Synthesis of complex allylic esters via C-H oxidation vs C-C Bond formation

Article abstract of DOI:10.1021/ja104826g

A highly general, predictably selective C-H oxidation method for the direct, catalytic synthesis of complex allylic esters is introduced. This Pd(II)/sulfoxide-catalyzed method allows a wide range of complex aryl and alkyl carboxylic acids to couple directly with terminal olefins to furnish (E)-allylic esters in synthetically useful yields and selectivities (16 examples, E/Z ≤ 10:1) and without the use of stoichiometric coupling reagents or unstable intermediates. Strategic advantages of constructing allylic esters via C-H oxidation vs C-C bond-forming methods are evaluated and discussed in four case studies.

Full text of DOI:10.1021/ja104826g

Published on Web 07/28/2010
Synthesis of Complex Allylic Esters via C-H Oxidation vs
C-C Bond Formation
Nicolaas A. Vermeulen, Jared H. Delcamp, and M. Christina White*
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
Urbana, Illinois 61801
Received June 2, 2010; E-mail: white@scs.uiuc.edu
Abstract: A highly general, predictably selective C-H oxidation method for the direct, catalytic synthesis
of complex allylic esters is introduced. This Pd(II)/sulfoxide-catalyzed method allows a wide range of complex
aryl and alkyl carboxylic acids to couple directly with terminal olefins to furnish (E)-allylic esters in synthetically
useful yields and selectivities (16 examples, E/Z g 10:1) and without the use of stoichiometric coupling
reagents or unstable intermediates. Strategic advantages of constructing allylic esters via C-H oxidation
vs C-C bond-forming methods are evaluated and discussed in four “case studies”.
Introduction
Well-accepted bond-forming strategies exist for the construc-
tion of heteroatom rich complex compounds through the
coupling of simple preoxidized molecules. Inherently, oxygen-
ated functional groups often require oxidation state changes and
protection/deprotection sequences both to install and be compat-
ible with further manipulations on the molecule. Selective C-H
oxidation of preassembled hydrocarbon frameworks represents
an alternative strategy for the rapid assembly of complex
oxygen1,2 and nitrogen1,3 rich structures at late stages of
synthesis. When these reactions are predictably selective, mild,
and incorporate the desired functionality without the need for
further manipulation, unnecessary functional group manipula-
tions (FGMs) can be bypassed, reducing synthetic steps and
increasing overall yield.4
Figure 1. Common strategies for generating complex allylic esters.
partner to be used in large excess.5 A catalytic, general
esterification method that oxidatively couples a hydrocarbon
with a carboxylic acid would be a significant advance.
Common approaches to linear (E)-allylic esters are shown
in Figure 1. A Horner-Wadsworth-Emmons (HWE) or
Complex Allylic Ester Synthesis. Esterification, one of the
most important reactions in organic synthesis, involves coupling
preoxidized carboxylic acid and alcohol fragments.5 Significant
“synthetic overhead” is required to install these oxidized
moieties in the correct oxidation state. Moreover, coupling
generally involves stoichiometric amounts of a condensation
reagent or the generation of an activated, and often unstable,
acid derivative. Although catalytic esterification methods exist,
they suffer from limited scope and often require one coupling
(2) Pd-catalyzed allylic C-H oxidations: (a) Chen, M. S.; White, M. C.
J. Am. Chem. Soc. 2004, 126, 1346. (b) Chen, M. S.; Prabagaran, N.;
Labenz, N. A.; White, M. C. J. Am. Chem. Soc. 2005, 127, 6970. (c)
Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.; White, M. C. J. Am.
Chem. Soc. 2006, 128, 9032. (d) Delcamp, J. H.; White, M. C. J. Am.
Chem. Soc. 2006, 128, 15076. (e) Covell, D. J.; White, M. C. Angew.
Chem., Int. Ed. 2008, 47, 6448. (f) Mitsudome, T.; Umetani, T.;
Nosaka, N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Angew.
