Catalytic, asymmetric α-halogenation [17]

Full text of DOI:10.1021/ja005791j

J. Am. Chem. Soc. 2001, 123, 1531-1532
1531
reagent then reacts at the R-position of the enolate to afford an
acylammonium salt, which undergoes transacylation with the
leaving group (LG-) to regenerate the catalytic nucleophile (eq
1). The primary goal here is to employ a less reactive halogenating
reagent that possesses minimal background rate with the substrate
of interest under the reaction conditions. Along these lines, mild
sources of electrophilic halogen such as N-halosuccinimides (NCS,
NBS) and alkylhypochlorites6 were screened, employing easy-
to-prepare, inexpensive benzoylquinine (BQ) 2a as the catalyst.7
Phenylacetyl chloride 1a was used as a test substrate to screen
the various halogenating agents using 10 mol % alkaloid catalyst
in toluene at -78 °C in the presence of 1.1 equiv of 3.
Unfortunately, the N-halosuccinimides and alkylhypochlorites
yielded only small amounts of product, and they were not
investigated further.
Catalytic, Asymmetric r-Halogenation
Harald Wack, Andrew E. Taggi, Ahmed M. Hafez,
William J. Drury, III, and Thomas Lectka*
Department of Chemistry, Johns Hopkins UniVersity
3400 North Charles Street, Baltimore, Maryland 21218
ReceiVed NoVember 15, 2000
The central importance of halogenation reactions, in which
organic molecules are formally oxidized, is a widely accepted
fact in synthetic organic chemistry. Halocarbon products are useful
chemical intermediates, serving as branch points in the synthesis
of numerous functionalized molecules.1 Within this context,
R-halogenations of carbonyl compounds have played a particularly
notable role.2 For over 100 years, the most commonly used
halogenation reagents for this purpose have been diatomic halides,
which are known to be highly reactive and in some cases very
nonselective. For this reason R-halogenation reactions are not
often deliberately catalyzed, and the chemical control and
selectivity derived from a finely tuned catalytic process is not
brought to bear. Similarly, the full utility of chiral, optically active
R-carbonyl halides3 could be extended by suitable catalytic,
asymmetric halogenation reactions.4 The products would serve
as useful precursors for optically active amines, ethers, and
sulfides. We report herein a tandem asymmetric halogenation/
esterification process of inexpensive acyl halides that successfully
addresses the twin problems of catalysis and enantioselectivity
to yield highly optically enriched R-haloesters as versatile products
(eq 1).
At this point we were attracted by the electrophilic perhalo-
quinone-derived reagents 5a8 and 5b,9 in which “positive” halogen
is transferred to release aromatic phenolate anions in a thermo-
dynamically more favorable process. The safe, commercially
available perchlorinated quinone 5a gave good results, affording
product in moderate yield and high enantioselectivity (ee). To
our surprise, we found that derivatives of cinchona alkaloids such
as BQ (2a) are significantly more catalytically active than typical
tertiary amines in this halogenation reaction. For example, 1a was
treated with 1.1 equiv of 3 in toluene at -78 °C in the presence
of 10 mol % 2a and 1 equiv of halogenating reagent 5a to form
a dark red solution at -78 °C. After 2 h, quenching the reaction
with saturated NaHCO3 and chromatography yielded product (S)-
6a in 40% yield and 95% ee.10 We detected achiral ester 8a
(∼30%) as the product of the reaction of phenylketene with
pentachlorophenol, implying that under certain conditions 3
becomes an unwanted participant in the halogenation.
The first problem we addressed concerned catalysis. We
envisioned a strategy wherein chiral nucleophiles would attack
in situ generated ketenes 4a-f to form zwitterionic enolates. In
our initial attempts, we generated ketenes through our previously
reported “relay” deprotonation strategy,5 in which protons are
shuttled from the chiral amine catalyst to a thermodynamically
strong, but kinetically weak base. An electrophilic halogenating
We found that 3 is very easily ring-chlorinated by 5a under
reaction conditions to yield proton sponge derivative 7,11 in a
process that not only consumes chlorinating agent but liberates
pentachlorophenol that can engage in competitive ketene alco-
holysis (eq 2). When 7 was used as a base in the reaction of 1a
(1) (a) March, J. AdVanced Organic Chemistry: Reactions, Mechanisms
and Structure, 4th ed.; John Wiley & Sons: New York, 1992. (b) Carey, F.
