Palladium-catalyzed decarboxylative benzylation of diphenylglycinate lmines

Article abstract of DOI:10.1021/ol902651j

(Figure presented) General reaction conditions for the Pd-catalyzed decarboxylative benzylation of benzyl diphenylglycinate lmines are described. The overall procedure requires a simple catalyst/ligand combination to form a new Csp³-Csp³ bond. Microwave Irradiation greatly accelerated the transformation. Moreover, various heteroaromatlc moieties are tolerated in both the imine and ester components.

Full text of DOI:10.1021/ol902651j

ORGANIC
LETTERS
2010
Vol. 12, No. 2
316-319
Palladium-Catalyzed Decarboxylative
Benzylation of Diphenylglycinate Imines
Wendy H. Fields and Jason J. Chruma*
Department of Chemistry, UniVersity of Virginia, CharlottesVille, Virginia 22904-4319
jjc5p@Virginia.edu
Received November 17, 2009
ABSTRACT
General reaction conditions for the Pd-catalyzed decarboxylative benzylation of benzyl diphenylglycinate imines are described. The overall
procedure requires a simple catalyst/ligand combination to form a new Csp3-Csp3 bond. Microwave irradiation greatly accelerated the
transformation. Moreover, various heteroaromatic moieties are tolerated in both the imine and ester components.
Transition-metal-mediated pathways for the formation of
Csp3-Csp3 bonds have received substantial attention.1 Pd-
catalyzed decarboxylative alkylation (Tsuji-Trost reac-
tion), in particular, has emerged as a versatile and efficient
strategy for the construction of these bonds.1b,2 Despite
the rapidly growing interest in this arena, the reaction scope
remains generally limited to allylation of enolate nucleo-
philes3 with π-allylPd(II) species generated via insertion of
a Pd(0) catalyst into an allyl ester or carbonate C-O bond.
We recently reported that R-imino anions (2-azaallyl anions)
also can be generated and alkylated via Pd-catalyzed decar-
boxylative allylation of allyl diphenylglycinate imines.2d,4
Inspired by reports that benzyl esters and carbonates are
viable substrates for Pd(0)-catalyzed nucleophilic alkyla-
tions,5 we envisioned advancing a similar strategy for the
benzylation of R-imino anions. Herein, we report general
reaction conditions for the decarboxylative benzylation of
benzyl diphenylglycinate imines 1 into the corresponding
homobenzylic imines 2 (Scheme 1). Heterocyclic function-
Scheme 1
.
Decarboxylative Formation and Benzylation of
(1) (a) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. ReV. 2001,
101, 2067. (b) Trost, B. M.; VanVranken, D. L. Chem. ReV. 1996, 96, 395.
(c) Saito, B.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 6694. (d) Arp, F. O.;
Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482. (e) Smith, S. W.; Fu, G. C.
Angew. Chem., Int. Ed. 2008, 47, 9334. (f) Dai, X.; Strotman, N. A.; Fu,
G. C. J. Am. Chem. Soc. 2008, 130, 3302. (g) Bi, H.-P.; Zhao, L.; Liang,
Y.-M.; Li, C.-J. Angew. Chem., Int. Ed. 2009, 48, 792. (h) Li, C.-J. Acc.
Chem. Res. 2009, 42, 335. (i) Li, C.-J.; Li, Z. Pure Appl. Chem. 2006, 78,
935.
R-Imino Anions
(2) Representative examples: (a) Burger, E. C.; Tunge, J. A. Org. Lett.
2004, 6, 4113. (b) Imao, D.; Itio, A.; Yamazaki, A.; Shirakura, M.; Ohtoshi,
R.; Ogata, K.; Ohmori, Y.; Ohta, T.; Ito, Y. J. Org. Chem. 2007, 72, 1652.
(c) Trost, B. M.; Bream, R. N.; Xu, J. Angew. Chem., Int. Ed. 2006, 45,
3109. (d) Yeagley, A. A.; Chruma, J. J. Org. Lett. 2007, 9, 2879. (e) Enquist,
J. A., Jr.; Stoltz, B. M. Nature 2008, 453, 1228. (f) White, D. E.; Stewart,
alities, e.g., furan, indole, thiazole, and pyridine, on either
the imine or ester groups are well tolerated by the reaction
conditions. To the best of our knowledge, this represents the
I. C.; Grubbs, R. H.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 810
.
(3) For some notable exceptions: (a) Burger, E. C.; Tunge, J. A. J. Am.
Chem. Soc. 2006, 128, 10002. (b) Weaver, J. D.; Tunge, J. A. Org. Lett.
2008, 10, 4657. (c) Waetzig, S. R.; Tunge, J. A. J. Am. Chem. Soc. 2007,
129, 4138. (d) Waetzig, S. R.; Tunge, J. A. J. Am. Chem. Soc. 2007, 129,
(4) (a) Yeagley, A. A.; Lowder, M. A.; Chruma, J. J. Org. Lett. 2009,
11, 4022. (b) Fields, W. H.; Khan, A. K.; Sabat, M.; Chruma, J. J. Org.
Lett. 2008, 10, 5131.
14860
.
10.1021/ol902651j  2010 American Chemical Society
Published on Web 12/14/2009