Chem., Int. Ed. 2006, 45, 481. (g) Pilarski, L. T.; Selander, N.; Bose,
D.; Szabo, K. J. Org. Lett. 2009, 11, 5518. (h) Lin, B.-L.; Labinger,
J. A.; Bercaw, J. E. Can. J. Chem. 2009, 87, 264. (i) Thiery, E.; Aouf,
C.; Belloy, J.; Harakat, D.; Le Bras, J.; Muzart, J. J. Org. Chem. 2010,
75, 1771. (j) Henderson, W. H.; Check, C. T.; Proust, N.; Stambuli,
J. P. Org. Lett. 2010, 12, 824.
(1) General C-H oxidation, aminations, alkylations: (a) Muller, P.; Fruit,
C. Chem. ReV. 2003, 103, 2905. (b) Espino, C. G.; DuBois, J. In
Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.;
Wiley-VCH: Weinheim, 2005; p 379. (c) Dick, A. R.; Sanford, M. S.
Tetrahedron 2006, 62, 2439, and references therein. (d) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (e) Chen, M. S.;
White, M. C. Science 2007, 318, 783. (f) Davies, H. M. L.; Manning,
J. R. Nature 2008, 451, 417. (g) Lewis, J. C.; Bergman, R. G.; Ellman,
J. A. Acc. Chem. Res. 2008, 41, 1013. (h) Young, A. J.; White, M. C.
J. Am. Chem. Soc. 2008, 130, 14090. (i) Lafrance, M.; Lapointe, D.;
Fagnou, K. Tetrahedron 2008, 64, 6015. (j) Chen, X.; Engle, K. M.;
Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (k)
Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593. (l) Chen, M. S.;
White, M. C. Science 2010, 327, 566. (m) Jazzar, R.; Hitce, J.;
Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem.sEur. J. 2010,
16, 2654. (n) Das, S.; Incarvito, C. D.; Crabtree, R. H.; Brudvig, G. W.
Science 2006, 312, 1941.
(3) Pd-catalyzed allylic C-H aminations: (a) Larock, R. C.; Hightower,
T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584.
(b) Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129,
7274. (c) Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2008, 130,
3316. (d) Liu, G.; Yin, G.; Wu, L. Angew. Chem., Int. Ed. 2008, 47,
4733. (e) Rice, G. T.; White, M. C. J. Am. Chem. Soc. 2009, 131,
11707. (f) Reed, S. A.; Mazzotti, A. R.; White, M. C. J. Am. Chem.
Soc. 2009, 131, 11701. (g) Nahra, F.; Liron, F.; Prestat, G.; Mealli,
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Shimizu, Y.; Obora, Y.; Ishii, Y. Org. Lett. 2010, 12, 1372.
9
10.1021/ja104826g  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 11323–11328 11323

A R T I C L E S
Vermeulen et al.
Figure 2. Progress toward a general allylic C-H esterification protocol.
stabilized Wittig olefination approach generally involves taking
a preoxidized starting material through a four-step route: (1)
aldehyde formation via oxidation [O] or reduction [H-], (2)
olefination to form the R,ꢀ-unsaturated ester, (3) reduction to
the allylic alcohol, and (4) acylation to obtain the target ester.
If other functionality on the molecule is incompatible with this
diverse set of conditions (i.e., oxidation, base, reduction),
protecting group manipulations are also required. An alternative
olefination strategy involves cross-metathesis of a terminal olefin
with a preformed allylic ester.6 Although highly efficient,
challenges associated with this route are predictable control of
olefin geometry and the requirement for an excess of one of
the olefin coupling partners to achieve high yields. Additionally,
as in the HWE route, esterification often requires extensive
screening of stoichiometric reagents, many of which generate
waste that is difficult to remove from the product. We anticipated
that the direct, catalytic coupling of terminal olefins with
carboxylic acids via a predictably selective C-H esterification
reaction would streamline the synthesis of certain (E)-allylic
esters by minimizing the need for oxygenated intermediates.
Allylic C-H Esterification. In 2004, we first described a
DMSO-promoted, Pd(OAc)2-catalyzed allylic C-H oxidation
of R-olefins with solvent quantities of acetic acid (AcOH) to
furnish linear (E)-allylic acetates with high regio- and stereo-
selectivities and outstanding functional group tolerance (Figure
2A).2a As synthetic intermediates acetates often serve as
precursors to more complex esters via the intermediacy of
alcohols. Ideally, any carboxylic acid could be directly incor-
porated into the hydrocarbon framework via C-H oxidation to
furnish complex esters. Although this allylic C-H acetoxylation
method has since been explored extensively by other researchers
with respect to ligands, oxidants, and activators,2f,h-j no general
linear allylic esterification method has emerged. In a preliminary
study directed toward streamlining polyol synthesis, we devel-
oped specific conditions to couple p-anisic acid and a chiral
homoallylic ether to directly furnish a hexose precursor (Figure
2B).4b Unfortunately, these conditions did not prove to be
general (Vide infra). In this article, we describe a general reaction
manifold for the linear allylic C-H oxidation reaction (LAO)
that enables coupling of a wide range of carboxylic acids and
R-olefins to furnish complex linear (E)-allylic ester products
(Figure 2C).
