Diastereoselective palladium-catalyzed α-arylation of 4-substituted cyclohexyl esters

Article abstract of DOI:10.1021/ol8021758

(Chemical Equation Presented) 17 Examples 37-85% yield up to 37:1 dr A diastereoselective palladium-catalyzed arylation of 4-substituted cyclohexyl esters has been developed. The reaction proceeds at room temperature in the presence of [(t-Bu₃P)PdBr]₂ providing products in up to 37:1 dr.

Full text of DOI:10.1021/ol8021758

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5251-5254
Diastereoselective Palladium-Catalyzed
r-Arylation of 4-Substituted Cyclohexyl
Esters
Eric A. Bercot,* Seb Caille,* Tracy M. Bostick, Krishnakumar Ranganathan,
Randy Jensen, and Margaret M. Faul
Chemical Process R&D, Amgen Inc., One Amgen Center DriVe,
Thousand Oaks, California 91320
ebercot@amgen.com; scaille@amgen.com
Received September 17, 2008
ABSTRACT
A diastereoselective palladium-catalyzed arylation of 4-substituted cyclohexyl esters has been developed. The reaction proceeds at room
temperature in the presence of [(t-Bu3P)PdBr]2 providing products in up to 37:1 dr.
Target molecules containing quaternary carbon centers are
particularly challenging to assemble, and methods to access
these substrates continue to be an area of intense investiga-
tion.1 The reaction of R,R-disubstituted enolates with a
carbon-based electrophiles provides direct, efficient, and
selective access to carbonyl compounds possessing fully
substituted R-carbons.2 Palladium-catalyzed vinylation3 and
arylation4 of carbonyl compounds has emerged as a particu-
larly powerful method to access carbonyl compounds bearing
C(sp2)-hybridized subustituents at the R-position.5
element, the selective preparation of either of the two possible
achiral diastereomers represents a significant synthetic chal-
lenge.6
We envisioned accessing the desired ester 1 via a diastereo-
selective Pd-catalyzed arylation of 4-substituted cyclohexyl ester
2 (Scheme 1).7,8 Oxidative addition of a low-valent palladium
catalyst to aryl halide 3 followed by ligand substitution by
(3) (a) Piers, E.; Marais, P. C. J. Org. Chem. 1990, 55, 3454–3455. (b)
Chieffi, A.; Kamikawa, K.; Ahman, J.; Fox, J. M.; Buchwald, S. L. Org.
Lett. 2001, 3, 1897–1900. (c) Huang, J.; Bunel, E.; Faul, M. M. Org. Lett.
2007, 9, 4343–4346.
During the course of a recent research program, we required
a concise and selective method to access 4-substituted cyclo-
hexyl aryl ester 1. Although 1,4 disubstituted cyclohexane
derivatives are achiral due to the presence of a C2-symmetry
(4) For seminal examples of ketone arylation, see: (a) Palucki, M.;
Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108–11109. (b) Hamann,
B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382–12383. (c) Satoh,
T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem., Int. Ed. 1997,
36, 1740–1742.
(5) For recent reviews on Pd-catalyzed arylation of carbonyl compounds,
see: (a) Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2002, 41, 953–956. (b)
Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234–245.
(6) For stereoselective approaches to a similar 4-substituted cyclohexane
core, see: (a) Scott, J. P.; Lieberman, D. R.; Beureux, O. M.; Brands,
K. M. J.; Davies, A. J.; Gibson, A. W.; Hammond, D. C.; McWilliams,
C. J.; Stewart, G. W.; Wilson, R. D.; Dolling, U.-H. J. Org. Chem. 2007,
72, 4149–4155. (b) Davies, A. J.; Scott, J. P.; Bishop, B. C.; Brands,
K. M. J.; Brewer, S. E.; DeSilva, J. O.; Dormer, P. G.; Dolling, U.-H.;
Gibb, A. D.; Hammond, D. C.; Lieberman, D. R.; Palucki, M.; Payack,
J. F. J. Org. Chem. 2007, 72, 4864–4871.
(1) For reviews, see: (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem.,
Int. Ed. 1998, 37, 388–401. (b) Christoffers, J.; Baro, A. Angew. Chem.,
Int. Ed. 2001, 40, 4591–4597. (c) Douglas, C. J.; Overman, L. E. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5363–5367.
(2) For a review on the use of chiral bicyclic lactam auxiliaries, see: (a)
Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56, 9843–9873. For a
review on enolate alkylation stratergies, see: (b) Denissova, I.; Barriault,
L. Tetrahedron 2003, 59, 10105–10146. (c) Eames, J.; Suggate, M. J. Angew.
Chem., Int. Ed. 2005, 44, 186–189. (d) Christoffers, J.; Baro, A. Angew.
Chem., Int. Ed. 2003, 42, 1688–1690.
10.1021/ol8021758 CCC: $40.75
Published on Web 10/28/2008
2008 American Chemical Society