first example of a Pd-catalyzed decarboxylative benzylation
involving a nonenolate C-centered nucleophile.
0.1 M solution of imine 1a in dimethylacetamide (DMA)
with 3 mol % Pd(OAc)2 and 20 mol % rac-BINAP to be
optimal, affording the desired decarboxylative benzylation
product 2a in high yield.7 This high ligand-to-Pd ratio (∼6.7
vs 2.0 for conventional heating) proved critical for the
success of the microwave-accelerated conditions, presumably
by encouraging the formation of the requisite Pd(0)-ligand
complex within the relatively short time frame of the reaction.
Side products emanating from decarboxylative protonation
(3)8 and acetate serving as a competitive nucleophile for the
benzyl-Pd(II) intermediate (4) comprised the majority of
the remaining mass balance (Figure 1). Replacing Pd(OAc)2
We initially rationalized that incorporation of an
electron-withdrawing group into the benzyl ester would
facilitate insertion of Pd(0) into the ester C-O bond.5
Similarly, based on our previous experience,2d,4 we
predicted that electron-withdrawing substituents on the imine
component would accelerate decarboxylation and predispose
the resonance-stabilized R-imino anion intermediate toward
benzylation at the least substituted carbon. Accordingly, our
initial investigations began with (4-trifluoromethyl)benzyl
ester 1a. In accord with related studies by Kuwano and co-
workers,5e,f only bidentate ligands proved effective in
catalyzing the decarboxylative benzylation (Table 1). More-
Table 1. Reaction Optimizationa
Figure 1. Major side products for the decarboxylative benzylation
of imino ester 1a.
Pd source
(mol %)
temp
(°C)
yield
(%)b
with Pd(O2CCF3)2 did not afford a notable reduction in the
amount of side products from protonation (3) or (tri-
fluoro)acetylation.
ligand (mol %)
time
Pd(PPh3)4 (10)
Pd(PPh3)2Cl2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (3)
Pd(OAc)2 (3)
s
110c 20 h
110c 20 h
110c 20 h
110c 20 h
110c 20 h
110c 20 h
110c 20 h
150c 20 h
150d 15 min
0e
0e
s
To evaluate the scope of this decarboxylative benzy-
lation reaction, the imine and ester moieties were varied
(Table 2). While ideal reaction temperatures/times were
substrate specific, heating to 150 °C for as little as 5 min
afforded complete conversion of imino ester 1a and
typically provided some conversion for all other substrates
investigated. The electronic composition of the benzyl
ester significantly impacted product distribution, with
electron-withdrawing groups reducing the preference for
desired imines 2 (entries 1-8). As an extreme comparison,
4-methoxybenzyl ester 1c afforded 85% of the desired
product 2c, whereas 4-nitrobenzyl ester 1f was converted
almost exclusively to 3 (32%), 4-nitrobenzyl acetate
(10%), and other unidentified side products (cf. entries 3
and 6). Gratifyingly, heteroaromatic benzyl esters proved
to be viable substrates for the decarboxylative benzylation
protocol (entries 7 and 8), suggesting potential application
toward the synthesis of 2-aryl-ꢀ-carboline alkaloid ana-
logues.9 To the best of our knowledge, this represents the
first example of the formation of a catalytically relevant
Pd(II)-3-methylindole species via insertion into the cor-
responding ester as well as the first example of an indole
participating in a Pd-catalyzed decarboxylative alkylation.
P(o-tol)3 (20)
dppe (20)
xantphos (20)
dppf (20)
rac-BINAP (20)
rac-BINAP (20)
rac-BINAP (50)
0e
0e
37e
49
61
60
70
78
0e
rac-BINAP (20) 150d 15 min
rac-BINAP (6)
150d 15 min
200d 45 min
Pd(O2CCF3)2 (10) rac-BINAP (50)
60
a Reaction conditions: imine (0.05 mmol), Pd catalyst, and ligand in
DMA (0.1 M). Unless otherwise noted, all reactions were run to complete
conversion of imine 1a. b Isolated yield. c Conventional heating. d Microwave
heating (CEM Discover, 300 W maximum power). e Starting material
recovered.
over, the bite angle of the bidentate ligands demonstrated a
significant impact on both the rate of reaction and the relative
percentage of side products generated.6 Extensive screening
of reaction conditions identified microwave irradiation of a
(5) (a) Legros, J.-Y.; Fiaud, J.-C. Tetrahedron Lett. 1992, 33, 2509. (b)
Boutros, A.; Legros, J.-Y.; Fiaud, J.-C. Tetrahedron Lett. 1999, 40, 7329.
(c) Legros, J.-Y.; Toffano, M.; Fiaud, J.-C. Tetrahderon 1995, 51, 3235.
(d) Legros, J.-Y.; Primault, G.; Toffano, M.; Rivie`re, M.-A.; Fiaud, J.-C.
Org. Lett. 2000, 2, 433. (e) Kuwano, R.; Kondo, Y.; Matsuyama, Y. J. Am.
Chem. Soc. 2003, 125, 12104. (f) Kuwano, R.; Yokogi, M. Org. Lett. 2005,
7, 945. (g) Kuwano, R.; Kondo, Y.; Shirahama, T. Org. Lett. 2005, 7, 2973.
(h) Kuwano, R.; Yokogi, M. Chem. Commun. 2005, 5899. (i) Narahashi,
H.; Shimizu, I.; Yamamoto, A. J. Organomet. Chem. 2008, 693, 283. (j)
Miller, K. J.; Abu-Omar, M. M. Eur. J. Org. Chem. 2003, 1294. (k) Kuwano,
R. Synthesis 2009, 1049. (l) Lie´gault, B.; Renaud, J.-L.; Bruneau, C. Chem.
Soc. ReV. 2008, 37, 290.
(7) Under these conditions, R-BINAP did not confer any enantioselec-
tivity for the conversion of 1a to 2a, as monitored by chiral HPLC
analysis.
(8) The exact mechanism/source of protonation is unclear and currently
under investigation. Stoltz and Tunge have both reported similar difficulty
identifying the proton source for related decarboxylative protonation events:
Mohr, J. T.; Toyoki, N.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc.
2006, 128, 11348, and ref 3b.
(6) Bite angles in relevant Pd(II) complexes: xantphos ) 108.1°, dppf
) 102.2°, BINAP ) 96.0°, dppe ) 86°: (a) Johns, A. M.; Utsunomiya,
M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 1828. (b)
Steffen, W. L.; Palenik, G. J. Inorg. Chem. 1976, 15, 2432.
(9) (a) Ohmoto, T.; Koike, K. The Alkaloids; Brossi, A., Ed.; Academic
Press: San Diego, 1989; Vol. 36, pp 135-150. (b) Love, B. E. Org. Prep.
Proced. Int. 1996, 28, 1.
Org. Lett., Vol. 12, No. 2, 2010
317

