One-pot tandem decarboxylative allylation-heck cyclization of allyl diphenylglycinate imines: Rapid access to polyfunctionalized 1-aminoindanes

Article abstract of DOI:10.1021/ol801986m

(Figure Presented) 1-Aminoindanes are generated from allyl diphenylglycinate imines employing a one-pot palladium-catalyzed decarboxylative allylation-Hecyclization cascade. Variation of both the aryl and allyl moieties leads to a diverse range of polycyclic imines, amenable to the synthesis natural products and other biologically relevant small molecules.

Full text of DOI:10.1021/ol801986m

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5131-5134
One-Pot Tandem Decarboxylative
Allylation-Heck Cyclization of Allyl
Diphenylglycinate Imines: Rapid Access
to Polyfunctionalized 1-Aminoindanes
Wendy H. Fields, Ali K. Khan, Michal Sabat, and Jason J. Chruma*
Department of Chemistry, UniVersity of Virginia, CharlottesVille, Virginia 22904-4319
jjc5p@Virginia.edu
Received August 25, 2008
ABSTRACT
1-Aminoindanes are generated from allyl diphenylglycinate imines employing a “one-pot” palladium-catalyzed decarboxylative allylation-Heck
cyclization cascade. Variation of both the aryl and allyl moieties leads to a diverse range of polycyclic imines, amenable to the synthesis of
natural products and other biologically relevant small molecules.
Palladium-catalyzed decarboxylative coupling reactions,
which typically proceed through an η3 π-allyl palladium
intermediate, have emerged as efficient and essentially neutral
pathways for carbon-carbon bond formation.1 A unique
value inherent to Pd-catalyzed transformations is the ability
to couple them to other powerful carbon-carbon bond-
forming events in one reaction vessel.2 Despite intense
interest in Pd-mediated decarboxylative alkylations,1,3 to the
best of our knowledge, very few examples exist that couple
this technique with other Pd-catalyzed carbon-carbon bond-
forming reactions in one reaction vessel.4 Herein, we report
a two step-one-pot decarboxylative allylation-Heck cy-
clization to rapidly afford 3-alkylidenyl-1-aminoindanes.
Recent studies have identified the functionalized 1-ami-
noindane motif as both a unique platform for ventures in
diversity-oriented synthesis5a and for the construction of
potent atypical antipsychotic agents.5b We reasoned that the
Pd-catalyzed decarboxylative allylation of diphenylglycinate
(1) For recent examples of decarboxylative enolate alkylations, see: (a)
Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 4113–4115. (b) Enquist,
J. A., Jr.; Stoltz, B. M. Nature 2008, 453, 1228–1231. (c) Trost, B. M.;
Xu, J. J. Am. Chem. Soc. 2005, 127, 2846–2847. (d) McFadden, R. M.;
Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 7738–7739.
(2) (a) Metal Catalyzed Cascade Reactions. Top. Organomet. Chem.
Mu¨ller, T. J. J., Ed. 2006, 19, 1-91, 149-205. (b) Nicolaou, K. C.; Bulger,
P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442–4489. (c) Poli,
G.; Giambastiani, G.; Heumann, A. Tetrahedron 2000, 56, 5959–5989. (d)
de Meijere, A.; Bra¨se, S. Organomet. Chem. 1999, 576, 88–110.
(3) (a) Burger, E. C.; Tunge, J. A. J. Am. Chem. Soc. 2006, 128, 10002–
10003. (b) Tunge, J. A.; Burger, E. C. Eur. J. Org. Chem. 2005, 9, 1715–
1726. (c) Rayabarapu, D. K.; Tunge, J. A. J. Am. Chem. Soc. 2005, 127,
13510–13511. (d) Yamamoto, Y.; Nakamura, H.; Sekido, M.; Ito, M. J. Am.
