1-adamantyl amide, however, give very low
yields. Aromatic carboxamides are not as effective, showing
a lower conversion, less regioselectivity, and lower levels
of asymmetric induction.
Scheme 1
mild and highly effective brominating agent (Scheme 1).
Using DBI11 we were able to efficiently monobrominate a
variety of carboxamides. The bromination typically proceeds
in 90-99% conversion; filtration of the poorly soluble
isocyanuric acid and a single recrystallization gives the
N-bromocarboxamide in high purity.12
Variation of the electronic nature of the carboxamides
established a narrow window for successful asymmetric
aminohydroxylation reactivity. Electron-deficient amides
react more slowly, but as they are less likely to undergo
Hoffmann rearrangement, higher temperatures can be used.
Amides that are more electron-deficient than chloroacetamide
give lower aminohydroxylation yields, and the diol becomes
a major product, presumably because hydrolysis of the
putative osmium imido intermediate is more rapid. Con-
versely, N-bromo, N-lithio species from electron-rich amides
react faster but are also more sensitive to decomposition, so
that lower temperatures are beneficial.
Addition of an N-bromocarboxamide 1 to a tert-butyl
alcohol/water solution of the olefin, osmium, ligand, and base
causes the lavender solution to turn deep green, consistent
with the expected formation of a dioxo osmium(VI) monoaza-
glycolate species.13 Upon completion of the reaction as
monitored by TLC, workup affords the AA product 2 in
isolated yields as high as 94%. All four stereo- and
regioisomers are accessible by varying the ligand.14 A variety
of carboxamides were tested using isopropyl cinnamate as
the olefin (Table 1).
2-Chloroacetamide was used as a standard amide to
explore the scope of the olefin component because it
performs well and because its R-chloro substituent makes it
very useful for subsequent derivitization reactions (see Table
2). Moreover, it is a useful amine-protecting group, being
Table 1. Asymmetric Aminohydroxylation of Isopropyl
Cinnamate Using Various Amides as the Nitrogen Source
(11) Procedure: to a well-stirred solution of cyanuric acid (12.9 g, 100
mmol) and LiOH (8.4 g, 200 mmol) in water (1 L) is slowly added Br2
(63.9 g, 400 mmol). After the bromine is dissolved, the solution is placed
in the refrigerator overnight. The solution is then filtered, and the filtrate is
dried in vacuo to yield DBI as a white powder. Taken from: Encyclopedia
of Reagents for Organic Synthesis; Paquette, L., Ed.; Wiley: West Sussex,
1995; p 1560.
(12) Representative bromination: To a solution of chloroacetamide (4.34
g, 46.4 mmol) in DCM (300 mL) was added DBI (8.00 g, 1.2 equiv) and
the suspension was refluxed in the dark for 5 h. The reaction mixture was
filtered, and the precipitate was washed with CH2Cl2 (2 × 150 mL, or, in
the case of poorly soluble N-bromoamides, with boiling EtOAc), and the
solvent was removed under reduced pressure to afford the crude product
as a white powder10 (7.75 g, 97%), which by 1H NMR analysis was shown
to be 99% N-bromo chloroacetamide and 1% starting material. N-
Bromoamides were stored under vacuum.
(13) Representative asymmetric aminohydroxylation [isopropyl (2R,3S)-
3-(butyramido)-2-hydroxy-3-phenylpropanoate]: To a 500 mL round-bottom
flask was added water (150 mL), in which was fully dissolved K2OsO4‚
2H2O (81 mg, 4.4 mmol) and LiOH‚H2O (273 mg, 1.3 equiv). The ligand,
(DHQ)2PHAL (156 mg, 4.0 mmol), and isopropyl cinnamate (951 mg, 5.0
mmol) were dissolved in t-BuOH (100 mL), and the two solutions were
combined and stirred until homogeneity was achieved. The solution was
cooled to 4 °C. N-bromo butyramide (1.16 g, 1.40 equiv) was added in one
portion. The reaction mixture was vigorously shaken until the pink solution
turned a bright green. In some cases sonication was necessary. The reaction
mixture was left to stir a constant temperature (4 °C). When the reaction
had reached completion, Na2SO3 (1.0 g) was added and the solution was
stirred for 30 min. The aqueous layer was extracted with ethyl acetate (3 ×
100 mL). The combined organic layers were washed with brine (20 mL),
dried over Na2SO4, and filtered, and the solvent removed under reduced
pressure. Chromatography of the crude product on silica gel with 2% MeOH
in CH2Cl2 afforded 2a as a white powder (1.38 g., 94%, 21:1 regioisomeric
ratio).
