Regio- and enantiospecific rhodium-catalyzed arylation of unsymmetrical fluorinated acyclic allylic carbonates: Inversion of absolute configuration

Article abstract of DOI:10.1021/ja035216q

The transition metal-catalyzed allylic substitution with unstabilized carbon nucleophiles represents an important cross-coupling reaction for the construction of ternary carbon stereogenic centers. We have developed a new regio- and enantiospecific rhodium-catalyzed allylic alkylation of acyclic unsymmetrical chiral nonracemic allylic alcohol derivatives with aryl zinc bromides. This study demonstrates that the hydrotris(pyrazolyl)borate rhodium catalyst and zinc(II) halide salt are crucial for efficiency, while the addition of lithium bromide to the catalyst is necessary for obtaining optimal regiospecificity. The stereochemical course of this reaction was established through the synthesis of (S)-ibuprofen, which demonstrated that the alkylation proceeds with net inversion of absolute configuration consistent with direct addition of the nucleophile to the metal center followed by reductive elimination. Copyright

Full text of DOI:10.1021/ja035216q

Published on Web 05/23/2003
Regio- and Enantiospecific Rhodium-Catalyzed Arylation of Unsymmetrical
Fluorinated Acyclic Allylic Carbonates: Inversion of Absolute Configuration
P. Andrew Evans* and Daisuke Uraguchi
Department of Chemistry, Indiana UniVersity, Bloomington, Indiana 47405
Received March 18, 2003; E-mail: paevans@indiana.edu
Table 1. Effect of Lithium Halide Salts on the Nucleophile and
Catalyst in the Regiospecific Rhodium-Catalyzed Allylic Alkylation
The transition metal-catalyzed allylic substitution with unstabi-
lized carbon nucleophiles represents an important cross-coupling
reaction for the construction of ternary carbon stereogenic centers.1
A key and significant limitation with this approach is the necessity
to employ allylic alcohol derivatives that provide symmetrical
π-allyl intermediates, which thereby circumvent problems associated
with regiochemical infidelity.2 Another serious issue arises from
the basic nature of the unstabilized nucleophile, which either
promotes elimination of the metal-allyl intermediate or hydrolysis
of the leaving group in the allylic alcohol fragment. Furthermore,
the stereospecific alkylation is often subject to stereochemical
inversion through the direct addition of the nucleophile to the metal
center followed by concomitant reductive elimination.3
organozinc reagenta
in situ LiX
(equiv)b
catalyst
additive
2°:1°
2a:3ae
yield
c
f
entry
PhLi/ZnX
(%)
2
1
2
3
4
5
6
7
8
Ph3ZnLi
LiCl
(2)
“
“
(2)
“
(1)
“
-
1:1
3:1
NA
3:1
13:1
1:1
13:1
15:1
55
88
0
96
92
86
95
99
“
LiBr
LiI
LiBr
“
“
“
-
-
“
Ph2Zn
“
PhZnBr
“
-
LiBr
-
LiBr
PhZnBr
LiBr
(1)
LiBr/dbad
a All the reactions were carried out on a 0.1 mmol reaction scale using
10 mol % of TpRh(C2H4)2 and 2.0 equiv of the arylzinc reagent at 0 °C for
e15 min. b The amount of lithium halide generated is a consequence of
the phenyllithium/zinc halide stoichiometry. c The catalyst was modified
with 200 mol % lithium bromide where indicated. d 20 mol % dibenzylidene-
acetone (dba). e Ratios of regioisomers were determined using capillary GLC
on aliquots of the crude reaction mixture. f GLC yields.
