Synthesis of aromatic α-aminoesters: Palladium-catalyzed long-range arylation of primary Csp3-H bonds

Article abstract of DOI:10.1002/anie.201206237

Remote control: The title reaction for β-Iζ arylation of α-amino esters with aryl bromides is described. This reaction, which occurs selectively at the terminal position of linear alkyl chains, gives rise to synthetically useful (hetero)arylalanines and homologues after debenzylation (see scheme). Copyright

Full text of DOI:10.1002/anie.201206237

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DOI: 10.1002/anie.201206237
À
C C Coupling
Synthesis of Aromatic a-Aminoesters: Palladium-Catalyzed Long-
À
Range Arylation of Primary Csp3 H Bonds**
Sam Aspin, Anne-Sophie Goutierre, Paolo Larini, Rodolphe Jazzar, and Olivier Baudoin*
Aromatic noncoded a-amino acids are very important build-
ing blocks for natural product synthesis and drug discov-
ery.[1–2] Figure 1 shows representative examples (1–4) of
Scheme 1. The b arylation of ester enolates. dba=dibenzylidene-
acetone.
palladium enolate A to the palladium homoenolate C, from
which reductive elimination occurs more readily.[4] However,
the reaction was found to be limited to aryl halides containing
Figure 1.
an electronegative substituent at the ortho position. Other
bioactive molecules, containing a noncoded (hetero)arylala-
nine fragment, which have been recently developed by
pharmaceutical companies. In light of the interest for these
compounds, there is a great need for direct preparation
methods that avoid multistep sequences.[3]
substitution patterns provided unproductive mixtures of a-
and b-arylated products. Herein, we report a much more
general b arylation of a protected alanine ester, a reaction
that gives rise to a range of synthetically useful (hetero)ar-
ylalanine building blocks. In addition, we report the extension
of this reaction to longer-range (g to z) arylations at the
terminal position of a linear alkyl chain on the amino ester.[7]
We first examined the reactivity of various a-amino acid
precursors that were previously used in a arylations such as
imines and azlactones,[8] but none of them provided any
substantial amount of the b-arylated product. Gratifyingly,
the readily available benzyl-protected alanine methyl ester 5a
was found to be the best arylalanine precursor (Scheme 2).
Indeed, when the in situ generated lithium enolate of 5a was
reacted with p-fluorobromobenzene under reoptimized reac-
tion conditions using [Pd(dba-3,5,3’,5’-OMe)2] as the palla-
dium source[9] and DavePhos (L1) as the ligand in toluene at
708C,[10] the compound 6a was isolated as the sole arylation
product in 67% yield. Interestingly, the reaction of the
NBnMe-substituted ester 5b also gave the b-arylated product
6b efficiently, whereas the NMe2-substituted ester 5c failed to
undergo arylation, apparently because of the degradation of
its lithium enolate under the reaction conditions. These
results stand in sharp contrast to our previous observation
that p-fluorobromobenzene gives an approximately 1:1 mix-
ture of a- and b-arylated products from isobutyric esters (i.e.,
with Me instead of NR1R2),[4] thus showing that the presence
We recently reported the intermolecular palladium(0)-
À
catalyzed Cb H arylation of ester enolates as an extension of
the more established a-arylation reaction (Scheme 1).[4–6] This
reaction was shown to proceed by rearrangement of the
[*] S. Aspin,[+] A.-S. Goutierre,[+] Dr. P. Larini,[+] Dr. R. Jazzar,
Prof. Dr. O. Baudoin
Universitꢀ Claude Bernard Lyon 1, CNRS UMR 5246, Institut de
Chimie et Biochimie Molꢀculaires et Supramolꢀculaires
CPE Lyon, 43 Boulevard du 11 Novembre 1918 (France)
E-mail: olivier.baudoin@univ-lyon1.fr
Homepage: http://cosmo.univ-lyon1.fr/Index.html
[+] These authors contributed equally.
[**] This work was supported financially by the Agence Nationale de la
Recherche (programme blanc “EnolFun”), the Ministꢁre de
l’Enseignement Supꢀrieur et de la Recherche, Rꢀgion Rhꢂne-Alpes
(programme CIBLE), the Universitꢀ Claude Bernard Lyon 1, and the
Institut Universitaire de France. We also thank A. Ledoux for
preliminary synthetic work, and Dr. E. Jeanneau (UCBL) and Dr. C.