(14) In the case of 2-chloroacetamide as the N-source, and isopropyl
cinnamate as olefin, when the (DHQ)2AQN ligand is used, the benzylic
alcohol is favored over the benzylamine by a ratio of 3.2:1. For precedence
see: Tao, B.; Schlingloff, G.; Sharpless, K. B. Tetrahedron Lett. 1998, 39,
2507-2510. When the (DHQD)2PHAL ligand is used, the enantioselectivity
was also 95%, with the (2S,3R) product predominating.
a As determined by 1H NMR spectroscopy of crude product. b Combined
isolated yield of both regioisomers. c Major product. d Hoffmann rearrange-
ment product interfered with isolation of product.
2222
Org. Lett., Vol. 2, No. 15, 2000

narrow window for optimal reactivity. Unexpectedly, we
found that when the nonrecrystallized N-bromoamide con-
taining several percent of the primary amide starting material
is used, the reaction is more reliable,17 especially when
2-chloroacetamide is used as the nitrogen source. The amount
of primary amide impurity present should be kept below 5%
if possible.
Table 2. Asymmetric Aminohydroxylation of Various Olefins
Using R-Chloroacetamide as the Nitrogen Source
The diol byproducts, very similar in polarity to the desired
hydroxyamides, are often challenging to remove chromato-
graphically. A useful method to remove the diol is to simply
treat the crude reaction product in a 4:1 (v:v) THF:water
mixture with roughly 2 equiv of periodic acid (with respect
to estimated diol content, monitor by TLC). This effects
selective cleavage of the diol to the aldehydes which are
then readily separated from the desired product.
In cases where solubility was an issue, for example with
N-bromo-p-methoxybenzamide, we used 1-propanol in place
of tert-butyl alcohol with no noticeable difference. Reactions
were also carried out in acetonitrile/water and THF/water,
but lower yields were observed.
The concentration of the reaction is of paramount impor-
tance. When the AA reaction was run under more dilute
conditions, we observed higher regioselectivities, presumably
due to the more selective first cycle being favored.18
However, since decomposition of the N-bromo, N-lithio
carboxamides is assumed to be concentration independent,
too dilute conditions should favor Hoffman rearrangements
again a compromise is needed.
The reaction temperature employed depended on the
electronic nature of the amide: for acetamides and benz-
amides with electron-withdrawing substituents the reaction
was run at 12 °C, with electron-donating substituents it was
run at 0 °C, otherwise it was run at 4 °C.
a Combined isolated yield of both regioisomers. b Major product. c As
determined by H NMR spectroscopy of crude product.
1
readily removed in the presence of 1 equiv of thiourea at
reflux first in ethanol and then in water.15
Acknowledgment. We thank the National Institute of
General Medical Sciences, National Institutes of Health (GM-
28384), the National Science Foundation (CHE-9531152),
the National Science Foundation graduate fellowship (DGE-
9616174) (Z.D.), the W. M. Keck Foundation, and the
German Academic Exchange Service (DAAD) (M.B.) for
financial support and are grateful to Dr. M. G. Finn for
helpful discussions.
Cinnamates were shown to give the highest regioselec-
tivities (see entries 2a-f), presumably due to the favorable
aromatic interactions in the binding pocket.16 Styrene and
its derivatives also reacted well with excellent enantioselec-
tivities, but poor to moderate regioselectivities (3a,b).
Nonconjugated olefins gave inferior results compared to
conjugated olefins (3c). Similar observations have been made
for other versions of the AA process.3,6
We found the amount of base to be critical. Excess base
is known to shut down the catalytic cycle entirely.5a On the
other hand we also observed that insufficient base can
significantly reduce catalytic turnover rates, leaving a very
Supporting Information Available: Full character-
ization for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL000098M
(15) (a) Masaki, M.; Kitahara, T.; Kurita, H.; Ohta, M. J. Am. Chem.
Soc. 1968, 90, 4508-4509. (b) Steglich, W.; Batz, H. G. Angew. Chem.,
Int. Ed. Engl. 1971, 10, 75-76. (c) Greene, T. W.; Wuts, P. G. M. ProtectiVe
Groups in Organic Synthesis; John Wiley & Sons: New York, 1991; pp
352-353.
(16) Kolb, H. C.; Andresson, P. G.; Sharpless, K. B. J. Am. Chem. Soc.
1994, 116, 1278-1291.
(17) Use of 10 mol % catalyst and ligand greatly increased both the
reliability and the selectivity of the reaction. It also was noted that when
the pH of the solution was above 9, or above 8 for electron-deficient amides,
no reaction was observed.
(18) Chang, H.-T. Ph.D. Thesis, The Scripps Research Institute (US),
1996.
Org. Lett., Vol. 2, No. 15, 2000
2223