Palladium-catalyzed decarboxylative generation and asymmetric allylation of α-imino anions

Article abstract of DOI:10.1021/ol502693r

A palladium-catalyzed asymmetric decarboxylative allylic alkylation of allyl 2,2-diphenylglycinate imines using (S,S)-f-binaphane as a chiral supporting ligand has been developed. This transformation allows for decarboxylative generation and enantioselective allylation of nonenolate α-imino (2-azaallyl anions) to afford α-aryl homoallylic imines.

Full text of DOI:10.1021/ol502693r

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Decarboxylative Generation and Asymmetric
Allylation of α‑Imino Anions
Xiaoyan Qian,† Pengfei Ji,† Chang He,† Jean-Olivier Zirimwabagabo,‡ Michelle M. Archibald,‡
Andrew A. Yeagley,‡,§ and Jason J. Chruma*,†
†Key Laboratory of Green Chemistry & Technology, College of Chemistry, Sichuan University, Chengdu, Sichuan 610064, P. R.
China
‡Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904-4319, United States
S
* Supporting Information
ABSTRACT: A palladium-catalyzed asymmetric decarboxyla-
tive allylic alkylation of allyl 2,2-diphenylglycinate imines using
(S,S)-f-binaphane as a chiral supporting ligand has been
developed. This transformation allows for decarboxylative
generation and enantioselective allylation of nonenolate α-
imino (2-azaallyl anions) to afford α-aryl homoallylic imines.
Scheme 1. Pd-Catalyzed ADAA of Imines 7
nterest in transition-metal-catalyzed decarboxylative allylation
1
Ireactions has expanded rapidly within the past decade. Since
the initial reports of Tsuji2 and Saegusa,3 palladium catalysis has
been used to concomitantly generate and allylate a variety of C-,
O-, N-, and S-centered anionic nucleophiles. Despite these
advances, asymmetric decarboxylative allylic alkylations (ADAA)
that generate a new chirality center on the incoming nucleophilic
partner have been confined predominately to reactions
proceeding via conformationally defined enolates.4−6 For Pd-
catalyzed ADAA, two classes of chiral ligands have distinguished
themselves: Trost’s diamide bisphosphine ligands4d−f and the P/
N Phox ligands7 championed by Stoltz.4a−c Depending on ligand
and substrate, the key enantiodetermining C−C bond-forming
event can proceed via either an inner sphere8 or an outer sphere
mechanism in regard to the metal center.9 Herein, we report that
the ferrocenyl binaphane ligand 6 first introduced by Zhang for
asymmetic hydrogenations10 is superior for the Pd-catalyzed
decarboxylative generation and asymmetric allylic alkylation of
α-imino anions (2-azaallyl anions) to afford enantioenriched
homoallylic imines (Scheme 1). Increasing solvent polarity
resulted in improved enantioselectivity, with DMSO typically
affording the best results. Overall, this represents a unique
example of an ADAA involving a nonenolate nucleophile.11
In 2007, we introduced the Pd-catalyzed decarboxylative
allylation of allyl diphenylglycinate imines 7 to afford the
corresponding racemic homoallylic imines 8, with the
regioisomers 9 occasionally produced as minor side products.12a
The regioisomeric ratio (8:9) demonstrated a positive linear
Hammett correlation and could be improved by increasing
solvent polarity. Empirical and computational studies suggest
that the rate-determining step of this transformation is the
decarboxylation of a solvent-separated ion pair, whereas the
regio- and enantiodetermining event is a later-stage outer sphere
attack of an α-imino anion onto a π-allylPd(II) cationic
intermediate (Scheme 1, inset).12b In an attempt to identify an
enantioselective variant of this process,11 we initiated a screen of
several chiral mono- and bidentate ligands for the Pd-catalyzed
Received: September 11, 2014
Published: September 22, 2014
© 2014 American Chemical Society
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Letter
ADAA of p-cyanobenzaldimine 7a (Table 1).13 Conversion was
determined by H NMR analysis of the concentrated reaction
and inconsistent results in our hands.15 A more forgiving and
general alternative was found using 5 mol % of ferrocenyl
binaphane 6 with 2.5 mol % of Pd2(dba)3 in THF at 20 °C (entry
7). Cooling the reaction mixture to −5 °C resulted in a
moderately improved er (entry 8). More importantly, the er of
the final product could be increased to essentially homochirality
by preferentially crystallizing out the racemate from cold hexanes
(entry 9).