that a variety of 4-substituted cyclohexyl ester derivatives
undergo smooth R-arylation in the presence of a com-
mercially available catalyst at room temperature providing
the product aryl esters in moderate to excellent diastereo-
selectivity.
Scheme 1. Proposed Diastereoselective R-Arylation
The coupling of aminocyclohexyl ester 214 and p-fluoro-
bromobenzene (3) was examined under several different
conditions (Table 1). To our gratification, treatment of ester
Table 1. Reaction Optimization
entrya
catalystb (mol %)
base
T (°C) yieldc (%) dre
1
2
3
4
5
6
7
8
[(t-Bu3P)PdBr]2 (2.5) LiNCy2
[(t-Bu3P)PdBr]2 (2.5) LiNCy2
[(t-Bu3P)PdBr]2 (1.0) LiNCy2
[(t-Bu3P)PdBr]2 (1.0) LDA
Pd2(dba)3/t-Bu3P (1.0) LDA
80
23
23
23
23
23
23
23
78
92
77
19:1
ND
ND
the enolate derived from 2 would result in the formation of
three interconverting Pd-enolates, O-bound complex A and
C-bound complexes B and C.9 Reductive elimination of B
and C leads to undesired trans-ester 4 and desired cis-ester
1, respectively.10 We reasoned that the substituent at the
4-position should reside in the equatorial position11 in
intermediates B and C, thereby controlling the stereochemical
course of the reaction.12 Furthermore, the reaction should
proceed via complex C due to the equatorial disposition of
the group at the 4-position of the cyclohexyl ring and the
sterically demanding arylpalladium substituent leading to
desired ester 1.13If the proposed reaction pathway is opera-
tive, not only should the reaction favor cis-ester products,
but reaction selectivity should be a function of the steric
profile (A value) of the ring substituent. Herein, we report
83 (73) 32:1
37d
14d
76d
66d
32:1
24:1
99:1
99:1
Pd2(dba)3/5 (1.0)
Pd2(dba)3/6 (1.0)
Pd2(dba)3/7 (1.0)
LDA
LDA
LDA
a Ester 2 was treated with 1.1 equiv of base at 0 °C for 15 min followed
by addition of catalyst and 1.3 equiv of aryl bromide 3 and warming to
indicated temperature for 3 h. b Ligand/Pd ratio 1:1. c HPLC assay yield,
isolated yields in parentheses. d Reaction run for 24 h at ambient temperature.
e Diastereomeric ratios determined by 19F NMR of crude reaction mixtures.
2 with LiNCy2 in toluene followed by exposure to aryl
(7) The Pd-catalyzed arylation of 4-methylcyclohexyl esters has been
reported but no selecitvity data was provided; see: John, V.; Maillard, M.;
Tucker, J.; Jagodzinske, B.; Brogley, L.; Tung, J.; Shah, N.; Neitz, J. R.
2005, WO 05087752.
bromide 3 in the presence of 2.5 mol % of [(t-
15,16
Bu3P)PdBr]2
at elevated temperatures provided the
desired product in 78% yield and 19:1 dr, favoring the desired
diastereomer 1. Further optimization revealed that the
reaction reaches completion at ambient temperature in less
than 3 h; furthermore, catalyst loading was reduced to 1 mol
% (entries 2 and 3). Although LiNCy2 was an effective base,
its use complicated the reaction workup due to the formation
of insoluble amine salts. The use of LDA as base proved
effective and alleviated workup problems providing the
desired product 1 in 73% isolated yield and 32:1 dr (entry
(8) For selected examples of diastereoselective intramolecular Pd-
catalyzed R-arylation reactions, see: (a) Reisman, S. E.; Ready, J. M.; Weiss,
M. M.; Hasuoka, A.; Hirata, M.; Tamaki, K.; Ovaska, T. V.; Smith, C. J.;
Wood, J. L. J. Am. Chem. Soc. 2008, 130, 2087–2100. (b) MacKay, J. A.;
Bishop, R. L.; Rawal, V. H. Org. Lett. 2005, 7, 3421–3424. (c) Sole, D.;
Vallverdu, L.; Solans, X.; Font-Bardia, M.; Bonjoch, J. J. Am. Chem. Soc.
2003, 125, 1587–1594. (d) Muratake, H.; Nakai, H. Tetrahedron Lett. 1999,
40, 2355–2358. (e) Muratake, H.; Natsume, M. Tetrahedron Lett. 1997,
38, 7581–7582. For selected examples of diastereoselective intermolecular
R-aryaltion reactions, see: (f) Iwama, T.; Rawal, V. H. Org. Lett. 2006, 8,
5725–5728. (g) Konopelski, J. P.; Lin, J.; Wenzel, P. J.; Deng, H.; Elliot,
G. I.; Gerstenberger, B. S. Org. Lett. 2002, 4, 4121–4124. (h) Elliott, G. I.;
Konopelski, J. P.; Olmstead, M. M. Org. Lett. 1999, 1, 1867–1870.
(9) (a) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816–
5817. (b) Culkin, D. A.; Hartwig, J. F. Organometallics 2004, 23, 3398–
3416.
(13) We postulated that not only should the equilibrium favor complex
C, but reductive elimination from C to 1 should proceed via a lower energy
transition state versus the reductive elimination of B to 4.
(14) Cyclohexyl ester 2 was accessed in two steps from commercially
available materials and used as a 2:1 mixture of isomers.
(15) Commercially available from Johnson Matthey (CAS no. 185812-
86-6; catalog no. Pd-113).
(10) The trans and cis descriptor refer to the relationship between the
carbonyl functional group present on the fully substituted carbon atom and
the substituent at the 4-position.
(11) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley and Sons: New York, 1994; pp 686-771.
(12) For the diastereoselective alkylation of 4-substituted cyclohexyl
carbonyl derivatives, see: (a) House, H. O.; Bare, T. M. J. Org. Chem.
1968, 33, 934–949. (b) Ziegler, F. E.; Wender, P. A. J. Org. Chem. 1977,
42, 2001–2002. (c) Krapcho, A. P.; Dundulis, E. A. J. Org. Chem. 1980,
45, 3236–3245.
(16) For recent reports detailing the use of this catalyst, see: (a) Stambuli,
J. P.; Kuwano, R.; Hartwig, J. F. Angew. Chem., Int. Ed. Engl. 2002, 41,
4746–4748. (b) Hama, T.; Liu, X.; Culkin, D. A.; Hartwig, J. F. J. Am.
Chem. Soc. 2003, 125, 11176–11177. (c) Hama, T.; Hartwig, J. F. Org.
Lett. 2008, 10, 1545–1548. (d) Hama, T.; Hartwig, J. L. Org. Lett. 2008,
10, 1549–1552
.
5252
Org. Lett., Vol. 10, No. 22, 2008