We envisioned that the rhodium-catalyzed allylic alkylation with
an organozinc would facilitate the regio- and enantiospecific
alkylation as a result of the propensity for the reaction to proceed
through a configurationally stable π-allyl or enyl (σ + π) organo-
metallic intermediate and the low basicity of the nucleophilic
reagent.4,5 Herein, we now describe the first regio- and enantio-
specific metal-catalyzed intermolecular allylic alkylation of unsym-
metrical allylic alcohol derivatives (S)-1, using aryl organozinc
halides, for the construction of 3-aryl propenyl derivatives (R)-2
with inversion of absolute configuration (eq 1).
Preliminary studies demonstrated that the trimethyl phosphite-
modified Wilkinson’s catalyst that had proven so general for the
allylic alkylation using stabilized carbon and heteroatom nucleo-
philes was not an effective catalyst with organozinc reagents.
Interestingly, although the application of a hydrotris(pyrazolyl)-
borate rhodium complex had not been examined in the context of
an allylic substitution reaction, this catalyst proved optimum for
organozinc reagents as nucleophiles.6 While traditional leaving
groups favored the formation of the primary allylic alkylation
adducts, fluorinated leaving groups dramatically improved the
specificity (2°:1° ) (CF3)2CHOCO > CF3CO > MeOCO >
MeCO). Table 1 outlines the optimization of the nucleophile and
catalyst components of this challenging cross-coupling reaction with
the optimal leaving group. Treatment of the allylic carbonate 1a
with a catalytic amount of TpRh(C2H4)2 and the organozinc reagent
derived from the transmetalation of phenyllithium with a zinc halide
salt, furnished the alkylation products 2a/3a, demonstrating that
zinc bromide was the optimum salt for the alkylation (entry 2 vs
1/3). Additional studies examined the effect of the organozinc
reagent on selectivity (entries 2, 4, and 6). This study suggested
that lithium bromide, generated as a consequence of the transmeta-
lation step, might influence the regiospecificity through catalyst/
nucleophile modification (entries 2/4 vs 6).7 Interestingly, the
Table 2. Scope of the Regiospecific9 Rhodium-Catalyzed Allylic
Alkylation with Aryl Zinc Halides (eq 1; (Lg ) CO2CH(CF3)2)a
allylic alcohol
derivative, R )
2°:1°
2:3b,c
yield
(%)d
entry
1
nucleophile (Ar)
1
2
3
4
5
6
7
8
9
Ph(CH2)2
a
Ph-
15:1
13:1
15:1
g19:1
13:1
12:1
g19:1
g19:1
9:1
13:1
14:1
87
81
84
85
76
91
74
72
91
91
87
95
“
“
“
“
“
“
b
c
d
e
f
p-MeO-C6H4-
p-Me-C6H4-
p-F-C6H4-
Me
Ph-
“
“
“
“
“
“
“
Me(CH2)8
iPr
cHex
iBu
10
11
12
PhCH2
TBSO(CH2)5
AcO(CH2)5
g
h
i
g19:1
a All reactions were carried out on a 0.1 mmol reaction scale. b Ratios
of regioisomers were determined by 400 MHz 1H NMR. c The primary
products 3 were prepared for comparison using Ph3ZnLi at room temper-
ature. d Isolated yields.
addition of lithium bromide to the catalyst prior to the introduc-
tion of the organozinc and allylic carbonate 1a, furnished the
secondary allylic alkylation adduct 2a with significantly improved
regiospecificity (entries 5 and 7). Finally, dibenzylidenacetone (dba)
was added to improve the selectivity and reproducibility of the
cross-coupling reaction, by serving as a surrogate ligand, given the
volatility of the ethylene ligands (entry 8).