1
Table 1. Selected Examples from Chiral Ligand Screen13,14
Having identified suitable reaction conditions, we next applied
them to a selection of aryl and heteroaryl imine substrates 7
(Scheme 2). The overall sense of chirality for the products 8 was
determined to be (S) by conversion of the 3-pyridinyl 8m to
scalemic (S)-nornicotine and comparison with reported optical
rotation values (Scheme 3).16 A general trend observed was a
corresponding decrease in enantioselectivity upon increasing the
electron-donating nature of the arylimine substituent in 7.17 This
a,b
Scheme 2. Pd-Catalyzed ADAA of Imines 7 Using Ligand 6
a
Conversion determined by 1H NMR analysis of concentrated
b
reaction mixture. The enantiomeric ratio (er) of 8a was determined
by chiral HPLC. The ratios are listed corresponding to the order of
c
elution. Conversion ranged from 52 to >95%, and er varied from
d
e
32:68 to 5:95 under these conditions. Only performed once. Isolated
yield after removal of crystalline racemate.
mixture, and the resultant enantiomeric ratios (er) were
determined by chiral HPLC analysis after column chromatog-
raphy.14 The P/N ligands 4 and 5 both provided essentially
racemic product in varying amounts (entries 1 and 2). The Trost
ligands, on the other hand, showed more promise (entries 3−6),
particularly when 1 was used with Pd(dba)2 in toluene (entry 6).
Unfortunately, these reaction conditions provided highly variable
a
All reactions proceeded to complete conversion as judged by TLC.
b
Er determined by chiral HPLC with the first number referring to the
c
initially eluted (S) enantiomer; see ref 14. Isolated yield (200 mg scale
in DMSO) and er after recrystallization from hexane. Isolated yield
(200 mg scale in DMSO) of liquid product after chromatography.
d
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Letter
a,b
Scheme 3. Synthesis of Scalemic (S)-Nornicotine
Scheme 4. Pd-Catalyzed ADAA with Substituted Allyls
a
See ref 16a.
is consistent with our previous mechanistic analysis which
suggests that the enantiodetermining step is an outer-sphere
process involving an ion pair between a resonance-stabilized α-
imino anion and an η3-π-allylPd(II) cationic electrophile (in
contrast to a nonionic inner sphere process).12b Reaction
conditions that better stabilize the ion-pair intermediate should
result in improved enantioselectivity.18 Switching the reaction
medium from THF to more polar acetonitrile proved fruitless
due to the poor solubility of the 6−Pd complex in the latter
solvent. Changing the solvent to DMF, however, did provide
higher average er values for almost every substrate investigated.
Increasing the solvent polarity further by using DMSO
consistently generated our best results. These conditions are
most appropriate for para monosubstituted benzaldimines,
affording an average er just over 90:10 prior to recrystallization.
Alternatively, heteroarylimino substrates, particularly the smaller
thiazole 7k, tend to afford poorer enantioselectivities.
In addition to improved overall er values, the use of DMF or
DMSO as solvent offers significant technical advantages. For
example, the product can be separated from any remaining
starting material and catalyst simply by selective extraction from
the reaction mixture with hexane. After concentration of the
combined hexane fractions, 1H NMR analysis indicated that they
only contain 8 and occasionally the regioisomer 9. As noted in
our previous studies, the undesired minor product 9 can be
removed by selective hydrolysis on slightly acidified silica gel
prior to chromatography through a short plug of silica gel.12a,19 In
most cases, the enantiopurity of the homoallylic imine product 8
can be enriched by recrystallization from hexane; in several
circumstances (e.g., 8a, 8e, 8j, and 8k), the racemate
preferentially crystallizes out and the mother liquor is
enantioenriched.
a
Unless otherwise indicated, all yields and er values are an average of
b
at least two runs on a 200 mg scale. Reaction conducted at 40 °C.
c
Values in parentheses indicate isolated yield and er after
recrystallization.
Scheme 5. Phosphine-Free Decarboxylative Allylation
mirrors formed in DMSO when ligand 6 was included in the
reaction mixture. The exact role of sulfoxide in our reaction is still
under investigation.
Very recently, Zhao reported an “intermolecular” variant of
our decarboxylative allylation reaction.21 Specifically, relatively
stable lithium diphenylglycinate imines will readily decarboxylate
to the corresponding α-imino anions upon dissolution in aprotic
solvents and react with in situ-generated π-allylPd(II) electro-
philes. Given the increased simplicity that this modification
offers, we sought to determine if it also could be made
enantioselective by using chiral ligand 6 (Scheme 6). While
Scheme 6. “Intermolecular” ADAA of Carboxylate 13a
Substitution on the 2-position of the allyl moiety was tolerated
but required higher catalyst loading. Even so, both conversion
and er values were still significantly reduced (Scheme 4).
Moreover, electron-neutral (11a) or electron-rich (11b)
benzaldimines converted to the corresponding homoallylic
imines 12a and 12b, respectively, in THF but not in DMSO.
This was not an issue for the other imino esters investigated
(11c−e).