Results and Discussion
Design Principles. Our working mechanistic hypothesis for
the Pd(OAc)2/DMSO catalyzed LAO reaction suggests that a
carboxylate counterion on the palladium is needed to effect C-H
cleavage to form a π-allylPd intermediate and that high
concentrations of DMSO and AcOH are optimal for effecting
functionalization.7 Within this original reaction manifold, chal-
lenges encountered in expanding the scope of the LAO to a
general esterification method included (1) formation of allylic
acetate byproduct from the Pd(OAc)2 catalyst, (2) requirement
for high equivalents of carboxylic acid, and (3) poor solubilities
of many carboxylic acids in DMSO. Switching to a
Pd(CH3CN)4(BF4)2 catalyst that can undergo counterion ex-
change with the carboxylic acids eliminated acetate byproduct.
The introduction of N,N-diisopropylethylamine (DIPEA), be-
lieved to promote functionalization through deprotonation of
the acid, enabled lowering the amount of carboxylic acid from
solvent quantities to 1.5-3 equiv.3,4b Increasing the amount of
DIPEA from 50 to 70 mol % and lowering the amount of DMSO
to 1.4 equiv made possible using more CH2Cl2 as a solvent to
improve the solubility of both the R-olefin and the carboxylic
acid. Collectively, these changes significantly widened the range
of complex allylic esters that could be generated via C-H
oxidation.
(4) Streamlining synthesis via late-stage C-H oxidation: (a) For first
explicit demonstration of this concept, see: Fraunhoffer, K. J.;
Bachovchin, D. A.; White, M. C. Org. Lett. 2005, 7, 223. (b) Covell,
D. J.; Vermeulen, N. A.; White, M. C. Angew. Chem., Int. Ed. 2006,
45, 8217. (c) Stang, E. M.; White, M. C. Nat. Chem. 2009, 1, 547.
For excellent reviews, see: (d) Hoffman, R. W. Synthesis 2006, 21,
3531. (e) Hoffman, R. W. In Elements of Synthesis Planning; Springer:
Heidelberg, 2009. For some elegant examples of late stage C-H
hydroxylation and amination, see: (f) Wender, P. A.; Hilinski, M. K.;
Mayweg, A. V. W. Org. Lett. 2005, 7, 79. (g) Hinman, A.; Du Bois,
J. J. Am. Chem. Soc. 2003, 125, 11510. (h) Reference 1e,1l.
(5) (a) Otera, J. Esterification; Wiley-VCH: Weinheim, 2003 and refer-
ences therein. (b) Ishihara, K. Tetrahedron 2009, 65, 1085.
Reaction Scope. The expansive scope and streamlining
potential of this methodology is represented in the construction
of known allylic ester intermediates (Table 1). Oxidative
coupling of unsaturated aryl acids and R-bromo-carboxylic acids
with allyl arenes provides a direct and modular route to
compounds 18 and 29 (entries 1-5), some of which have been
shown to exhibit antibacterial and antifungal activities8 (entry
1). It is notable that 1.5 equiv of acid can be used with only a
moderate reduction in isolated yield (entry 2). This feature of
the reaction is particularly significant when using complex
carboxylic acids that require lengthy synthetic sequences to
(6) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
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Complex Allylic Esters via C-H Oxidation
A R T I C L E S
Table 1. Linear Allylic Oxidation (LAO) for the Construction of
Known Allylic Ester Intermediates
monoprotected (E)-pent-2-en-1,5-diol (synthesized via a HWE
route, Table 1, entries 7 and 9). Although DCC is one of the
most widely used coupling reagents to form esters in organic
synthesis, it is a potent skin irritant and generates byproducts
(dicyclohexylurea) that are relatively insoluble and difficult to
remove.13 In contrast, direct, oxidative coupling of the same
carboxylic acids with silyl-protected pentenol afforded 4 and 5
in good yields, half the number of steps, and without the use of
any stoichiometric condensing reagents (entries 7 and 9). We
have found that the reduced form of the quinone oxidant is easily
removed via aqueous, basic extraction during the workup
procedure (see Experimental Section). Significantly, reactions
run under the previously reported conditions for benzoylation
(Figure 2B) resulted in significantly lower yields (Table 1,
entries 8 and 10).