Chem. Soc. 1998, 120, 6838–6839. (e) You, S.-L.; Dai, L.-X. Angew. Chem.,
Int. Ed. 2006, 45, 5246–5248. (f) Tsuji, J. Pure Appl. Chem. 1986, 58,
869–878. (g) Imao, D.; Itoi, A.; Yamazaki, A.; Shirakura, M.; Ohtoshi, R.;
Ogata, K.; Ohmori, Y.; Ohta, T.; Ito, Y. J. Org. Chem. 2007, 72, 1652–
1658.
(4) (a) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc.
2002, 124, 11250–11251. (b) Moon, J.; Jeong, M.; Nam, H.; Ju, J.; Moon,
J. H.; Jung, H. M.; Lee, S. Org. Lett. 2008, 10, 945–948. (c) Forgione, P.;
Brochu, M. C.; St-Onge, M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F.
J. Am. Chem. Soc. 2006, 128, 11350–11351. (d) Goossen, L. J.; Deng, G.;
Levy, L. M. Science 2006, 313, 662–664.
(5) (a) Kesavan, S.; Panek, J. S.; Porco, J. A. Org. Lett. 2007, 9, 5203–
5206. (b) Graham, J. M.; Coughenour, L. L.; Barr, B. M.; Rock, D. L.;
Nikam, S. S. Bioorg. Med. Chem. Lett. 2008, 18, 489–493.
10.1021/ol801986m CCC: $40.75
Published on Web 10/29/2008
2008 American Chemical Society

imines recently developed by our group6 could be coupled
to an intramolecular Heck reaction to rapidly generate
functionalized 1-aminoindanes. Accordingly, o-iodobenzaldi-
mine 1a was subjected to our standard decarboxylative
allylation conditions (10 mol % of Pd(dba)2, dppf, DMF, 20
°C). We were gratified to observe the formation of the
cyclized product 3a in addition to the expected homoallylic
imine 2a in a 1:10 ratio and excellent combined yield
(Scheme 1). It is worth noting that 3a was obtained even
Table 1. Optimization Studies of One-Pot Reaction
isolated
isomer
entry
time (i:ii)
additive
none
TBAC
TBAI
TBAB
yield (%) ratio (3a:4a)
1
2
3
4
5 min:5 min
5 min:5 min
5 min:5 min
5 min:5 min
g99
72
73
1:1a
9.4:1
2.7:1
3.4:1
g20:1
Scheme 1. Two-Step Decarboxylative Allylation-Heck Cascade
65
5
6
7
8
9
5 min:5 min Ag2SO4
91
2 hb:10 min
2 hb:10 min
2 hb:10 min
5 min:5 min
5 min:5 min
AgNO3
AgOTf
AgO2CCF3
Tl2CO3
K2CO3
NR
NR
NR
72
16:1
2.6:1
10
70
a This represents an average ratio; specific ratios per run were highly
variable. b No conversion to homoallylic imine; subjection to Heck reaction
conditions after 2 h led to complete decomposition of 1a. c 2 equiv of K2CO3
instead of Et3N. NR ) no reaction. TBAC ) tetrabutylammonium chloride.
TBAI ) tetrabutylammonium iodide. TBAB ) tetrabutylammonium
bromide.
tributed to the production of an ephemeral palladium hydride
species that can isomerize the double bond to the more
substituted position via a series of addition-elimination
events.10 Remarkably, the resulting enimine 4a was stable
to standard flash chromatography through nonbuffered silica
gel. We investigated a variety of additives to enhance the
selectivity of the Heck cyclizations (Table 1).10 Tetraalky-
lammonium salts10f did not have an appreciable effect on
the reaction rate or alkene isomer ratios (entries 2-4).