Table 2. Substrate Scope for the Pd-Catalyzed Decarboxylative Benzylation of Imino Esters 1a
a Reaction conditions: imino ester 1 (100 mg), Pd(OAc)2 (3 mol %), and rac-BINAP (20 mol %) in DMA (0.1 M), microwave irradiation to the indicated
temperature for an indicated time. b Isolated yield after chromatographic purification. The remaining mass balance was predominantly the protonation and
c
1
acetaylation side products, a` la 3 and 4. Determined by H NMR spectroscopy of an inseparable mixture of 2f and 3 with durene as an internal standard.
d Reaction Conditions: imine (100 mg), Pd(OAc)2 (10 mol %), and rac-BINAP (40 mol %) in DMA (0.1 M).
Variation of the imine moiety was also tolerated (entries
9-18), though increasing the size of the ortho substituent
dramatically impacted the corresponding isolated yields
(cf. entries 12-14). It is noteworthy that heteroaryl imines
2-benzofuranyl 1o, 3-pyridyl 1p, and 2-thiazolyl 1q
successfully underwent the transformation in moderate to
good yields (entries 15-17). Moreover, conversion of
R-imino ester 1r into fully protected phenylalanine 2r
simply required higher catalyst and ligand loading (10 mol
% Pd(OAc)2 and 40 mol % rac-BINAP), a phenomenon
specific to this substrate.
Scheme 2. Possible Mechanism for Decarboxylative Benzylation
A preliminary mechanistic explanation for the Pd-catalyzed
decarboxylative benzylation of imino esters 1 is provided in
Scheme 2. Reduction of Pd(OAc)2 with BINAP generates the
active BINAP-Pd(0) catalyst.10 Insertion into the ester C-O
bond5 forms an ephemeral Pd(II)-carboxylate species I that
undergoes irreversible decarboxylation to the 2-azaallylPd(II)
intermediate II, which is in equilibrium with the η1 complex
III and the tight-ion-paired π-benzylPd(II):R-imino anion
species IV. Reductive elimination (from III) or regioselective
nucleophilic attack (from IV) then regenerates the Pd(0) catalyst
with concomitant formation of homobenzylic imines 2.
In summary, we report general reaction conditions for the
Pd-catalyzed decarboxylative benzylation of benzyl diphenylg-
(10) Since the reduction of Pd(OAc)2 with BINAP also results in
formation of the corresponding monophosphine oxide (BINPO), the
involvement of this species in the catalytic cycle cannot be rigorously
excluded at this time: Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett. 1992,
2177.
318
Org. Lett., Vol. 12, No. 2, 2010

lycinate imines. This transformation expands the scope of our
previously identified Pd-catalyzed decarboxylative generation
and derivatization of stabilized R-imino anions.2d Given the
broad substrate scope and utility of the Tsuji-Trost decarboxy-
lative allylation manifold, our evidence supporting extension
to benzyl ester substrates is expected to have a significant impact.
J.J.C. thanks Prof. Michael Krische (UT-Austin) for an
inspiring conversation.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.
org.
Acknowledgment. Partial financial support provided by
the Thomas F. and Kate Miller Jeffress Memorial Trust.
OL902651J
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