Phase-transfer-catalyzed asymmetric acylimidazole alkylation

Article abstract of DOI:10.1021/ol702197r

(Chemical Equation Presented) 2-Acylimidazoles are alkylated under phase-transfer conditions with cinchonidinium catalysts at -40°C with allyl and benzyl electrophiles in high yield with excellent enantioselectivity (79 to >99% ee). The acylimidazole substrates are made in three steps from bromoacetic acid via the N-acylmorpholine adduct. The catalyst is made in high purity allowing for S-product formation (6-20 h) under mild conditions, consistent with an ion-pair mechanism. The products are readily converted to useful ester products using methyltriflate and sodium methoxide, via a dimethylacylimidazolium intermediate without racemization. The process is efficient, direct, and amenable to other electrophiles and transformations that proceed through an enolate intermediate.

Full text of DOI:10.1021/ol702197r

ORGANIC
LETTERS
2007
Vol. 9, No. 23
4865-4868
Phase-Transfer-Catalyzed Asymmetric
Acylimidazole Alkylation
Merritt B. Andrus,* Michael A. Christiansen, Erik J. Hicken, Morgan J. Gainer,
D. Karl Bedke, Kaid C. Harper, Shawn R. Mikkelson, Daniel S. Dodson, and
David T. Harris
Department of Chemistry and Biochemistry, Brigham Young UniVersity, C100 BNSN,
ProVo, Utah 84602
mbandrus@chem.byu.edu
Received September 6, 2007
ABSTRACT
2-Acylimidazoles are alkylated under phase-transfer conditions with cinchonidinium catalysts at
−40
°
C with allyl and benzyl electrophiles in
high yield with excellent enantioselectivity (79 to >99% ee). The acylimidazole substrates are made in three steps from bromoacetic acid via
the N-acylmorpholine adduct. The catalyst is made in high purity allowing for S-product formation (6 20 h) under mild conditions, consistent
−
with an ion-pair mechanism. The products are readily converted to useful ester products using methyltriflate and sodium methoxide, via a
dimethylacylimidazolium intermediate without racemization. The process is efficient, direct, and amenable to other electrophiles and
transformations that proceed through an enolate intermediate.
Asymmetric alkylation is a powerful transformation for
carbon-carbon bond formation, accommodating various
electrophilic coupling partners. While the transformation is
strategic for a wide range of targets, it yet remains limited
to auxiliaries for synthetic applications.1 In an effort to
improve efficiency with a broader scope for sp3-electrophiles,
catalytic versions have been extensively explored. Enolate
alkylations with chiral amine catalysts by Koga employ
cyclic silylenol ethers,2 and more recently, stannylenol ethers
have been developed using chromium-salen catalysts by
Jacobsen.3 Intramolecular proline-catalyzed alkylation is
successful for five- and six-ring formations using iodo-
aldehyde bisesters according to List.4 We now report an
efficient, broadly applicable approach to asymmetric enolate
alkylation using acylimidazoles reacted under mild phase-
transfer conditions with cinchonidine-derived catalysts. This
approach produces a range of products with high selectivity
and is suitable for multistep applications (Scheme 1).
Scheme 1. Phase-Transfer Acylimidazole Alkylation
Phase-transfer-catalyzed (PTC) glycine alkylation, using
either liquid-liquid or solid-liquid conditions, has become
a practical approach to amino acid synthesis.5 The highly
(1) Eames, J.; Suggate, M. J. Angew. Chem., Int. Ed. 2005, 44, 186-
189.
(2) Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga, K. J. Am.
Chem. Soc. 1994, 116, 8829-8830.
(3) (a) Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 62-
63. (b) Doyle, A. G.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2007, 46,
3701-3705.
(5) (a) Ooi, T.; Maruoka, K. Acc. Chem. Res. 2004, 37, 526-533. (b)
Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518-525. (c) Patterson,
D. E.; Xie, S.; Jones, L. A.; Osterhout, M. H.; Henry, C. G.; Roper, T. D.
Org. Process Res. DeV. 2007, 11, 624-627.
(4) Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450-451.
10.1021/ol702197r CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/18/2007

