Tandem C-C bond-forming processes: Interception of the Pd-catalyzed decarboxylative allylation of allyl diphenylglycinate Lmines with activated olefins

Article abstract of DOI:10.1021/ol901745x

Interception of the Pd-catalyzed decarboxylase allylation of allyl diphenylglycinate imines with appropriately functionalized Michael acceptors, followed by Heck cyclization, allows for the efficient construction of relatively complex organoamine framewor

Full text of DOI:10.1021/ol901745x

ORGANIC
LETTERS
2009
Vol. 11, No. 17
4022-4025
Tandem C-C Bond-Forming Processes:
Interception of the Pd-Catalyzed
Decarboxylative Allylation of Allyl
Diphenylglycinate Imines with Activated
Olefins
Andrew A. Yeagley, Melissa A. Lowder, and Jason J. Chruma*
Department of Chemistry, UniVersity of Virginia, CharlottesVille, Virginia 22904-4319
jjc5p@Virginia.edu
Received July 29, 2009
ABSTRACT
Interception of the Pd-catalyzed decarboxylative allylation of allyl diphenylglycinate imines with appropriately functionalized Michael acceptors,
followed by Heck cyclization, allows for the efficient construction of relatively complex organoamine frameworks in one reaction vessel. The
initial intercepted decarboxylative allylation is remarkably insensitive toward solvent and catalyst, typically proceeding under ambient conditions.
Since the pioneering work of Tsuji,1 Saegusa2 and Trost,3
Pd-catalyzed decarboxylative allylations (DcAs) have emerged
Scheme 1
.
Decarboxylative Allylation (DcA) and
Intercepted DcA
as mild and versatile procedures for rapidly constructing
complex molecular frameworks.4,5 Each DcA transformation
proceeds through the intermediacy of an electrophilic π-allyl-
Pd(II) species and a corresponding N-, O-, or C-centered
nucleophilic anion counterpart (R-, Scheme 1). Yamamoto6
and others7 have demonstrated that activated Michael ac-
ceptors and related electrophiles (YdX, Scheme 1) can
intercept the nucleophilic intermediates prior to allylation
and regeneration of the Pd(0) catalyst. Reports of C-centered
anions participating in such intercepted Pd-catalyzed DcA
transformations typically have been limited to enolates.8 We
recently introduced the R-imino anion (2-azaallyl anion) as
a viable intermediate for the aldehyde-intercepted Pd-
catalyzed DcA of allyl diphenylglycinate imines.7c Herein,
we report that alkene derivatives of malononitrile (2)9 and
Meldrum’s acid (4) are potent electrophiles for the inter-
cepted DcA of allyl diphenylglycinate imines.10 The resulting
products are appropriately functionalized for a variety of
further transformations, for example, Heck cyclization,11
(1) (a) Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron Lett. 1980, 21,
3199. (b) Shimizu, I.; Tsuji, J. J. Am. Chem. Soc. 1982, 104, 5844.
(2) Tsuda, T.; Chujo, Y.; Nishi, S.-i.; Tawara, K.; Saegusa, T. J. Am.
Chem. Soc. 1980, 102, 6381.
(3) (a) Trost, B. M. Tetrahedron 1977, 33, 2615. (b) Trost, B. M.; Hung,
M. H. J. Am. Chem. Soc. 1984, 106, 6837.
10.1021/ol901745x CCC: $40.75
Published on Web 08/06/2009
 2009 American Chemical Society