Given that sulfoxides typically are not innocent spectators in
Pd-catalyzed processes,20 we investigated the conversion of both
7a and 7b at 25 °C overnight in DMSO with Pd2(dba)3 but
without any bisphosphine 6 (Scheme 5). In the absence of
phosphine ligand, complete conversion to the corresponding
racemic products 8 was observed for both substrates in addition
to formation of a palladium mirror on the walls of the reaction
vials. No conversion was observed in the absence of phosphine
when THF was employed as solvent. Likewise, no palladium
benzaldimine 13a was converted quantitatively into the
corresponding homoallylic imine 8h in THF using 6 as ligand,
the product was essentially racemic. Performing the reaction in
DMF improved the resulting er, but it remained significantly
lower in comparison to our “intramolecular” option (74:26
versus 82:18). Given that both reactions should proceed via the
same 2-azaallyl anion intermediate species, the presence of
lithium acetate is the presumed culprit for the reduced
enantioselectivity.18 Indeed, changing the leaving group to a
carbonate improved the enantioselectivity dramatically, albeit at
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a lower overall yield.22 A more serious issue, however, is that the
highly electron-withdrawing p-nitrobenzaldimine 13b could not
be prepared due to premature decarboxylation both in the solid
state and in methanolic solutions. A one-pot imine formation/
decarboxylation/allylation tactic is not a likely option since
highly electron-withdrawing aryl aldehydes are known to
intercept the incipient 2-azaallyl anion intermediate prior to
allylation.12a Since benzaldimines with strongly electron-with-
drawing substituents, e.g., 7b, afford the best enantioselectivies,
this represents a significant advantage of our “intramolecular”
process over the otherwise more convenient “intermolecular”
variant.
In conclusion, we have presented a Pd-catalyzed ADAA of allyl
diphenylglycinate imines 7 to afford enantioenriched α-
arylhomoallylic imines 8. These results represent the first
examples of bisphosphine 6 as a chiral ligand for any transition
metal-catalyzed asymmetric C−C bond-forming reaction. More-
over, they provide the first examples of highly enatioselective
ADAAs involving nonenolate nucleophilic intermediate.6,11
Future studies will involve the application of this method toward
the synthesis of homochiral peptidomimetics and an exploration
into the impact of chiral ligand 6 and related analogues on other
Pd-catalyzed decarboxylative alkylation processes.
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anions, see: Zhu, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2014, 136, 4500.
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(8) (a) Keith, J. A.; Behenna, D. C.; Sherden, N.; Mohr, J. T.; Ma, S.;
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ASSOCIATED CONTENT
* Supporting Information
■
S
(10) Xiao, D.; Zhang, X. Angew. Chem., Int. Ed. 2001, 40, 3425.
(11) Following a complimentary method, Burger and Tunge reported
that use of (R)-BINAP as a chiral ligand for the Pd-catalyzed ADAA of
allyl N-(diphenylmethyleneimino)phenylglycinate at 100 °C in dioxane
afforded the corresponding homoallylic imine in 30% ee: Burger, E. C.;
Tunge, J. A. J. Am. Chem. Soc. 2006, 128, 10002.
Experimental procedures, complete chiral ligand studies,
preliminary Hammett plot analysis, and characterization of
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) (a) Yeagley, A. A.; Chruma, J. J. Org. Lett. 2007, 9, 2879. (b) Li, Z.;
Jiang, Y.-Y.; Yeagley, A. A.; Bour, J. P.; Liu, L.; Chruma, J. J.; Fu, Y.
Chem.Eur. J. 2012, 18, 14527.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chruma@scu.edu.cn.
Present Address
§Longwood University, Department of Chemistry & Physics,
Farmville, VA 23909.
(13) See the Supporting Information for a complete synopsis of our
ligand studies.
(14) Unless otherwise noted, all reported values represent an average
of at least three trials.
(15) This may be a result of competition between the highly selective
monomeric and the less selective polymeric forms of the Pd−ligand
complex at the catalyst concentrations investigated, see ref 9b.
(16) (a) Kisaki, T.; Janaki, E. Arch. Biochem. Biophys. 1961, 92, 351.
Notes
The authors declare no competing financial interest.
(b) Spath, E.; Zaijc, E. Chem. Ber. 1935, 68, 1667.
̈
(17) See the Supporting Information for a preliminary Hammett plot
ACKNOWLEDGMENTS
■
analysis of the enatiomeric ratios.
Financial support provided by the Thomas F. & Kate Miller
Jeffress Memorial Trust (J-808) and the NSFC (21372159). J.-
O.Z. was supported by a summer externship from University
Paris Diderot. J.J.C, X.Q., P.J., and C.H. thank Profs. Cheng Yang,
Jinsong You, and Xiaoqi Yu (SCU) for use of their HPLCs and
Prof. Xiaoming Feng (SCU) for use of his NMR spectrometer.
(18) Evans, L. A.; Fey, N.; Harvey, J. N.; Hose, D.; Lloyd-Jones, G. C.;
Murray, P.; Orpen, A. G.; Osborne, R.; Owen-Smith, G. J. J.; Purdie, M.
J. Am. Chem. Soc. 2008, 130, 14471.
(19) Yeagley, A. A.; Lowder, M. A.; Chruma, J. J. Org. Lett. 2009, 11,
4022.
(20) (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) Steinhoff, B. A.; Fix, S. R.; Stahl, S. S. J.
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