Palladium-catalyzed asymmetric allylic alkylation of 3-aryloxindoles with allylidene dipivalate: A useful enol pivalate product

Article abstract of DOI:10.1002/anie.201209783

Triple A: The catalytic asymmetric allylic alkylation (AAA) of 3-aryloxindoles with allylidene dipivalate is described. This reaction affords stable, synthetically useful enol pivalates in high yield and with excellent regio- and enantioselectivity. A broad range of substrates is tolerated, including unprotected and 3-heteroaryl nucleophiles. Copyright

Full text of DOI:10.1002/anie.201209783

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DOI: 10.1002/anie.201209783
Asymmetric Catalysis
Palladium-Catalyzed Asymmetric Allylic Alkylation of 3-Aryloxindoles
with Allylidene Dipivalate: A Useful Enol Pivalate Product**
Barry M. Trost,* James T. Masters, and Aaron C. Burns
Asymmetric allylic alkylation (AAA)[1] is a powerful and
versatile method for the catalytic, asymmetric construction of
quaternary stereocenters.[2] In the Mo- and Pd-AAA in
particular, a broad range of functionalized electrophiles has
been utilized, enabling the rapid synthesis of complex
molecules in an atom- and step-economical manner.[3,4]
Geminal dicarboxylates (e.g., allylidene dicarboxylates) con-
stitute an under-explored set of electrophiles in this area.[5]
We envisioned a new Pd-AAA reaction employing
prochiral nucleophiles and geminal dicarboxylate electro-
philes, one that would yield a quaternary stereocenter bearing
a linear, three-carbon, enol carboxylate unit. This enol
carboxylate could be transformed into a variety of useful
Scheme 1. Asymmetric Michael additions of oxindoles to acrolein.
functional groups, such as the saturated protected alcohol or
the aldehyde arising from a formal Michael addition to
acrolein. However, previous research has indicated that
geminal dicarboxylate-derived, chiral p-allylpalladium com-
plexes generally undergo intermolecular reaction at the ipso
position, affording branched products.[6] In addition to
requiring regioselective formation of linear products, the
proposed transformation must also proceed with high chemo-
and enantioselectivity. When examining prochiral nucleo-
philes in the Pd-AAA, the latter parameter represents an
especially significant challenge, as the nucleophile must
approach the p-allylpalladium distal to its chiral information,
potentially rendering enantiodiscrimination difficult.[7]
We selected oxindoles as nucleophiles for this trans-
formation as the 3,3-disubstituted oxindole structural motif
and its derivatives feature prominently in biologically active
natural products and pharmaceutical compounds. Moreover,
the enantioselective construction of 3,3-disubstituted oxin-
doles is a significant synthetic challenge.[8] Further, an
asymmetric Michael addition to acrolein represents its own
challenge. Possibly owing to the tendencies for acrolein to
undergo 1,2- (vs. 1,4-) reaction and to polymerize,[9] only one
strategy for the asymmetric Michael addition of an oxindole
to acrolein has been reported by Maruoka and co-workers[10]
and only for a limited set of N-Boc, 3-Ph oxindoles
(Scheme 1).[11]
Maruoka and co-workers have demonstrated the con-
version of these products into valuable alkaloid structural
motifs, underscoring synthetic interest in this transforma-
tion.[10] Though it stands out as a pioneering result, this
process requires cryogenic temperatures, excess base, and
dilute conditions. We postulated that our Pd-AAA approach
to an enol carboxylate would, via a subsequent hydrolysis
stage, enable a formal Michael addition that could be
performed at ambient temperature, higher concentration,
and with sufficient chemoselectivity to employ unprotected
oxindoles.