Both R- and ꢀ-amino acids can be used as coupling partners
in the oxidative esterification reaction without any epimerization.
It is significant to note that tert-butyl ester (+)-6 can be
synthesized via a C-C bond-forming route with equal efficiency
to the C-H oxidation route by alkylating symmetric dibromo-
2-butene with the enolate of acetic acid tert-butyl ester (Table
1, entry 11).14 However, when a more complex ester is required,
for example, to afford orthogonally protected aspartate (+)-
7,15 the C-H esterification reaction enables a significant
streamlining of the route (entry 12). It is notable that, in all
cases examined, the E:Z selectivity of this C-H esterification
reaction does not drop below 10:1.
Scheme 1. C-H Oxidation vs C-C Bond Forming Strategies for
the Synthesis of Key Linear Allylic Ester Intermediate (-)-8 in the
Synthesis of (-)-Lepadiformine
a Isolated yields of >20:1 L:B. Unless otherwise noted, E:Z does not
change after purification. b Crude values of 1H NMR. c 1.5 equiv of
acid. d 24
h %
reaction time. e 5 mol Pd[CH3CN]4[BF4]2. f Using
previously published conditions, ref 4b. g THP protected version of this
compound was made. h Determined after methanolysis and acetylation
i
1
1
by H NMR. Determined by H NMR of purified material.
prepare (Vide infra). A decrease in the reaction time (72 hf24
h) and catalyst loadings (10 mol % f5 mol %) is possible while
maintaining synthetically useful yields (entries 3 and 4, respec-
tively). It is interesting to note that under these modified
conditions even fatty acids, insoluble at high concentrations of
DMSO, are useful functionalization reagents (entry 6).10
Bifunctional allylic esters 411 and 512 have been synthesized
via N,N-dicyclohexyl carbodiimide/4-dimethylaminopyridine
(DCC/DMAP) coupling of the respective carboxylic acids and
Streamlining Synthesis. A series of case studies were
undertaken to evaluate the strategic advantages of constructing
complex allylic esters via C-H oxidation routes versus C-C
bond-forming routes. A total synthesis of (-)-lepadiformine
features an (E)-allylic ester intermediate (-)-8 that undergoes
diastereoselective amino acid enolate Claisen rearrangement
followed by a ring closing metathesis to forge the complex
(7) Under a C-H cleavage reaction manifold, high linear regioselectivity
may be rationalized by outer sphere functionalization at the least
sterically hindered position of a cationic π-allylPd(DMSO)2 intermedi-
ate. However, we cannot exclude the possibility of an alternative, albeit
unprecedented, mechanism involving anti-Markovnikov oxy-pallada-
tion followed by regioselective ꢀ-hydride elimination.2a Significantly,
when using catalytic amounts of a bidentate bis-sulfoxide ligand, high
branched regioselectivity for ester formation is observed.2a,b Mecha-
nistic studies suggest this regio-outcome arises from inner sphere
functionalization from an electronically dissymmetric π-allylPd(BQ)-
carboxylate species.2b,c,4c
(11) (a) Castro, P. J. L.; Owen, S. N.; Seward, E. M.; Swain, C. J.; Williams,
B. J. PCT Int. Appl. WO 2002016343, 2002. (b) Hubshwerlen, C.;
Angehrn, R.; Gubernator, K.; Page, M. G. P.; Specklin, J.-L. J. Med.
Chem. 1998, 41, 3972.
(12) (a) Dell, C.; Khan, K. M.; Knight, D. W. J. Chem. Soc., Perkin Trans.
1 1994, 341. (b) Dell, C.; Khan, K. M.; Knight, D. W. J. Chem. Soc.,
Chem. Commun. 1989, 1812. (c) Ren, Q.; Dai, L.; Zhang, H.; Tan,
W.; Xu, Z.; Ye, T. Synlett 2008, 15, 2379.