Table 2 summarizes the application of the optimized reaction
conditions (Table 1, entry 8)8 to a variety of racemic secondary
allylic carbonates (Vide supra). The allylic alkylation is clearly
9
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J. AM. CHEM. SOC. 2003, 125, 7158-7159
10.1021/ja035216q CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
tolerant of electron-withdrawing and -donating substituents within
the organozinc reagent, in which the former provides optimum
selectivity (Table 2, entries 2-4). Additional studies demonstrated
that linear and branched allylic carbonates serve as suitable
substrates (entries 5-12), in which the R-branched derivatives
afford the secondary alkylation products with optimum selectivity
(entries 7 and 8) in sharp contrast to our previous studies.4 The
allylic alkylation also proved feasible for the benzyl and acetate
derivatives (entries 10 and 12), illustrating excellent substrate
tolerance to the organozinc reagent. Hence, the regiospecific
rhodium-catalyzed allylic alkylation with aryl zinc halides proVides
an important new method for the construction of ternary carbon
stereogenic centers.
The ability to obtain excellent regiospecificity prompted the
examination of the enantiomerically enriched allylic carbonate (S)-
1b with the aryl zinc bromide necessary for the synthesis of (S)-
ibuprofen 6,10 to determine the stereochemical course of this
reaction. Treatment of (S)-1b (95% ee) under the optimized reaction
conditions, furnished the 3-aryl propenyl derivatives (R)-4/5 in 90%
yield (2°:1° ) 10:1), with inversion of absolute configuration (100%
cee). This result is consistent with direct addition of the nucleophile
to the metal followed by reductive elimination and thereby indicates
a significant departure from our previous studies.4 The synthesis
of (S)-ibuprofen was then completed through the oxidative cleavage
of the alkenes (R)-4/5 using catalytic ruthenium trichloride and
sodium periodate at room temperature to afford 6 in 74% yield.11
Teacher-Scholar Award (P.A.E.) from the Camille and Henry
Dreyfus Foundation, and a JSPS Research Fellowship for Young
Scientists (D.U.) from the Japan Society for the Promotion of
Sciences.
Supporting Information Available: Representative experimental
procedure for the preparation of 1 and the spectral data for 1-2, 4,
and 6 (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) (a) Consiglio, G.; Waymouth, R. M. Chem. ReV. 1989, 89, 257. (b) Tsuji,
J. Palladium Reagents and Catalysts; Wiley: New York, 1996; Chapter
4, pp 290-404. (c) Trost, B. M.; Lee, C. in Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; Chapter
8, pp 593-649.
(2) For leading references on metal-catalyzed allylic arylation, see: (a) Del
Valle, L.; Stille, J. K.; Hegedus, L. S. J. Org. Chem. 1990, 55, 3019. (b)
Legros, J.-Y.; Flaud, J.-C. Tetrahedron Lett. 1990, 31, 7453. (c) Kobayashi,
Y.; Mizojiri, R.; Ikeda, E. J. Org. Chem. 1996, 61, 5391. (d) Matsuhashi,
H.; Asai, S.; Hirabayashi, K.; Hatanaka, Y.; Mori, A.; Hiyama, T. Bull.
Chem. Soc. Jpn. 1997, 70, 1943. (e) Uozumi, Y.; Danjo, H.; Hayashi, T.
J. Org. Chem. 1999, 64, 3384. (f) Macsa´ri, I.; Hupe, E.; Szabo, K. J. J.
Org. Chem. 1999, 64, 9547. (g) Chung, K.-G.; Miyake, Y.; Uemura, S.
J. Chem. Soc., Perkin Trans. 1 2000, 2725. (h) Hoke, M. E.; Brescia,
M.-R.; Bogaczyk, S.; DeShong, P.; King, B. W.; Crimmins, M. T. J. Org.
Chem. 2002, 67, 327. (i) Kabalka, G. W.; Dong, G.; Venkataiah, B. Org.
Lett. 2003, 5, 893 and pertinent references therein.
(3) Hayashi, T.; Yamamoto, A.; Hagihara, T. J. Org. Chem. 1986, 51, 723.
(4) (a) Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581. (b)
Evans, P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999,
121, 6761, 12214. (c) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2000,
122, 5012. (d) Evans, P. A.; Kennedy, L. J. J. Am. Chem. Soc. 2001, 123,
1234. (e) Evans, P. A.; Robinson, J. E. J. Am. Chem. Soc. 2001, 123,
4609. (f) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2002, 124, 7882.