allowing for the efficient construction of relatively complex
organoamine frameworks in as few as one reaction vessel.
Our results emphasize that Pd-mediated decarboxylation is
a mild and versatile strategy for the generation and deriva-
tization of stabilized R-imino anions.
As an initial assessment of the capability of arylidene
malononitriles to act as electrophilic interceptors in the DcA
of allyl diphenylglycinate imines, a solution of imine 1a (1.0
equiv) and alkene 2a (1.1 equiv) was subjected to our
standard DcA reaction conditions (10 mol % Pd(PPh3)4,
MeCN, 20 °C).7c Gratifyingly, the intercepted DcA product
3aa was generated quantitatively as a roughly 1:1 ratio of
diatereomers (Table 1, entry 1). The transformation proved
presence of water does not significantly impact the trans-
formation (Table 1, entry 6). This stands in marked contrast
to the 2-azaallyllithium dipolar nucleophiles described by
Kauffmann12 and Pearson.13
Inspired by these results, we next investigated the scope
of the electrophiles and imines (1, R1). Arylidene malono-
nitriles bearing electron-rich (2c and 2d) or electron-deficient
(2b and 2e) aromatic R2-groups, as well as heteroaromatics
(2f), were successfully incorporated into the DcA of imine
1a, providing the corresponding allylated products 3 in high
yield (Table 2, entries 2-6). The branched aliphatic i-Pr
substituent (2g) also was effective (Table 2, entry 7) The
bulkier t-Bu substrate 2h, however, was a much poorer
intercepting electrophile. Geminal dinitrile 3ah was isolated
in low yield with the non-intercepted DcA product 6 (R1 )
4-CN-Ph, Figure 1) comprising the remainder of converted
starting material. For all other alkylidene malononitriles
(Table 2, entries 1-7 and 9-12), homoallylic imines 6 were
detected in, at most, trace quantities. The results obtained
by variation of the imine R1 group mirrored our previous
non-intercepted DcA studies.7c Specifically, electron-with-
drawing aromatic (1a and 1b) and heteroaromatic (1d)
substituents afforded a single regioisomer. Alternatively, the
electron-donating p-methoxybenzaldimine 1c provided a 5:1
ratio of regioisomeric products 3ca:7 in 95% combined yield;
imine 7 selectively hydrolyzed on silica gel, thus facilitating
purification of the other regioisomer (Figure 1). While no
diastereoselectivity was observed for the intercepted DcA
of imino esters 1 with alkenes 2, the majority of product (3)
diastereomeric mixtures could be resolved via standard
chromatographic means.
Table 1. Solvent Studies for the Intercepted DcA
entry
solvent
MeCN
2-Me-THF
PhCH3
product dr (syn:anti)a isolated yield
1
2
3
4
3aa
3aa
3aa
3aa
3aa
3ac
1.0:1.2
1.0:1.4
1.0:1.1
1.0:1.1
1.0:1.1
1.0:1.2
99%
99%
89%
97%
95%
86%d
DMF
5
CH2Cl2
6b
PhCH3:H2Oc
a Determined by 1H NMR analysis of the unpurified reaction mixtures.
b Alkene 2c was used. c 10 mol % of (-)-O-9-allyl-N-(9-anthracenylmeth-
yl)cinchondium bromide added as a phase-transfer catalyst. d 88% with
MeCN as solvent.
To further explore the electrophile scope, arylidene Mel-
drum’s acid derivatives 4 also were investigated as intercept-
ing agents (Table 2, entries 13-17). Alkenes 4 proved to be
weaker electrophiles than their malononitrile counterparts 2;
significant quantities (e20%) of the homoallylic imine 6 (R1
) 4-CN-Ph) were produced in competition with interception
products 5. Interestingly, the 2-furanyl alkene 4e severely
deactivated the Pd(0) catalyst, resulting in very slow conver-
sion of imine 1a to either 5ae or 6 (Table 2, entry17). Unlike
highly independent of the reaction medium; nearly identical
yields and diastereomeric ratios were obtained employing a
variety of solvents (Table 1). Despite the relatively high
basicity of the putative R-imino anion intermediate, the
(4) (a) Tunge, J. A.; Burger, E. C. Eur. J. Org. Chem. 2005, 1715. (b)
Imao, D.; Itio, A.; Yamazaki, A.; Shirakura, M.; Ohtoshi, R.; Ogata, K.;
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(9) CAUTION: Many arylidenemalononitriles are powerful irritants and
should be handled in a well-ventilated fume hood!
(10) For a related Ru-catalyzed intercepted DcA of ꢀ-ketoesters: Wang,
(5) Recent applications in natural product total synthesis: (a) Enquist,
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Org. Lett., Vol. 11, No. 17, 2009
4023

Table 2. Intercepted DcA of Imines 1 with Activated Alkenes
a 1.1 equiv compared to imine 1. b Isolated yield of diastereomeric mixture after preliminary chromatography. c The dr was ∼2:1 in favor of the anti
diastereomer. d The remaining mass balance corresponded to the regioisomeric product 7. e Only one diastereomer isolated. f The anti diastereomer was
isolated exclusively. g Isolated yield after Et3N-buffered SiO2 chromatography.
malononitriles 2, the nonplanar cyclic diesters 4 typically
demonstrated a subtle diastereoselectivity favoring the anti-5
stereoisomer. Moreover, to varying degrees, the syn epimer
selectively decomposed upon passage through nonbuffered
silica gel, allowing for the exclusive isolation of the anti-5
isomer in acceptable yields. This stereoselective decomposi-
tion during chromatography was eliminated by addition of
1% Et3N to the eluent, but the diastereomers typically
coeluted.
The presence of catalytic Pd(0), requisite for the inter-
cepted DcA transformation, allows for further C-C bond-
forming events in the same reaction vessel. Toward this end,
Figure 1. Noteworthy side-products.
(14) Previous DcA-Heck cascade studies from our group: Fields, W. H.;
Khan, A. K.; Sabat, M.; Chruma, J. J. Org. Lett. 2008, 10, 5131.
4024
Org. Lett., Vol. 11, No. 17, 2009