Our initial discovery efforts focused on the alkylation of
oxindole nucleophile 1, in the presence of [Pd2(dba)3]·CHCl3
ligated by our dppba ligands (Table 1). Drawing on our prior
methodology for the allylation of this substrate,[8h] PhMe was
used as the reaction solvent, with tBuOH included as an
additive. Unsurprisingly, the reaction of this nucleophile with
allylidene diacetate led to a complex mixture of branched,
linear, aldehydic, and possibly dimeric products. However,
switching to the bulkier allylidene dipivalate provided much
cleaner reactivity as well as higher selectivity for linear
product 2 over branched product 3. Importantly, this electro-
phile is readily prepared in one step and in very good yield
(81%) on gram-scale, from the reaction of acrolein with
pivalic anhydride (see Supporting Information).[12]
[*] Prof. B. M. Trost, J. T. Masters, Dr. A. C. Burns
Department of Chemistry, Stanford University
Stanford CA 94305-4401 (USA)
E-mail: bmtrost@stanford.edu
Homepage: http://www.stanford.edu/group/bmtrost
We evaluated this reaction with respect to our standard
ligand set, to optimize the formation of 2 (Table 1, entries 1–
4). Although L1 provided 2 with moderate conversion,
regioselectivity, and enantioselectivity, the use of stilbene-
derived ligand L2 provided very good conversion, essentially
complete selectivity for the desired linear product, and
excellent enantioselectivity. Surprisingly, ligands L3 and L4
[**] We thank the National Institutes of Health (R01GM033049) and the
National Science Foundation for their generous support of our
programs. J.T.M. is supported by an Abbott Laboratories Stanford
Graduate Fellowship. We also thank Johnson-Matthey for their
generous gift of palladium salts.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209783.
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Table 1: Selected optimization experiments.[a]
occurred when the reaction was performed in pure tBuOH,
but the enantioselectivity decreased. These results suggest
that the mixed PhMe/tBuOH or THF/tBuOH systems afford
high enantioselectivity while minimizing side reactions,
potentially including further reactions of 2 or 3.
With these optimized conditions in hand, the substrate
scope was evaluated. Thus, a number of oxindole nucleophiles
were prepared according to standard procedures and sub-
jected to the optimized reaction conditions (Table 2).
The Pd-AAA reaction was compatible with significant
structural variation on both the aryl group and the oxindole
core. Notably, electron-neutral (2), electron-rich (5a), and
electron-deficient (5b–5d) aryl substituents were all well-
tolerated.[13,14] These included aryl halides, which underwent
Entry
Solvent
Ligand
Conv./Yield
l:b
ee (2)
(2+3) [%][b]
(2:3)[b]
[%][c]
1
2
3
4
5
6
7
PhMe
PhMe
PhMe
PhMe
dioxane
DCE
THF
THF
tBuOH
PhMe
THF
L1
L2
L3
L4
L2
L2
L2
L2
L2
L2
L2
68/65
81/80
9/8
<5/<5
66/65
53/52
>95/>95
>95/91[e]
>95/85
75/65
4.9:1
>19:1
–
60
91
–
–
–
>19:1
5.8:1
76
83
92
92
76
90
92
>19:1
>19:1
>19:1
>19:1
>19:1
8[d]
9
Table 2: Scope of Pd-AAA with oxindole nucleophiles.[a]
10[f]
11[f]
>95/75
Product
R
Yield
[%][b]
l:b[c]
ee
[%][d]
H (2)
91
>19:1
92
(90)[e] (>19:1)[e] (90)[e]
p-OMe (5a) 88
>19:1
>19:1
>19:1
>19:1
>19:1
83
90
88
88
88
p-CF3 (5b)
p-Br (5c)
p-Cl (5d)
m-Me (5e)
98
82
93
87
[a] Unless specified otherwise, reactions were performed with 0.05 mmol
1, 5.0 mol% [Pd2(dba)3]·CHCl3, 15.0 mol% L1–L4, 1.5 equiv electrophile,
and 5.0 equiv tBuOH at 0.20m for 24 h. [b] Determined by 1H NMR
analysis of the crude reaction mixture, with mesitylene as an internal
standard. [c] Determined by chiral HPLC. [d] Reaction performed with
0.10 mmol 1, 2.5 mol% [Pd2(dba)3]·CHCl3, 7.5 mol% L2, 1.5 equiv
electrophile, and 5.0 equiv tBuOH at 0.40m for 24 h. [e] Yield of isolated
product after chromatography. [f] Reactions performed without tBuOH.
89
>19:1
90
afforded low conversion. Notably, the addition of exogenous
base (e.g., Et3N, Cs2CO3, or tetramethylguanidine) led to
poorer regio- and/or enantioselectivity, implicating significant
counter-ion effects and suggesting that the hydroxyoxindole
tautomer of 1 is the best nucleophile in terms of selectivity.