unsaturated diphenylimine tert-butyl ester substrate of
O’Donnell is well suited for enolate formation and alkyl-
ation.6 We recently reported PTC alkylation of aryl ketones
to provide R-hydroxy products with good selectivity, together
with applications for the syntheses of ragaglitazar and
kurasoin A.7 The selectivities were high with a range of
electrophiles, yet a problematic Baeyer-Villiger transforma-
tion was required to convert the PTC product to esters needed
for synthetic applications. 2-Acylimidazoles 1 are now shown
to be suitable for PTC alkylation, possessing an R-hydrogen
sufficiently acidic for low-temperature reactivity through the
ion-paired enolate 2, and the product 3 can be readily
transformed for applications (Scheme 1). Evans recently
reported the use of R,â-unsaturated acylimidazoles for Lewis
acid catalyzed additions.8 2-Acylimidazoles are readily
N-methylated to give an imidazolium intermediate, which
can undergo nucleophilic displacement.9
Figure 1. PTC catalysts.
plete quinuclidine N-arylmethylation with 2,7-bisbromo-
methyl naphthalene.10
PTC reactions were performed to identify the optimal
substrate-catalyst combination and reaction conditions
(Table 1). Solid-liquid conditions were found to be optimal
Acylimidazole 1 was produced in three steps using
inexpensive, convenient reagents (Scheme 2). Bromoacetic
Table 1. Acylimidazole PTC Benzylation
Scheme 2. Synthesis of Acylimidazoles
acid was reacted with benzyloxy nucleophiles corresponding
to the alkoxy group incorporated at the 2-position to give 4.
Intermediate 4 was converted to the N-acyl product 5 using
oxalyl chloride in DMF, and finally, lithiated N-methyl-
imidazole was added to give 1 (P ) 2-naphthylmethyl,
2-NPM) in 73% overall isolated yield. The benzyloxy
substrate (P ) Bn) was also efficiently produced using this
sequence. A variety of cinchona-derived PTC catalysts were
screened for reactivity and selectivity, including N-arylmethyl
cinchonidine as used previously for glycine alkylation (Figure
1).6 The N-trifluorobenzyl hydrocinchonidine (HCD) catalyst
6 and the HCD dimer catalyst 7, based on 2,7-dimethyl-
naphthalene, proved to be most efficient.6g These catalysts
are available in three simple steps from inexpensive cin-
chonidine. The original Park-Jew synthesis of 7 was
modified to ensure high catalyst purity and to avoid the
production of nonselective ammonium salts due to incom-
a RbOH used as base.
using insoluble cesium hydroxide hydrate as base in di-
choromethane (DCM) at -40 °C. Use of liquid-liquid
conditions with aqueous KOH-toluene proved to be unpro-
ductive. With benzyl acylimidazole 1 (N-methyl, P ) Bn),
S-product was produced in high yield (86%) with good
selectivity (74% ee, chiral HPLC) using either catalyst 6 or
7 (10 mol %) with benzyl bromide (entries 1 and 2). Under
these conditions, no N-alkylation or acylimidazole cleavage
was observed, and the reactions were remarkably fast, being
complete in 6-8 h. The 2-naphthylmethyloxy (2-NPM)
acylimidazole substrate 1 was then explored (entries 3-5).
Use of catalyst 6 for PTC benzylation showed improved
selectivity (86% ee), and the cinchonidinium dimer catalyst
(6) (a) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc.
1989, 111, 2353-2354. (b) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem.
Soc. 1997, 119, 12414-12415. (c) Lygo, B.; Wainwright, P. G. Tetrahedron
Lett. 1997, 38, 8595-8598. (d) Ooi, T.; Kameda, K.; Maruoka, K. J. Am.
Chem. Soc. 1999, 121, 6519-6520. (e) Jew, S.; Yoo, M.; Jeong, B.; Park,
I. Y.; Park, H. Org. Lett. 2002, 4, 4245-4248. (f) Park, H.; Jeong, B.;
Yoo, M.; Lee, J.; Park, M.; Lee, Y.; Kim, M.; Jew, S. Angew. Chem., Int.
Ed. 2002, 41, 3036-3038. (g) O’Donnell, M. J.; Delgado, F.; Hostettler,
C.; Schwesinger, R. Tetrahedron Lett. 1998, 39, 8775-8778.
(7) (a) Andrus, M. B.; Hicken, E. J.; Stephens, J. C.; Bedke, D. K. J.
Org. Chem. 2005, 70, 9470-9479. (b) Andrus, M. B.; Hicken, E. J.;
Stephens, J. C.; Bedke, D. K. J. Org. Chem. 2006, 71, 8651-8654.
(8) Evans, D. A.; Fandrick, K. R.; Song, H.-J. J. Am. Chem. Soc. 2005,
127, 8942-8943.
(9) Miyashita, A.; Suzuki, Y.; Nagasaki, I.; Ishiguro, C.; Iwamoto, K.-
I.; Higashino, T. Chem. Pharm. Bull. 1997, 45, 1254-1258.
(10) See refs 6f,g. See Supporting Information for details.
4866
Org. Lett., Vol. 9, No. 23, 2007