(8) (a) Mahajan, R. P.; Patil, U. K.; Patil, S. L. Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem. 2007, 46B, 1459. (b) Mali, R. S.;
Papalkar, A. S. J. Chem. Res. (S) 2001, 433.
(13) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6984.
(14) Nakahara, Y.; Ando, S.; Itakura, M.; Kumabe, N.; Hojo, H.; Ito, Y.;
Hakahara, Y. Tetrahedron Lett. 2000, 41, 6489.
(9) Belletire, J. L.; Mahmoodi, N. O. J. Nat. Prod. 1992, 55, 194.
(10) Kanjilal, S.; Shanker, K. S.; Rao, K. S.; Reddy, K. K.; Rao, B. V. S. K.;
Kumar, K. B. S.; Kantam, M. L.; Prasad, R. B. N. Eur. J. Lipid Sci.
Technol. 2008, 110, 1175.
(15) Visitin, C.; Aliev, A. E.; Riddall, D.; Baker, D.; Okuyama, M.; Hoi,
P. M.; Hiley, R.; Selwood, D. L. Org. Lett. 2005, 7, 1699.
9
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A R T I C L E S
Vermeulen et al.
tricyclic backbone (Scheme 1).16 Starting from a fully oxidized
starting material 10 (1,4-butane-diol), allylic ester (-)-8 was
generated through a classic series of reactions: monoprotection,
oxidation, HWE olefination, reduction, and DCC-mediated
esterification with cyclic amino acid (-)-9. This route is reliable
and generally high-yielding; however, it requires five steps, two
of which are oxidation state manipulations. Direct installation
of the (E)-allylic ester from the catalytic coupling of a terminal
olefin and carboxylic acid affords a dramatic streamlining effect
on this route. Using 1.5 equiv of the same cyclic amino acid
(-)-9, oxidative C-H esterification of TBDPS-protected 5-hexen-
1-ol 13 provided (-)-8 in only two steps and 50% overall yield.
The importance of using fragment coupling quantities of
reagents is underscored here, as an eight-step sequence is
required to synthesize carboxylic acid (-)-9.
While terminal olefins may also be used as intermediates in
olefination sequences, FGMs are generally required. To illustrate
this point, we compare a C-H oxidation strategy to an
olefination strategy to allylic ester (()-19, which serves as a
precursor to trans-fused polycyclic ethers in brevetoxins (Scheme
3).19 Both routes start with alkylation and protection of
cyclohexene oxide to rapidly afford homologous terminal olefin
intermediates 21 and 24. The established HWE sequence to
allylic alcohol 22 requires that the terminal olefin be oxidatively
cleaved to afford the aldehyde precursor for olefination followed
by reduction of the allylic ester to the desired oxidation state.
The resulting (E)-allylic alcohol 22 was subsequently coupled
to an acylchloride to form the desired (E)-allylic ester (()-19
in a total of six steps and 19% overall yield (Scheme 3). In the
C-H esterification route, olefin 24 can be coupled directly to
2,4-dichlorobenzoic acid to furnish desired product (()-19 in a
total of only three steps and 47% overall yield (Scheme 3).
Scheme 2. C-H Oxidation vs C-C Bond Formation Routes in the
Synthesis of Linear E-Allylic Ester Intermediate (-)-14 en Route to
(-)-Laulimalide
Scheme 3. C-H Oxidation vs C-C Bond Forming Routes
Proceeding via Analogous Terminal Olefin Intermediates
Synthetic routes for chiral molecules are often driven by
practical considerations of availability of chiral starting material.
In addition to providing more expedient routes to (E)-allylic
esters, a C-H oxidation approach expands the options for using
simpler chiral starting materials by minimizing total oxygen-
ation. Chiral (E)-allylic ester (-)-14, an intermediate en route
to (-)-laulimalide, was previously obtained from a highly
oxygenated chiral pool material (S)-ꢀ-hydroxy-γ-butyrolactone
(-)-15.17 Manipulation of the preinstalled oxygen functionality
to arrive at the desired structure required a six-step HWE route
comprised of two protections, serial reductions, and esterification
(Scheme 2). In contrast, C-H esterification is a simplifying
transform that enables targeting less oxygenated intermediates.