(5) For a related example of an enantioselective rhodium-catalyzed allylic
arylation, see: Lautens, M.; Dockendorff, C.; Fagnou, K.; Malicki, A.
Org. Lett. 2002, 4, 1311.
(6) For a recent review of rhodium-tris(pyrazolyl)borate complexes, see:
Slugovc, C.; Padilla-Martinez, I.; Sirol, S.; Carmona, E. Coord. Chem.
ReV. 2001, 213, 129.
(7) For a recent review on halide effects in transition metal catalysis, see:
Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26.
(8) RepresentatiVe experimental procedure: TpRh(C2H4)2 (3.7 mg, 0.01
mmol), lithium bromide (17.4 mg, 0.2 mmol) and dibenzylidenacetone
(4.7 mg, 0.02 mmol) were dissolved in anhydrous diethyl ether (3 mL) at
room temperature and stirred for ca. 1 h before being cooled to 0 °C.
Zinc bromide (45 mg, 0.2 mmol) was dissolved in anhydrous diethyl ether
(1 mL) and cooled with stirring to 0 °C. Phenyllithium (210 mL, 0.21
mmol, 1 M) was then added dropwise to the zinc bromide solution and
the resulting mixture stirred for ca. 30 min. The allylic carbonate 1a (35.6
mg, 0.1 mmol) was then added Via tared syringe to the catalyst solution,
followed by the dropwise addition of the phenyl zinc bromide solution.
The resulting reaction mixture then stirred at 0 °C for e15 min (TLC
control). The reaction mixture was quenched (aq NH4Cl) and partitioned
between saturated aqueous NH4Cl solution and pentane. The organic layers
were combined, dried (Na2SO4), filtered, and concentrated in Vacuo to
afford a crude oil. Purification by flash chromatography (eluting with
pentane) furnished the 3-phenyl propenyl deriVatiVes 2a/3a (19.3 mg, 87%)
as a colorless oil.
In conclusion, we have developed a new regio- and enantio-
specific rhodium-catalyzed allylic alkylation of acyclic unsym-
metrical chiral nonracemic allylic alcohol derivatives with aryl zinc
bromides. This study demonstrates that the hydrotris(pyrazolyl)-
borate rhodium catalyst and requisite zinc(II) halide salt are crucial
for efficiency, while the addition of lithium bromide to the catalyst
is necessary for obtaining optimal regiospecificity. The stereo-
chemical course of this reaction was established through the
synthesis of (S)-ibuprofen 6, which demonstrated that the alkylation
proceeds with net inversion of absolute configuration consistent
with direct addition of the nucleophile to the metal center followed
by reductive elimination.
(9) Treatment of the primary allylic carbonate 1e′ under the analogous reaction
conditions furnished the primary allylic alkylation product 3e as the major
isomer.
Acknowledgment. We sincerely thank the National Institutes
of Health (GM58877) and the donors of the Petroleum Research
Fund, administered by the American Chemical Society for generous
financial support. We also thank Johnson and Johnson for a Focused
GiVing Award and Pfizer Pharmaceuticals for the CreatiVity in
Organic Chemistry Award. We also acknowledge a Camille Dreyfus
(10) For recent enantioselective approaches to ibuprofen, see: (a) Park, H.;
RajanBabu, T. V. J. Am. Chem. Soc. 2002, 124, 734. (b) Ishihara, K.;
Nakashima, D.; Hiraiwa, Y.; Yamamoto, H. J. Am. Chem. Soc. 2003,
125, 24 and pertinent references therein.
(11) Carlsen, P.-H. J.; Katsuki, T.; Martin, V.-S.; Sharpless, K. B. J. Org. Chem.
1981, 46, 3936.
JA035216Q
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J. AM. CHEM. SOC. VOL. 125, NO. 24, 2003 7159