Alternatively, silver(I) sulfate successfully inhibited isomer-
ization, leading to the exclusive formation of 3a in excellent
isolated yield (entry 5).10a,e Similarily, addition of Tl2CO3,
shown in entry 9, for the tandem reaction led to a signifi-
cantly improved isomer ratio.10c It is worth noting that other
silver(I) salts (entries 6-8) completely inhibited the initial
decarboxylative allylation; none of the other additives were
found to impact this transformation.11 Van Vranken et al.
observed that use of an insoluble base was crucial for
inhibiting alkene migration of R,ꢀ-unsaturated esters in their
tandem carbene insertion-Heck cyclization tactic.12 For our
reaction, however, we obtained a disappointing 2.6:1 ratio
of alkenes 3a:4a when triethylamine was replaced with
K2CO3 as base.
without the addition of exogenous base or heat. Subjection
of the resulting reaction mixture to typical Heck reaction
conditions7 effected complete conversion to the 3-methyl-
enyl-1-aminoindane 3a, whose structure was confirmed by
X-ray crystallographic analysis (see inset).
Encouraged by these results, we next sought optimal
conditions to effect the two-step process in one reaction
vessel. Initial attempts employed 10 mol % of Pd(dba)2 and
dppf as catalyst, but coelution of the dibenzylidene-acetone
ligand during chromatography compromised the purity of
the product. Tetrakis(triphenylphosphine)palladium(0), how-
ever, provided rapid and effective decarboxylative allylation
and subsequent Heck cyclization without introducing intrac-
table purification issues. Furthermore, microwave irradiation
rapidly accelerated the Heck reaction,8 though in some cases
an additional isomerized product 4a was coisolated in
unpredictable ratios (Table 1).5a,9 This result may be at-
(6) Yeagley, A. A.; Chruma, J. J. Org. Lett. 2007, 9, 2879–2882.
(7) (a) Heck, R. F. Acc. Chem. Res. 1979, 12, 146–151. (b) Mizoroki,
T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581. (c) Beletskaya,
I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009–3066. (d) Daves, G. D.;
Hallberg, A. Chem. ReV. 1989, 89, 1433–144.
(10) (a) Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987,
52, 4130–4133. (b) Wheatley, B. M. M.; Keay, B. A. J. Org. Chem. 2007,
72, 7253–7259. (c) Reetz, M. T. Angew. Chem., Int. Ed. 1972, 11, 129–
130. (d) Grigg, R.; Loganathan, V.; Santhakumar, V.; Sridharan, V.;
Teasdale, A. Tetrahedron Lett. 1991, 32, 687–690. (e) Larock, R. C.; Gong,
W. H. J. Org. Chem. 1989, 54, 2047–2050. (f) Jeffery, T. Synthesis 1987,
70–71.
(8) (a) Xie, X.; Lu, J.; Chen, B.; Han, J.; She, X.; Pan, X. Tetrahedron
Lett. 2004, 45, 809–811. (b) Declerckz, V.; Ribie`re, P.; Ne´dellec, Y.;
Allouchi, H.; Martinez, J.; Lamaty, F. Eur. J. Org. Chem. 2007, 201–208.
(c) Svennebring, A.; Garg, N.; Nilsson, P.; Hallberg, A.; Larhed, M. J.
Org. Chem. 2005, 70, 4720–4725. (d) Donets, P. A.; Van der Eycken, E. V.
Org. Lett. 2007, 9, 3017–3020.
(11) We have observed a similar inhibition of the decarboxylative
allylation at rt with g10 mol % of other Lewis acids, e.g., LiCl, ZnCl2, or
Sc(OTf)3.
(9) Small amounts of the alkene disproportionation products 9 and 10
were also observed (1H NMR and LC/MS) in conjunction to 4a.
(12) Kudirka, R.; Van Vranken, D. L. J. Org. Chem. 2008, 73, 3585–
3588.
(13) (a) Knowles, J. P.; Whiting, A. Org. Biomol. Chem. 2007, 5, 31–
44. (b) Crisp, G. T. Chem. Soc. ReV. 1998, 27, 427–436.