For example, precursors for LAO, optically enriched bis-
homoallylic alcohols, can be directly accessed via allylation of
chiral terminal epoxides that are now readily available via
hydrolytic kinetic resolution (HKR) methodology.18 Thus, an
alternative approach to (-)-14 starts with allylation and protec-
tion of commercially available tert-butyldimethylsilyl (S)-(+)-
glycidyl ether to afford enantiomerically enriched bis-homoal-
lylic ether (-)-18 in just two steps. Benzoic acid was used as
the coupling partner to afford the desired (E)-allylic ester (-)-
14 in half the number of steps (three steps) and comparable
overall yield to the olefination route (Scheme 2).
An olefination strategy that is analogous to a C-H oxidation
strategy for the construction of (E)-allylic esters is cross
metathesis. These C-C bond-forming routes are expedient
because they also utilize terminal olefins and install the desired
oxygen moiety directly without further manipulation (Figure
1). Challenges associated with this method center around the
ability to control and predict the E:Z selectivity of the newly
formed internal olefin. In contrast, linear C-H oxidation
methodology under these mild conditions generates E-allylic
oxygenates with selectivities that are 10:1 or higher. Both the
olefination and C-H oxidation routes to macrocyclic lactam
(+)-25, a peptidomimetic, began with alkylation of macrocyclic
amide 26 to furnish homologous compounds 27 and 30 (Scheme
4).20 Allylation of the amino acid Boc-L-phenylalanine via DIC-
mediated esterification was required to furnish metathesis
coupling partner (-)-29. Cross-metathesis coupling of allylated
compounds 27 and (-)-29 (2 equiv) provided phenylalanine
derived macrocycle (+)-25 in 28% overall yield with an E:Z
selectivity of 1.2:1. Using a linear C-H esterification strategy,
direct C-H esterification of 30 with 1.5 equiv of commercial
Boc-L-phenylalanine (+)-28 furnished (+)-25 in 40% overall
yield with an E:Z selectivity of 17:1 (Scheme 4).
(16) (a) Carter, R. G.; Weldon, D. J. Org. Lett. 2000, 2, 3913. (b) Lee, M.;
Lee, T.; Kim, E.; Ko, H.; Kim, D.; Kim, S. Org. Lett. 2006, 8, 745.
(17) Messenger, B. T.; Davidson, B. S. Tetrahedron Lett. 2001, 42, 801.
(18) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem.
Soc. 2002, 124, 1307.
(19) Bartlett, P. A.; Ting, P. C. J. Org. Chem. 1986, 51, 2230.
(20) Enholm, E.; Low, T. J. Org. Chem. 2006, 71, 2272.
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Complex Allylic Esters via C-H Oxidation
A R T I C L E S
Scheme 4. C-H Oxidation vs Cross-Metathesis Route for the
Formation of Complex Allylic Esters
Terminal olefin substrates containing moderately acid-sensi-
tive moieties such as primary tert-butyl N-tosyl carbamates and
ketals showed improvements in yield (51% f 75%; 50% f
64%, respectively) with no erosion of selectivities under the
new conditions (Table 2, entries 1 and 2). However, substrates
containing highly acid-sensitive functionality, i.e. p-methoxy-
benzyl (PMB)-acetals, primary TBS ethers, and triphenylmethyl
(Tr) ethers, all showed significant improvements in isolated
yields (Table 2, entries 5-8, 10-11). Significantly, when AcOH
loadings were reduced to 3 equiv under the original reaction
conditions, only trace reactivity was observed (Table 2, entry
9).
Conclusion
In summary, this study introduces the first general, predictably
selective C-H oxidation method for the direct synthesis of
complex allylic esters. The ability to forge esters using a
catalytic method that couples two highly stable compounds,
carboxylic acids and terminal olefins, provides an attractive
alternative to methods that use stoichiometric amounts of
coupling reagents or require reactive, unstable intermediates.
The milder conditions that employ low loadings of carboxylic
acid and catalytic base also enable broadening the substrate
scope of the allylic C-H acetoxylation reaction to include acid-
sensitive moieties. Strategic as well as practical advantages
emerge when comparing C-H oxidation versus C-C bond-
forming routes for the synthesis of complex allylic esters.