7 was most effective, generating product 2 with 91% ee.
Other imidazoles were also synthesized and investigated as
PTC substrates (entries 6-8). N-Methylbenzoimidazole
(entry 6) showed good reactivity (76%) with excellent
selectivity (93% ee), while N-phenylimidazole (entry 7) gave
low yields of racemic product. In contrast, N-benzylimidazole
(entry 8) produced a quantitative yield with moderate
selectivity (69% ee). The N-methylbenzoimidazole substrate
was not found to be general when reacted with other
electrophiles. PTC reactions with this substrate were ac-
companied by N-alkylation, and the conversion to ester
products was also found to be problematic.
good to excellent results to give novel products. Substituted
benzyl bromides (entries 7-9) required longer reactions
times (20 h), and in all cases, excellent yields and near
complete selectivities (>99% ee) were obtained.
The stereoinduction was established by conversion to the
methyl ester 9 (Scheme 3). Treatment with methyltriflate
Scheme 3. Elaboration to Methyl Ester
Other electrophiles were also found to be useful for PTC
alkylation with N-methyl-2-acylimidazole-2-NPM-1 (Table
2). Reactions were performed with 10 mol % of catalyst 7
provided the N,N-dimethylimidazolium intermediate which
was displaced with sodium methoxide to give 2-NPM ester
8 in quantitative yield with no racemization detected (chiral
HPLC). Previous procedures employing methanol and DBU
(diazabicyclo[5,4]undecene) or other bases proved to be less
effective in this case.8,9 Removal of the 2-NPM group with
DDQ (dichlorodicyanoquinone) gave the known (S)-methyl
ester 9 ([R]D -6.25, lit. [R]D -6.8).11
Table 2. PTC Alkylation with Various Electrophiles
The S-stereoinduction is consistent with the model pro-
posed for “pocket” binding mode with the (Z)-enolate located
between the quinoline and quinuclidine groups on the catalyst
and the enolate oxygen being ion paired with the least
hindered face of the catalyst ammonium nitrogen, as depicted
in Figure 2 for transition state A (Figure 2). In this
a Yields represent isolated, purified products. b Chiral HPLC.
Figure 2. Stereoinduction for PTC alkylation.
with 5 equiv of electrophile and CsOH•H2O in a 1:1 mixture
of hexanes and dichloromethane (-40 °C). In some cases,
the order of reagent addition was shown to affect the
outcome. With base added last, slightly higher reaction rates
and selectivities were noted. This effect is in accord with
large-scale investigations recently reported for glycine PTC.5c
With acylimidazole 1, this effect is not as pronounced.
Addition of electrophile or base as the last reagent to the
cold reaction mixture produced comparable results. The
catalyst load in some cases was lowered to 5 mol % without
significant reduction in either yield or selectivity, yet 1 mol
% of catalyst produced very slow reaction rates. Use of allyl
and methallyl bromides (entries 1 and 2) gave products in
high yields and very good selectivities (88 and 86% ee).
Other allylic electrophiles included (E)-2-pentenyl, geranyl,
and (Z)-2-octenyl bromides (entries 3-5), which reacted with
arrangement, the extended π-system of the enolate and the
imidazole interact with the quinoline of the catalyst, and the
2-NPM group of the substrate is also aligned with the aryl
moiety attached to the quinuclidine nitrogen, leading to the
observed S-product 2. A (Z)-enolate geometry is predicted
to be lower in energy for the acylimidazole, consistent with
trapping experiments made with arylketones reacted under
PTC conditions.7a In contrast, the corresponding E-geometry
is favored for the tert-butyl glycine enolate.6 Arrangement
B lacks the extended π-interactions with only minimal
contact with the enolate and the imidazole, leading to the
minor R-isomer of 2.
(11) Burk, M. J.; Kalberg, C. S.; Pizzano, A. J. Am. Chem. Soc. 1998,
120, 4345-4353.
Org. Lett., Vol. 9, No. 23, 2007
4867

Acylimidazole PTC alkylation is shown to be a general
approach to enantioenriched R-hydroxy products with broad
utility using simple, readily available substrates and catalysts.
Applications to other transformations and target directed
synthesis can now follow.
Opportunity Award, and the Brigham Young University
Cancer Research Center.
Supporting Information Available: Experimental pro-
cedures, characterization, and data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We are grateful for support provided
by the American Chemical Society, Petroleum Research
Fund-AC (41552-AC1), Research Corporation Research
OL702197R
4868
Org. Lett., Vol. 9, No. 23, 2007