The effect of the reaction solvent was next explored
(Table 1, entries 5–7), whereupon it was discovered that,
when performed in THF, the reaction was complete within
24 h yet maintained excellent regio- and enantioselectivity. To
improve reaction efficiency, the effects of catalyst loading and
concentration were also investigated (entry 8). Pleasingly,
halving the catalyst loading (to 2.5 mol% [Pd2(dba)3]·CHCl3
and 7.5 mol% L2) while simultaneously doubling the reaction
concentration (to 0.40m) led to essentially identical reactivity
(> 95% conversion, 91% isolated yield, 92% ee) within the
same time period.
88
91
>19:1
>19:1
94
96
96
82
>19:1
>19:1
95
93
The effect of the tBuOH additive was also investigated
(Table 1, entries 9–11). Reactions performed in PhMe or THF
without tBuOH resulted in good conversion and high regio-
and enantioselectivity; however, yields of 2 were diminished
compared to reactions that included tBuOH. Full conversion
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Table 2: (Continued)
Product
neutral substrate (5k), which in turn afforded slightly greater
selectivity than electron-rich substrates (5l, 5n). This suggests
that a subtle electronic influence may exist wherein the
oxindole enolate is destabilized by electron-donating sub-
stituents, resulting in a slightly greater propensity to attack
the p-allylpalladium at its more electrophilic ipso position,
leading to more branched product.[17]
Having demonstrated the utility of this method for the
synthesis of enantioenriched enol pivalates, we investigated
its application toward the synthesis of functionalized products
(Scheme 2). Focusing first on conversion to the corresponding
R
Yield
[%][b]
l:b[c]
ee
[%][d]
H (5k)
96
13:1
90
(91)[f]
88
(13:1)[f] (89)[f]
OMe (5l)
F (5m)
11:1
17:1
84
89
97
75
93
9:1
87
92
14:1
Scheme 2. Elaboration of enol pivalate 2.
[a] Unless specified otherwise, reactions were performed with 0.10 mmol
1 or 4a–4o, 2.5 mol% [Pd2(dba)3]·CHCl3, 7.5 mol% L2, 1.5 equiv
electrophile, and 5.0 equiv tBuOH at 0.40m in PhMe or THF for 18–72 h.
[b] Isolated yield of both regioisomers after chromatography. [c] Deter-
mined by 1H NMR analysis. [d] Determined by chiral HPLC. [e] Reaction
performed on 1.00 mmol scale. [f] Reaction performed on 0.50 mmol
scale.
aldehyde, we were pleased to find that simply treating 2 with
methanolic KOH cleanly provided the desired aldehyde 6 in
a gratifying 84% yield, without competitive aldol or retro-
Michael reactions. Theorizing that these reaction conditions
would not be incompatible with those from the Pd-AAA
reaction, we investigated a one-pot transformation of 1 to 6.
In this event, the Pd-AAA reaction was performed according
to the standard procedure. After complete consumption of 1,
the reaction mixture was directly treated with the basic
solution under ambient conditions, efficiently providing 6 in
only slightly decreased yield, validating our original proposal
for this application of the subject Pd-AAA reaction.
In addition, the catalytic hydrogenation of enol pivalate 2
could be accomplished in good yield, affording protected
alcohol 7. Related 3,3-disubstituted oxindoles featuring
a three-carbon alcohol have attracted attention from the
pharmaceutical industry and in natural products synthesis,[18]
and this strategy of two ambient temperature, Pd-catalyzed
steps provides a practical alternative to, for example, an
allylation/hydroboration/oxidation/protection sequence. This
application of the present Pd-AAA is especially significant, as
the enantioselectivity of this reaction is markedly greater than
that of the simple allylation of similar nucleophiles.[8h]
the Pd-AAA in high yield and without competitive oxidative
addition reactions. Further, the steric demands of the
nucleophile could be increased without ill effect, as meta-
substituted product 5e and 2-naphthyl product 5 f were
obtained in high yield and with excellent selectivity. Halogen
substitution on the oxindole core was also tolerated (5g),
again without competitive oxidative addition.
Oxindoles bearing heteroaryl substituents at the 3-posi-
tion proved among the best substrates for this reaction,
affording very high yields and enantioselectivities (5h–5j).