we successfully coupled the intercepted DcA between imine
1a and alkene 2b with a microwave-accelerated intramo-
lecular Heck reaction for a two-step, one-pot process to
rapidly generate exo-methylene 8 (Scheme 2, dr 1:1).14
Scheme 3. Proposed Catalytic Cycle for the Decarboxylative
Allylation (DcA) and Olefin-Intercepted DcA of Imino Esters 1
Scheme 2. Tandem Intercepted DcA-Heck Cyclization
A catalytic cycle for the formation of intercepted DcA
products 3 and 5 is proposed in Figure 1. The intercepted
DcA process required significantly longer (g30 times)
reaction times in comparison to the corresponding non-
intercepted DcA, that is, 1f6.7c Presumably, the electron-
deficient alkenes compete for a coordination site on the
π-basic Pd(0) catalyst requisite for either oxidative addition
into the allyl ester C-O bond or decarboxylation.15 Follow-
ing oxidative addition, intermediate I quickly undergoes
decarboxylation to yield the N-ligated 2-azaallylPd(II) species
II.16 The lack of any protonated products by the addition of
water to the reaction mixture suggests that an R-imino anion
stays in close contact with the Pd(II) metal center. Accord-
ingly, direct nucleophilic attack of Michael acceptors 2 or 4
by intermediate II leads to the 5-membered palladacycle III.
Reductive elimination then affords the corresponding inter-
cepted products 3/5 while regenerating the active Pd(0)
catalyst. In the absence of activated olefin or with sterically
encumberred Michael acceptors (e.g., 2h), the R-imino anion
can be displaced from the metal by a phosphine ligand to
afford the tight ion pair complex IV which rapidly goes on
to produce homoallylic imine 6.
In conclusion, we describe a mild and efficient method
for generating and functionalizing R-imino anions. The
resulting Pd(II)-R-imino anion intermediates are substantially
more resistant to aqueous protonation than to their Li(I)
counterparts. The olefin-intercepted DcAs employ readily
obtainable starting materials and occur at ambient temper-
ature in a variety of solvents at the sole expense of one
equivalent of CO2. These substrates can be further trans-
formed in the same reaction vessel into relatively complex
organoamine frameworks via additional Pd(0)-catalyzed
C-C bond-forming reactions. Efforts to apply this cascade
process toward the total synthesis of alkaloid natural
products, particularly karachine,17 are currently underway
and will be reported in due course.
Acknowledgment. Partial financial support provided by
the Thomas F. and Kate Miller Jeffress Memorial Trust. We
thank M. Sabat (Director, UVA Small Molecule X-ray
Facility) for obtaining X-ray crystallographic data for syn-
(()-3ab.
(15) Experimental and computational studies both suggest that the
monophosphine-Pd(0) complex is the active catalyst for oxidative addition:
(a) Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124,
6353. (b) Ahlquist, M.; Fristrup, P.; Tanner, D.; Norrby, P.-O. Organome-
tallics 2006, 25, 2066. (c) Li, Z.; Fu, Y.; Guo, Q.-X.; Liu, L. Organome-
tallics 2008, 27, 4043. (d) Li, Z.; Zhang, S.-L.; Fu, Y.; Guo, Q.-X.; Liu, L.
J. Am. Chem. Soc. 2009, 131, 8815.
Supporting Information Available: Experimental pro-
cedures, characterization data including X-ray crystallo-
graphic data and cif file for syn-(()-3ab. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL901745X
(16) The intermediacy of a bis-π-allylPd(II) species cannot be ruled out
at this point: (a) Nakamura, H.; Shim, J. G.; Yamamoto, Y. J. Am. Chem.
Soc. 1997, 119, 8113. (b) Nakamura, H.; Aoyagi, K.; Shim, J.-G.;
Yamamoto, Y. J. Am. Chem. Soc. 2001, 123, 372. (c) Solin, N.; Narayan,
S.; Szabo´, K. J. J. Org. Chem. 2001, 66, 1686.
(17) (a) Blasko´, G.; Murugesan, N.; Freyer, A. J.; Shamma, M.; Ansari,
A. A.; Rahman, A.-v. J. Am. Chem. Soc. 1982, 104, 2039. (b) Stevens,
R. V.; Pruitt, J. R. J. Chem. Soc., Chem. Commun. 1983, 1425.
Org. Lett., Vol. 11, No. 17, 2009
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