5132
Org. Lett., Vol. 10, No. 22, 2008

The substrate scope of the reaction was first evaluated
through variation of the imine moiety. Accordingly, imines
1 were subjected to our optimized two-step, one-pot reaction
conditions to afford the corresponding cyclic products 3
(Table 2). A variety of aryl and heteroaryl functionalities
The relatively electron-deficient pyridinyl heterocycle 1f,
however, smoothly converted to the corresponding tandem
decarboxylative allylation-Heck cyclization product 3e
(entry 7). As demonstrated in entry 2, combining all reagents
at once, including the amine base, followed by immediate
microwave irradiation, also produced the desired 1-iminoin-
dane, though in a lower isolated yield versus the two-step,
one-pot process (entry 1).
Diversification of the allyl ester was achieved by micro-
wave-accelerated olefin cross-metathesis either prior to or
after imine formation.14 For example, subjection of alkene
1a and stilbene to Grubbs’ second-generation catalyst15 under
microwave heating (90 °C, 10 min) rapidly afforded the
corresponding imine 5b in high isolated yield (Scheme 2).
Table 2. Tandem Decarboxylative Allylation-Heck Cyclization
Scheme 2
.
Diversification of the Allyl Ester Moeity Employing
Olefin Cross-Metathesis
The resultant R-imino esters 5 were subjected to our
optimized tandem decarboxylative allylation-Heck cycliza-
tion conditions (Table 3). For the methyl acrylate substrate
5a, the ratio of resultant isomers 6a and 7a proved to be
extremely variable, though combined yields were typically
high (entries 1 and 2). In contrast to allyl ester 1a, Ag2SO4
did not consistently improve the ratio of products in favor
of dihydrobenzofulvene 6a. Surprisingly, addition of Tl2CO3
to the reaction mixture resulted in the predominant formation
of the isomerized product 7a. Preferential formation of the
internalized alkene was unique to substrate 5a; cinnamyl ester
5b and furanyl imine 5c consistently afforded the corre-
sponding exomethylenes 6b and 6c, respectively, as the
exclusive cyclization products. The successful Heck cycliza-
tion of the election-rich furanyl substrate 5c is noteworthy,
given that the related allyl ester 1g did not proceed past
a 1.0 equiv of Ag2SO4 added to inhibit double-bond migration. b Ag2SO4
omitted. c Compound 1e was a 4.6:1 ratio of aryl iodide and aryl bromide.
d 100% conversion to homoallylic imine as a 9.3:1 ratio of regioisomers;
no cyclized product (3f) was observed. e Et3N added prior to decarboxylative
allylation.
(14) For examples of microwave-accelerated olefin cross-metathesis
reactions, see: (a) Coquerel, Y.; Rodriguez, J. Eur. J. Org. Chem. 2008,
1125–1132. (b) Gebauer, J.; Arseniyadis, S.; Cossy, J. Eur. J. Org. Chem.
2008, 2701–2704. (c) Aitken, S. G.; Abell, A. D. Aust. J. Chem. 2005, 58,
3–13.
(15) (a) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
1996, 118, 100–110. (b) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs,
R. H. Angew. Chem., Int. Ed. 1995, 34, 2039–2041.
(16) Young and Kerr noted a similar reliance on Ag2SO4 for a related
Heck cyclization in their total synthesis of nakadomarin A: Young, I. S.;
Kerr, M. A. J. Am. Chem. Soc. 2007, 129, 1465–1469.
successfully underwent the tandem reaction process. In
accord with our previous decarboxylative allylation studies
and the accepted mechanism of the Heck reaction,13 electron-
deficient o-halobenzaldimines provided superior yields and
rates versus electron-rich counterparts (compare entries 5 and
4). In an extreme case, the electron-rich furanyl bromide 1g
did not undergo Heck cyclization, halting at the intermediate
homoallylic imine as a 9.3:1 ratio of regioisomers (entry 8).6
(17) (a) Lautens, M.; Fang, Y.-Q. Org. Lett. 2003, 5, 3679–3682. (b)
Andersson, P. G.; Schab, S. Organometallics 1995, 14, 1–2. (c) Takacs,
J. M.; Lawson, E. C.; Clement, F. J. Am. Chem. Soc. 1997, 119, 5956–
5957. (d) Maeda, K.; Farrington, E. J.; Galardon, E.; John, B. D.; Brown,
J. M. AdV. Synth. Catal. 2002, 344, 104–109. (e) Bray, K. L.; Lloyd-Jones,
G. C.; Mun˜oz, M. P.; Slatford, P. A.; Tan, E. H. P.; Tyler-Mahon, A. R.;
Worthington, P. A. Chem.sEur. J. 2006, 12, 8650–8663. (f) Hudlicky, T.;
Olivo, H. F. J. Am. Chem. Soc. 1992, 114, 9694–9696.