4). The catalyst derived from mixing Pd2(dba)3 and t-Bu3P
in a 1:1 ratio proved much less effective (entry 5). Additional
ligand-Pd complexes were examined under optimized
conditions. Imidazolium-based ligand 517 provided material
in high selectivity, but the yield was low (entry 6). Phos-
phines 618 and 719 provided highly enriched product 1.
However, these reactions failed to reach complete conversion
after 24 h at ambient temperature (entries 7 and 8).
With the identification of effective conditions for the
diastereoselective arylation of ester 2, we sought to expand
the substrate scope of the present transformation. A variety
of 4-substituted cyclohexyl esters undergo diastereoselective
arylation (Table 2). Cyclohexyl esters bearing the sterically
demanding tert-butyl (8) and trifluoromethyl (10)20 groups
at the 4-position provide arylated products in 13.0:1 and
10.5:1 dr, respectively (entries 1 and 2). Methyl-substituted
ethyl ester 12 smoothly undergoes arylation providing 13 in
5.3:1 dr and 77% isolated yield (entry 3). The identity of
the ester plays and important role in the reaction. Methyl
ester 14 provides the product 15 in a slightly higher
diastereomeric ratio than the corresponding ethyl ester 12,
while tert-butyl ester 16 provides a marked increase in
selectivity providing 17 in 10.0:1 dr and 85% yield (entries
4 and 5). The diastereoselective arylation is not limited to
4-substituted cyclohexyl esters with 3-methyl cyclohexyl
ethyl ester 18 providing the product 1921 in good selectivity
and yield (entry 6). Oxygen substitutents at the 4-position
of the ring are well tolerated in the reaction providing
products in good yield; however, reaction selectivity is low
presumably due to the smaller steric profile of ether substit-
uents (entries 7 and 8).22 Substrates containing basic amines,
exemplified by 24, are competent in the reaction providing
25 in 4.0:1 dr and 81% isolated yield (entry 9). Intrigued by
the high selectivity observed for ester 2, we examined the
corresponding methyl carbamate (26) and dimethyl urea (28)
derivatives. Methyl carbamate 26 provided arylated product
27 in 37:1 dr while urea 29 provided product in a diminished
6.5:1 dr (entries 10 and 11). These results suggest that the
high selectivity observed for substrates 2 and 26 (even higher
than the t-Bu substituted ester 8) are in part a result of the
carbamate resident on the amine substituent and not the
nature of the alkyl group present on the carbamate.
Table 2. Ester Scope of Diastereoselective Arylation Reaction
Having established a range of nucleophilic coupling
partners capable of participating in the diastereoselective
arylation reaction, we next explored the electrophile scope
Table 3. Electrophile Scope
a Ester was treated with 1.1 equiv of LDA at 0 °C for 15 min followed
by addition of catalyst and 1.3 equiv of aryl bromide and warming to
ambient temperature. b Used as a mixture of cis,trans isomers. c Diastereomeric
ratios and relative stereochemistry determined by NMR. d Isolated yield.
e Isolated yield of major diastereomer.
a Ester was treated with 1.1 equiv of LDA at 0 °C for 15 min followed
by addition of catalyst and 1.3 equiv of electrophile and warming to ambient
temperature. b Used as a mixture of cis,trans isomers. c Diastereomeric ratios
and relative stereochemistry determined by NMR. d Isolated yield. e Reaction
carried out at 80 °C. f Isolated yield of 9.2:1 mixture ofdiastereomers.
Org. Lett., Vol. 10, No. 22, 2008
5253