Duhayon (LCC Toulouse) for crystallographic data collection,
structure solution, and refinement.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206237.
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as the ligand. In particular, the following products are
precursors of aryl- and heteroarylalanines found in drugs or
drug candidates: 6a, 6e (found in 2; see Figure 1), 6j, 6k
(found in l-DOPA), 6l (found in the drug Nafarelin), 6m
(found in 3), 6n (found in 1), and 6p (found in 4).
Recrystallization of 6g furnished crystals suitable for X-ray
diffraction analysis.[12] In all cases, the a-arylated product was
not observed, regardless of the substitution pattern, which is
in contrast to our previous results with isobutyric esters,[4] and
exclusive monoarylation was achieved.
Following intermolecular arylation, the benzyl groups
were successfully cleaved (debenzylation yield ca. 70–80%)
in selected cases by hydrogenolysis (Scheme 3). The addition
Scheme 3. Deprotection of the b-arylated a-amino esters. [a] Reaction
performed at 1 atm H2.
of acetic acid[13] and a sufficient pressure (40 bar) of hydrogen
were found to be crucial to ensure complete deprotection,
except for the naphthalene derivative 6l which was hydro-
genated more smoothly to give 7l.
As an extension to the preceding results, we examined the
reactivity of a-amino acids bearing other linear alkyl chains.
We hoped that, under similar reaction conditions, intermo-
lecular arylation would occur preferentially at the terminal
Scheme 2. The b arylation of a-amino esters. Reaction conditions:
ester 5a or 5b (1.6 equiv), Cy2NLi (1.6 equiv), toluene, 08C, then
[Pd(dba-3,5,3’,5’-OMe)2] (2.5 mol%), ligand (2.5 mol%), aryl bromide
(1 equiv), 708C. The yield of the isolated product is given for each
compound. [a] Yield of the isolated product after two steps, that is
after hydrogenolysis (see Scheme 3). Cy=cyclohexyl.
[14]
À
Csp3 H bond to yield useful arylalanine homologues. The
anticipated selectivity would result from palladium migration
along the alkyl chain and more favorable reductive elimi-
nation from the primary carbon atom (see Scheme 1).
However, we were aware that the arylation selectivity could
be also influenced by the electronic properties of the aryl
bromide.[4] Therefore, we first studied the reaction of the
amino ester 8a with 1-bromo-2,6-difluorobenzene, which is
a priori the most favorable aryl bromide for palladium
migration (g arylation section of Scheme 4). Indeed, both
of a tertiary a-amino group strongly favors b arylation. This
remarkable b-arylation selectivity was also evidenced with
other aryl and heteroaryl halides (Scheme 2), for which
exclusive b arylation was observed. However, to improve the
yield, new analogues of DavePhos were synthesized and
tested.[10] In particular, we found that replacing the phos-
phine-bearing aromatic group with a nitrogen heterocycle
such as a pyrrole (L2) and especially imidazole (L3) had
a positive impact on the yield for various aryl bromides (6a,
6d, 6e).[11] Scheme 2 shows selected examples of b-arylated
products (6a–p) which were obtained efficiently by using L3
À
ortho fluorine atoms should induce a very strong Ar Pd
bond[15] and therefore disfavor reductive elimination, thus
allowing palladium migration to occur by the b-hydride
elimination/rotation/olefin insertion manifold. Gratifyingly,
8a underwent exclusive g arylation at the terminal carbon
atom of the ethyl chain upon reaction with 1-bromo-2,6-
difluorobenzene, thus providing the amine 9a in 47% yield
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paralleling the reactivity trend observed in b arylation
(Scheme 2). For instance, the following g/b-arylation ratios
were obtained with ortho-fluorobromobenzene: 1:2.2 for L1,
4:1 for L2, and 9:1 for L3. Thus, by using L3, the products
10a–13a were obtained with high g selectivity in 27–40%
yield after two steps (49% yield for one step in the case of
13a). In all cases, the minor b-arylated product could be
separated by chromatographic purification after hydrogenol-
ysis. The g-arylated amino ester 10a was further derivatized to
the p-nitrobenzamide 18, thus furnishing single crystals
suitable for X-ray diffraction analysis (Scheme 4).[12] The
moderate yields obtained for the compounds 9a–13a (aver-
age yield per step is 49–63%) should be put into perspective
with the unprecedented and straightforward character of this
transformation which employs an unfunctionalized substrate
(8a).[7,16] A noteworthy amount of the olefin 17a (n = 1) was
observed in all cases, thereby impairing the arylation effi-
ciency. This olefin arises from the reductive elimination of
palladium/olefin intermediates (see intermediate B,
Scheme 1) which are formed during both palladium migra-
tions (a-to-b, then b-to-g) along the alkyl chain.[17] With m-
fluorobromobenzene as the aryl donor, the b-arylated prod-
uct 14a was obtained as a diastereoisomeric mixture in low
yield after hydrogenolysis. This b/g-arylation selectivity trend
observed with differently substituted aryl bromides (compare
10a and 14a) mirrors the a/b-arylation selectivity trend
previously observed with isobutyric esters,[4] with aryl bro-
mides bearing an ortho electronegative group favoring
palladium migration, and thus arylation at the terminal
position. Arylation was also achieved selectively from aryl
bromides bearing an ortho chlorine atom, and the corre-
sponding products underwent concomitant dechlorination
upon hydrogenolysis (Scheme 4, compounds 15a and 16a).