Org. Lett., Vol. 10, No. 22, 2008
5133

in one reaction vessel. Future efforts will be directed at the
application of this reaction cascade toward the total synthesis
of the manzamine-related alkaloid nakadomarin A18 as well
as libraries of B-norbenzomorphans 8, a conformationally
restricted benzazepine scaffold that has provided potent
analgesics and acetylcholinesterase inhibitors (Scheme 3).19
Table 3. Tandem Decarboxylative Allylation-Heck Cyclization
of Imines 5
Scheme 3. Future Targets Acessible via the Pd-Catalyzed
Decarboxylative Allylation-Heck Cascade
a This represents an average ratio; specific ratios are highly variable
sometimeswith6apredominating.b 2.0equivofTl2CO3added.c Decarboxylative
allylation required 15 min. d 1.5 equiv of Ag2SO4 added.
General Microwave Procedure. The reaction mixtures
were heated to the indicated temperatures (300 W maximum
power) for the indicated time in a sealed 10 mL CEM
IntelliVent microwave tube using a CEM Explorer-Discover
microwave reactor with IR temperature probe. Reaction
temperature, pressure, and temperature-time profiles were
monitored using the associated ChemDriver Explorer Ap-
plication program.
decarboxylative allylation following our standard reaction
conditions (see Table 2). Addition of Ag2SO4 to the reaction
mixture and longer reaction time, however, were crucial for
promoting the Heck cyclization to afford 6c.16 These results
suggest that successful Heck cyclization under our reaction
conditions relies on an intimate and complex interplay
between the electronic factors governing the reversible
oxidative addition and migratory insertion steps.
Extensive 2D-NMR spectroscopic analysis (NOESY) of
alkenes 6 indicated predominant formation of the E-alkene
geometry, as shown, thus representing a formal anti-ꢀ-
hydride elimination of the Pd(II) intermediate in the Heck
cyclization. Although Heck reactions typically require syn-
ꢀ-hydride elimination,13 several examples suggest the pos-
sibility of either an anti-ꢀ-hydride elimination or an isomer-
ization manifold.17
Acknowledgment. Partial financial support provided by
the Thomas F. and Kate Miller Jeffress Memorial Trust
(J-808). A.K.K. was supported by a UVA Bass Scholarship
for Summer Undergraduate Research.
Supporting Information Available: Experimental pro-
cedures, characterization data, and cif file for compound 3a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL801986M
In conclusion, we report a rapid and mild pathway toward
the synthesis of complex polycyclic organoamines using a
one-pot decarboxylative allylation-Heck reaction cascade.
This work stands as a proof-of-principle that decarboxylative
allylations can be coupled effectively to other powerful
transition-metal-mediated carbon-carbon bond-forming events
(18) (a) Kobayashi, J.; Watanabe, D.; Kawasaki, N.; Tsuda, M. J. Org.
Chem. 1997, 62, 9236–9239. (b) Kobayashi, J.; Tsuda, M.; Ishibashi, M.
Pure Appl. Chem. 1999, 71, 1123–1126.
(19) (a) Jacobson, A. E.; Mokotoff, M. J. Med. Chem. 1970, 13, 7–9.
(b) Chen, Y. L.; Liston, D.; Nielsen, J.; Chapin, D.; Dunaiskis, A.; Hedberg,
K.; Ives, J.; Johnson, J.; Jones, S. J. Med. Chem. 1994, 37, 1996–2000.
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