Especially notable is the synthesis of compound 5j, as 3-
indole oxindoles are established precursors to biologically
active indole alkaloids.[15] Specifically, the 3-indole, 3-enol
pivalate compound 5j bears similarity to synthetic intermedi-
ates toward gliocladin C.[8m,15]
To our delight, unprotected oxindoles underwent the Pd-
AAA with high chemoselectivity for alkylation at the 3-
position. Thus, products 5k–5o were obtained in high yield
and enantioselectivity, with only slight decreases in regiose-
lectivity.[16] Importantly, this compatibility with unprotected
oxindoles also extended to a 3-heteroaryl nucleophile, as
evidenced by the synthesis of 5o with high yield and
selectivity. Furthermore, 5-substitution on the oxindole core
was tolerated (5n).
The hydrolysis of N-unprotected enol pivalate 5k was also
accomplished, smoothly affording aldehyde 8 in very good
yield (Scheme 3). Initial attempts to convert this product to
known N-Boc aldehyde 9 were complicated by competitive N-
Boc and enol-Boc formation. However, chemoselective N-
Boc protection could be accomplished by treating 8 with NaH
Although small in magnitude, an interesting substituent
effect was observed in the unprotected oxindole series: while
yields and enantioselectivities were generally consistent for
these substrates, a more electron-deficient substrate (5m)
afforded slightly greater regioselectivity than an electron-
Scheme 3. Elaboration and stereochemical analysis of 5k.
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Synthesis 2006, 369; f) Quaternary Stereocenters (Eds.: J. Chris-
toffers, A. Baro), Wiley-VCH, Weinheim, 2005; g) J. P. Das, I.
Marek, Chem. Commun. 2011, 47, 4593.
at low temperature and subsequently quenching the mixture
with Boc2O. Aldehyde 9 was thus obtained in good yield,
revealing the absolute stereochemistry of enol pivalate 5k
and demonstrating our ability to selectively functionalize the
oxindole nitrogen.[19]
[3] a) B. M. Trost, Science 1991, 254, 1471; b) B. M. Trost, Angew.
Chem. 1995, 107, 285; Angew. Chem. Int. Ed. Engl. 1995, 34, 259.
[4] P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc.
Chem. Res. 2008, 41, 40.
In conclusion, we report a new Pd-AAA reaction of
oxindole nucleophiles with allylidene dipivalate, one which
proceeds under mild, practical conditions and which regiose-
lectively provides enantioenriched products bearing a syn-
thetically useful linear enol pivalate unit. This reaction
tolerates a variety of substitution patterns, including 3-
heteroaryl substitution and unprotected oxindoles. The syn-
thetic utility of the enol pivalate product has been illustrated
by the one-pot, ambient temperature conversion of the
nucleophile to the aldehyde arising from Michael addition
to acrolein and by the conversion to a protected alcohol unit.
Additional applications of this new Pd-AAA are the subject
of continued study in our laboratories, and these results will
be reported in due course.
[5] a) B. M. Trost, C. B. Lee, J. M. Weiss, J. Am. Chem. Soc. 1995,
117, 7247; b) B. M. Trost, C. B. Lee, J. Am. Chem. Soc. 1998, 120,
6818; c) B. M. Trost, C. B. Lee, J. Am. Chem. Soc. 2001, 123,
3671; B. M. Trost, C. B. Lee, J. Am. Chem. Soc. 2001, 123, 3687.
[6] See Ref. [5c]. It has been observed that dimethyl methylmalo-
nate reacts with allylidene diacetate to provide the linear
product when PPh3 is used as the ligand; however, the use of
ligand L1 with this system favors branched material. See also
B. M. Trost, J. Vercauteren, Tetrahedron Lett. 1985, 26, 131.
[7] See a) B. M. Trost, R. Radinov, E. M. Grenzer, J. Am. Chem.
Soc. 1997, 119, 7879; b) B. M. Trost, X. Ariza, J. Am. Chem. Soc.
1999, 121, 10727; c) B. M. Trost, G. M. Schroeder, Chem. Eur. J.
2005, 11, 174, and references therein.