A.; Sundberg, R. J. AdVanced Organic Chemistry, 3rd ed.; Plenum: New
York, 1990.
(2) (a) House, H. Modern Synthetic Reactions, 2nd ed.; W. A. Benjamin:
New York, 1972; pp 459-478. (b) De Kimpe, N.; Verhe´, R. The Chemistry
of R-Haloketones, R-Haloaldehydes, and R-Haloimines; John Wiley & Sons:
New York, 1988.
(3) (a) Togni recently reported an elegant Lewis acid-catalyzed asymmetric
fluorination of R-keto esters: Hintermann, L.; Togni, A. Angew. Chem., Int.
Ed. 2000, 39, 4359-4362. (b) Evans has developed an auxiliary-based route
to R-chloroimides: Evans, D. A.; Ellman, J. A.; Dorow, R. L. Tetrahedron
Lett. 1987, 28, 1123-1126.
(4) It is useful to distinguish between asymmetric processes in which
halogen adds as either an electrophile or a nucleophile. The latter category
includes the enantioselective opening of meso epoxides: Jacobsen, E. N. Acc.
Chem. Res. 2000, 33, 421-431.
(5) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J., III;
Lectka, T. J. Am. Chem. Soc. 2000, 122, 7831-7832.
(6) For example, tert-butyl hypochlorite was prepared by Walling’s
method: Walling, C.; Padwa, A. J. Org. Chem. 1963, 27, 2976-2977.
(7) For other timely uses of cinchona alkaloids in catalytic asymmetric
synthesis see ref 5 and others contained therein. Cinchona alkaloid derivatives
have recently been used as stoichiometric reagents for asymmetric halogena-
tion: (a) Cahard, D.; Audouard, C.; Plaquevent, J.-C.; Roques, N. Org. Lett.
2000, 2, 3699-3701. (b) Shibata, N.; Suzuki, E.; Takeuchi, Y. J. Am. Chem.
Soc. 2000, 122, 10728-10729.
(8) Guy, A.; Lemaire, M.; Guette, J.-P. Synthesis 1982, 12, 1018-1020.
Compound 5a can be purchased from Aldrich Chemicals.
(9) For a recent use of 5b, see: Tanaka, A.; Oritani, T. Biosci. Biotechnol.
Biochem. 1995, 34, 516-517.
(10) See Supporting Information for experimental details.
(11) Pietrzak, M.; Stefaniak, L.; Pozharskii, A. F.; Ozeryanskii, V. A.;
Nowicka-Scheibe, J.; Grech, E.; Webb, G. A. J. Phys. Org. Chem. 2000, 13,
35-58.
10.1021/ja005791j CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/26/2001

1532 J. Am. Chem. Soc., Vol. 123, No. 7, 2001
Communications to the Editor
Table 1. Alkaloid Catalyzed Reactions of Acyl Halides 1 with
Halogenating Agents 5a and 5b to Form R-Haloesters 6
yielding the enantiomer (R)-6b in high ee (entry 5). We undertook
a preliminary study with brominating agent 5b (entry 6) that
shows its viability as a halogenating reagent for a challenging
monoketene. Under standard conditions, the reaction provides
R-bromide (S)-6c in 50% yield and 99% ee. 1-Naphthylacetyl
chloride 1c (entry 7) affords product in fair yield and high ee
(95%) as does 2-naphthylacetyl chloride 1d (63% yield, 94% ee).
2-Thienylacetyl chloride leads to (S)-6f in good yield (66%) and
fair ee (80%). Entry 10 shows a R-chlorination in the presence
of CdC bond that migrated under the basic reaction conditions
to afford the achiral product 6g. Although 9 is exemplary at
forming solutions of many monoketenes, especially aromatic ones,
bromoacetyl bromide 1g (which generates the intermediate
bromoketene) affords the R,R-bromochloroester (S)-6h in high
ee but low yield. Poor mass recovery for the reaction suggests
that 9 reacts with bromoketene.14 High ee (97%) and moderate
yield (51%, entry 11) can be attained in this reaction by the use
of 1.1 equiv of 2a. In this instance 2a is a substoichiometric
catalyst, but also a stoichiometric dehydrohalogenating agent. This
result makes it clear that, in view of the large reactivity spectrum
of ketenes, each must be optimized on a case-by-case basis.