Introduction of oxygen functionality late in a sequence, without
the need for further manipulation, provides a significant
streamlining of the route by eliminating FGMs such as oxidation
state changes, protection/deprotection sequences, and functional
group transformations. Moreover, the ability to utilize simpler,
less oxygenated intermediates expands the options with respect
to chiral starting materials, often leading to more efficient routes.
Based on the generality and predictable selectivity of this C-H
oxidation method along with the strategic advantages it enables,
we anticipate that it will find widespread use in complex
molecule syntheses.
Allylic C-H Acetoxylation Revisited. Although our previously
reported allylic C-H acetoxylation reaction showed broad
functional group tolerance, acid-sensitive substrates were not
well tolerated under those conditions which employed solvent
quantities of AcOH. We hypothesized that these new conditions
employing only 1.5-3.0 equiv of carboxylic acid and 70 mol
% base may further expand the scope of this powerful
transformation (Table 2).
Table 2. Linear Allylic C-H Acetoxylation (LAO) with Acid
Sensitive Substrates
Experimental Procedures
A typical procedure for the Pd mediated oxidation of terminal
olefins to linear E-allylic esters is described. To a 4 mL borosilicate
vial was first added Pd(CH3CN)4(BF4)2 (44.4 mg, 0.1 mmol, 10
mol %) under an argon atmosphere. The following reagents were
then added in one portion under an ambient atmosphere: phenyl
benzoquinone (368 mg, 2.0 mmol, 2 equiv), carboxylic acid (3.0
mmol, 3.0 equiv), two 4 Å molecular beads (50 mg). Finally,
DMSO (100 µL, 1.4 mmol, 1.4 equiv), CH2Cl2 (500 µL), and
DIPEA (121.0 µL, 0.7 mmol, 0.7 equiv) were added sequentially
via glass syringe followed by a Teflon stir bar. This solution was
stirred at 41 °C for 5 min before starting material (1.0 mmol, 1.0
equiv) was added neat. The vial was then capped and stirred at 41
°C for 72 h. Upon completion as determined by NMR, the reaction
was transferred to a separatory funnel using minimal methylene
chloride (∼2 mL) [Note 1]. The solution was diluted with diethyl
ether (50 mL) and washed with 5% K2CO3 (aq.) solution twice
[Note 2]. The organic layer was dried with MgSO4, filtered, and
reduced in Vacuo. Purification was achieved via flash silica gel
chromatography. Notes: (1) The excess quinone may be reduced
by addition of solid Na2SO3 (2 g) to a reaction mixture diluted
with 50 mL of EtOAc and 50 mL of a 5% K2CO3 (aq.) solution.
The resulting biphasic mixture is then stirred rapidly for 30 min
before continuing with the extraction. (2) If an inseparable emulsion
a Pd(OAc)2 (10 mol %), DMSO/AcOH (1:1; 0.17 M), 4 Å MS, BQ
(2 equiv), air, 41 °C, 72 h. b Pd[CH3CN]4(BF4)2 (10 mol %), DMSO/
CH2Cl2 (1:5; 2.0 M), AcOH (3 equiv), 4 Å MS, PhBQ (2 equiv), air, 41
°C, 72 h. c Isolated yields of >20:1 L:B. Unless otherwise noted, E:Z
does not change after purification. d Crude values by 1H NMR.
e Previously reported; see ref 4. f Pd(OAc)2(10 mol %), DMSO (0.17
M), AcOH (3 equiv), 4 Å MS, BQ (2 equiv), air, 41 °C, 72 h. g When
the reaction was run under the “old” conditions at 0.33 M DMSO, 3
equiv of AcOH, only trace reactivity was observed: 10% yield.
9
J. AM. CHEM. SOC. VOL. 132, NO. 32, 2010 11327

A R T I C L E S
Vermeulen et al.
forms, filter the solution through a pressed pad of Celite with 20-30
mL of diethyl ether.
Matthey for a generous gift of Pd(OAc)2. We thank P. Gormisky
for checking our experimental procedure.
Full experimental details and characterization data are given in
the Supporting Information.
Supporting Information Available: Experimental procedures,
full characterization, and additional experiments. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support was provided by NIH/
NIGMS (Grant No. GM076153) and kind gifts from Pfizer, Eli
Lilly, Bristol-Myers Squibb, and Amgen. We thank Johnson
JA104826G
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11328 J. AM. CHEM. SOC. VOL. 132, NO. 32, 2010