[8] For reviews covering the biological significance of 3,3-disubsti-
tuted oxindoles and their derivatives as well as the asymmetric
synthesis of these compounds, see: a) A. B. Dounay, L. E.
Overman, Chem. Rev. 2003, 103, 2945; b) C. Marti, E. M.
Carreira, Eur. J. Org. Chem. 2003, 2209; c) C. V. Galliford,
K. A. Scheidt, Angew. Chem. 2007, 119, 8902; Angew. Chem. Int.
Ed. 2007, 46, 8748; d) A. Steven, L. E. Overman, Angew. Chem.
2007, 119, 5584; Angew. Chem. Int. Ed. 2007, 46, 5488; e) B. M.
Trost, M. K. Brennan, Synthesis 2009, 3003; f) F. Zhou, Y.-L. Liu,
J. Zhou, Adv. Synth. Catal. 2010, 352, 1381; g) J. E. M. N. Klein,
R. J. K. Taylor, Eur. J. Org. Chem. 2011, 6821, and references
therein. For the asymmetric allylic alkylation and benzylation of
oxindole nucleophiles using Mo- and Pd-AAA, see: h) B. M.
Trost, M. U. Frederiksen, Angew. Chem. 2005, 117, 312; Angew.
Chem. Int. Ed. 2005, 44, 308; i) B. M. Trost, Y. Zhang, J. Am.
Chem. Soc. 2006, 128, 4590; j) B. M. Trost, Y. Zhang, J. Am.
Chem. Soc. 2007, 129, 14548; k) B. M. Trost, Y. Zhang, Chem.
Eur. J. 2010, 16, 296; l) B. M. Trost, L. C. Czabaniuk, J. Am.
Chem. Soc. 2010, 132, 15534; m) B. M. Trost, J. Xie, J. D. Sieber,
J. Am. Chem. Soc. 2011, 133, 20611.
Experimental Section
Representative procedure for Pd-AAA: A reaction vial was charged
with a stir bar, oxindole 1 (223.0 mg, 1.0 mmol, 1 equiv), [Pd2-
(dba)3]·CHCl3 (25.9 mg, 0.025 mmol, 0.025 equiv), and (R,R)-L2
(59.2 mg, 0.075 mmol, 0.075 equiv). The vial was sealed with
a septum-lined cap and evacuated and backfilled with N2 three
times. THF (2.5 mL) was added, followed by tBuOH (478 mL, 370 mg,
5.0 mmol, 5.0 equiv). The reaction mixture was stirred until it was
homogeneous and an orange color persisted (ca. 10 min), then
allylidene dipivalate (387 mL, 364 mg, 1.5 mmol, 1.5 equiv) was
added. The gas inlet was removed, and the vial was sealed thoroughly.
The reaction mixture was stirred at room temperature for 24 h, then
the septum cap was removed and the reaction mixture was poured
into a mixture of Et2O (50 mL) and saturated aqueous NaHCO3
(50 mL). The phases were separated, and the aqueous phase was
extracted with Et2O (50 mL). The pooled organic phases were washed
with water (2 ꢀ 25 mL) then brine (25 mL), dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified by
column chromatography (6:1 to 4:1 hexanes:EtOAc), affording 2
(327 mg, 90%, > 19:1 linear:branched, 90% ee) as a viscous, light
yellow oil.
[9] a) G. S. Zweifel, M. H. Nantz, Modern Organic Synthesis, Free-
man, New York, 2007; b) Organocatalytic Enantioselective Con-
jugate Addition Reactions (Eds.: J. L. Vicario, D. Badia, L.
Carrillo, E. Reyes), RSC Catalysis Series No. 5, RSC Publishing,
Oxford, 2010.
[10] R. He, C. Ding, K. Maruoka, Angew. Chem. 2009, 121, 4629;
Angew. Chem. Int. Ed. 2009, 48, 4559. Following our submission
of this manuscript, a report from Lu and co-workers on chiral
phosphine catalyzed asymmetric Michael additions of N-Boc
oxindoles was published online (F. Zhong, X. Dou, X. Han, W.
Yao, Q. Zhu, Y. Meng, Y. Lu, Angew. Chem. 2012, DOI: 10.1002/
ange.201208285; Angew. Chem. Int. Ed. 2012, DOI: 10.1002/
anie.201208285). However, this method suffers from the same
operational drawbacks mentioned (i.e. high dilution and cryo-
genic temperatures) and the singular example of an asymmetric
addition into acrolein proceeds with more modest (71%) ee.