In conjunction with a solid-phase base, we investigated the
reaction employing a solid-phase catalyst of resin-bound quinine.13
Solutions of ketene 4a and chlorinating agent 5a were added to
a jacketed addition funnel cooled to -78 °C packed with the
catalyst-loaded beads. To our surprise, the reaction failed due to
apparent rapid catalyst deactivation. The quinine moiety was
cleaved from the polymeric support (NaBH4, EtOH) and rechar-
acterized. The spectroscopic data (NMR, MS) are consistent with
the unusually stable putative N-chloro species 2c.15 Isolation and
resubmission of 2c to reactions in solution show that it is
completely inactive under a spectrum of different conditions.16
In this experiment, we inadvertently shed light on a mechanistic
pointsnamely whether chlorine is transferred from the reagent
to a zwitterionic enolate, or through an intermediary such as 2c.
The inactivity of 2c seems to disfavor transfer of chlorine from
catalyst to ketene.
and 5a catalyzed by 2a, the amount of alcoholysis product was
reduced by ∼50%, confirming that in situ chlorination of proton
sponge can pose a problem. Given the potential byproducts of
the proton sponge reaction, we sought another method of ketene
generation using a solid-phase base that obviated the presence of
byproduct salts (eq 3).
As an illustration of the utility of the chlorinated products we
generated from our asymmetric reaction, we found that mixing 1
equiv of benzylamine with product (S)-6a at room temperature
in THF for 2 h produces a virtually quantitative yield of optically
pure derivatized amide 10a (eq 4). The racemic form of 10a is
known to exhibit powerful anticonvulsant activity.17 Further
studies on the asymmetric halogenation of organic molecules,
including catalytic fluorination processes, are underway and will
be reported in due course.
The basic resin BEMP (9), a triaminophosphonamide imine
bound to a polymeric support,12 produces many ketenes rapidly
and virtually quantitatively when a THF solution of 1a-f is passed
through an addition funnel at -78 °C containing the polymer.13
The ketene solution is added dropwise to a flask (-78 °C)
containing catalyst 2a (10 mol %) to which 5a (1 equiv) was
added. After stirring at -78 °C for 4 h, quenching was followed
by chromatography, and the product (S)-6a was isolated in 99%
ee and 80% yield, free from alcoholysis product 8a (Table 1,
entry 2). When we used “psuedoenantiomeric” benzoylquinidine
2b as catalyst, the opposite enantiomer (R)-6a was obtained in
comparable yield and ee (entry 3).
Acknowledgment. T.L. thanks the NIH and NSF Career Program
for general lab support, DuPont, Eli Lilly for a Grantee Award, the
Dreyfus Foundation for a Teacher-Scholar Award, and the Alfred P. Sloan
Foundation for a Fellowship. H.W. thanks Johns Hopkins for a Whittaker
Chambers Fellowship.
Supporting Information Available: Experimental procedures, com-
pound characterization, and stereochemical proofs (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
JA005791J
A number of other acid chlorides were screened in the reaction.
For instance, the R-chloroester (S)-6b derived from 3-phenoxy-
propionyl chloride 1b was obtained in 57% yield and 97% ee
(entry 4). This substrate also performed well with catalyst 2b,
(14) In this case, the color of the BEMP turned purple, an unusual
occurrence not witnessed when any other ketene was generated.
(15) Similar N-chloro amines have been investigated: Lindsay Smith, J.
R.; McKeer, L. C.; Taylor, J. M. J. Chem. Soc., Perkin Trans. 1987, 1533-
1537.
(12) Schwesinger, R.; Willaredt, J.; Schlemper, H.; Keller, M.; Schmitt,
D.; Fritz, H. Chem. Ber. 1994, 127, 2435-2454.
(13) Hafez, A. M.; Taggi, A. E.; Wack, H.; Drury, W. J., III; Lectka, T.
Org. Lett. 2000, 2, 3963-3965.
(16) The probable existence of BQ-Cl+ was based upon standard experi-
mental data; see Supporting Information for details.
(17) Choi, D.; Stables, J. P.; Kohn, H. Bioorg. Med. Chem. 1996, 12, 2105-
2114.