(Table 3). Bromo toluene 30 smoothly provided the desired
arylation product 31 in 8.6:1 dr (entry 1). The use of the
corresponding aryl triflate and chloride resulted in little to
no product formation even at elevated temperatures and
prolonged reaction times (entries 2 and 3). The efficiency
and selectivity of the reaction is sensitive to sterics as
exemplified by the coupling reaction of 2-bromo toluene (34)
which required high reaction temperatures and provided
arylated product 35 in modest selectivity and yield (entry
4). Both electron-rich and electron-deficient 4-substitued aryl
bromides efficiently couple providing 37 and 39 in good yield
(entries 5 and 6). It is interesting to note that the electronic
nature of the coupling partner has an impact on reaction
selectivity with electron rich aromatics providing products
in higher diastereomeric ratios. Vinyl bromides are competent
coupling partners with 2-bromopropene (40) providing
product 41 in 10.3:1 dr and 78% isolated yield (entry 7).
In conclusion, we have identified a palladium-catalyzed
diatasteroselective arylation of 4-substituted cyclohexylesters
that provides the product esters, bearing an R-quaternary
carbon center, in good yield and selectivity. The reaction
proceeds at room temperature in the presence of 1 mol % of
a commercially available catalyst providing the product of
equatorial approach of the electrophile as the major diaste-
reomer in all cases examined. Diastereoselectivity in the
present reaction generally increases with the A value of the
substituent present at the 4-position of ring; furthermore,
increasing the steric demand of the ester leads to increased
selectivity. Additionally, we have observed that the stereo-
chemical course of the reaction is also influenced by the
nature of the electrophilic coupling partner.
(17) Jørgensen, M.; Lee, S.; Liu, X.; Wolkowski, J. P.; Hartwig, J. F.
J. Am. Chem. Soc. 2002, 124, 12557–12565.
(18) (a) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. F. J. Am. Chem.
Soc. 2000, 122, 10718–10719. (b) Kataoka, N.; Shelby, Q.; Stambuli, J. P.;
Hartwig, J. F. J. Org. Chem. 2002, 67, 5553–5566.
Acknowledgment. We thank Dr. Tiffany Correll and Dr.
Kevin Turney for their assistance with DSC and HRMS
measurements. We also thank Dr. Jay Powers and Dr. Lisa
Julian for helpful discussions.
(19) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
7996–8002.
(20) The -CF3 group is estimated to be isosteric with -i-Pr; see: Ma,
J.-A.; Cahard, D. Chem. ReV. 2004, 101, 6119–6146, and references therein.
(21) The major diastereomer is the product resulting from the reductive
elimination of an intermediate in which the palladium and methyl substit-
uents are both disposed in equatorial positions in analogy to the arylated
products obtained in the 4-substituted series.
Supporting Information Available: General procedures
and spectra for obtained compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(22) Selected A values (kcal mol-1) for substituents in cyclohexane ring
systems (see ref 11): -Me ) 1.74; -t-Bu ) 4.7-4.9; -CF3 ) 2.4-2.5;
-OMe ) 0.55-0.75.
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