[11] For recent progress in the conjugate addition of 3-alkyloxindoles
to b-substituted enals, see: a) P. Galzerano, G. Bencivenni, F.
Pesciaioli, A. Mazzanti, B. Giannichi, L. Sambri, G. Bartoli, P.
Melchiorre, Chem. Eur. J. 2009, 15, 7846; b) N. Bravo, I. Mon, X.
Companyꢁ, A.-N. Alba, A. Moyano, R. Rios, Tetrahedron Lett.
2009, 50, 6624.
Received: December 7, 2012
Published online: January 17, 2013
Keywords: allylic alkylation · asymmetric catalysis ·
.
heterocycles · Michael addition · palladium
[1] For reviews, see: a) B. M. Trost, D. L. van Vranken, Chem. Rev.
1996, 96, 395; b) B. M. Trost, M. L. Crawley, Chem. Rev. 2003,
103, 2921; c) B. M. Trost, M. R. Machacek, A. Aponick, Acc.
Chem. Res. 2006, 39, 747; d) Z. Lu, S. Ma, Angew. Chem. 2008,
120, 264; Angew. Chem. Int. Ed. 2008, 47, 258; e) B. M. Trost,
Org. Process Res. Dev. 2012, 16, 185.
[2] For reviews covering the asymmetric synthesis of quaternary
stereocenters, see: a) E. J. Corey, A. Guzman-Perez, Angew.
Chem. 1998, 110, 402; Angew. Chem. Int. Ed. 1998, 37, 388; b) J.
Christoffers, A. Mann, Angew. Chem. 2001, 113, 4725; Angew.
Chem. Int. Ed. 2001, 40, 4591; c) C. J. Douglas, L. E. Overman,
Proc. Natl. Acad. Sci. USA 2004, 101, 5363; d) J. Christoffers, A.
Baro, Adv. Synth. Catal. 2005, 347, 1473; e) B. M. Trost, C. Jiang,
[12] For a larger-scale (67.5 mmol) synthesis of allylidene dipivalate,
see M. Lombardo, S. Licciulli, F. Pasi, G. Angelici, C. Trombini,
Adv. Synth. Catal. 2005, 347, 2015.
[13] When electron-deficient nucleophiles were reacted in THF/
tBuOH, a decrease in regioselectivity was observed. As a result,
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these reactions were performed in PhMe/tBuOH (see Support-
ing Information for full experimental details and solvent
selections for each nucleophile).
[18] a) M. Node, X.-J. Hao, K. Fuji, Chem. Lett. 1991, 57; b) W. W.
Wilkerson, A. A. Kergaye, S. W. Tam, J. Med. Chem. 1993, 36,
2899; c) M. Node, X.-J. Hao, K. Nishide, K. Fuji, Chem. Pharm.
Bull. 1996, 44, 715; d) S. Pellegrino, F. Clerici, A. Contini, S.
Leone, T. Pilati, M. L. Gelmi, Tetrahedron 2009, 65, 1995; e) G.
Chen, T. D. Cushing, P. Faulder, B. Fisher, X. He, K. Li, Z. Li, W.
Liu, L. R. Mcgee, V. Pattaropong, J. L. Seganish, Y. Shin, Z.
Wang, “Alkynyl Alcohols as Kinase Inhibitors”, U.S. Patent
Application 20110086834, Apr. 14, 2011.
[14] Attempts to extend this methodology to additional substrates
including 3-alkyloxindoles are the subject of continued study.
[15] L. E. Overman, Y. Shin, Org. Lett. 2007, 9, 339.
[16] PhMe was used as the reaction solvent, and products 5k–5o
were obtained in ca. 92–97% purity; see Supporting Information
for full details.
[19] The antipode of aldehyde 9 has previously been synthesized by
Maruoka and co-workers (see Scheme 1, Ref. [10], and the
Supporting Information). The absolute stereochemistry of enol
pivalates 2 and 5a–5o is assigned by analogy to 5k.
[17] Further experiments and mechanistic investigations to fully
elucidate these interesting results are the subject of continued
study.
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