Although the overall efficiency of this sequence still has to be
improved (average yield per step is 51–62%), it provides
a direct access to useful g-aryl amino esters without an ortho
electron-withdrawing group, which are not accessible in the
absence of the orienting chlorine atom. For instance, the
homophenylalanine ester 15a is a structural constituent of the
antihypertensive drug Enalapril.[2]
We next examined the arylation of the amino esters 8b–d,
bearing longer linear alkyl chains, with the most favorable
aryl bromide, that is, 1-bromo-2,6-difluorobenzene under the
same reaction conditions as used with 8a (d, e, and z arylation
section of Scheme 4). Again, arylation occurred exclusively at
the terminal carbon atom of the alkyl chain, thus providing d-,
e-, and even z-arylated products (9b–d) in progressively lower
yields as the length of the chain increased. These lower yields
can again result from the formation of the olefins 17b–d (and
olefin isomers), which accumulate as the number of palladium
migrations along the chain increases (there are five 1,2-
migrations of palladium to form the z-arylated product 9d).
With other aryl bromides, unproductive mixtures of arylated
isomers were obtained.[18]
Scheme 4. Long-range (g to z) arylation of amino esters. Reaction
conditions for step a): ester 8a–d (2.0 equiv), Cy2NLi or iPr2NLi
(2.0 equiv) toluene, 08C, then [{Pd(h3-allyl)Cl}2] (5 mol%), L1 or L3
(10 mol%), aryl bromide (1 equiv), 608C. The yield of the isolated
major arylation product is given for two steps, except for 13a. [a] With
Cy2NLi as the base. [b] With iPr2NLi as the base (which gave slightly
superior results to Cy2NLi in these cases). [c] Reaction conditions:
p-NO2C6H4COCl, iPrNEt2, DMF, 08C (92%). [d] Isolated pure as the
dibenzylamine. [e] Mixture of diastereoisomers; d.r. 65:35.
DMF=N,N’-dimethylformamide.
upon isolation after hydrogenolysis. With this aryl bromide,
optimal arylation conditions involved DavePhos (L1) as the
phosphine ligand in combination with [{Pd(h3-allyl)Cl}2] as
the palladium source.[10] With other aryl bromides containing
only one electron-withdrawing ortho substituent (F, CF3,
OCF3), the imidazole-based ligand L3 was found to provide
much higher g/b-arylation ratios than L1 and L2, thus
In conclusion, we have described a general palladium-
catalyzed long-range intermolecular arylation of a-amino
esters with aryl bromides, which occurs selectively at the
terminal position of linear alkyl chains to give rise to
synthetically useful (hetero)arylalanines and higher homo-
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[10] See the Supporting Information for details.
logues after debenzylation. All products obtained in this study
are racemic, but might be resolved by enzymatic methods to
obtain enantiomerically pure amino acids.[16i] Alternatively, an
efficient asymmetric version using chiral ligands remains to be
developed.[4a]
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Received: August 3, 2012
Published online: September 28, 2012
[12] CCDC 894091 (6g) and 894092 (18) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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Tetrahedron: Asymmetry 2007, 18, 1554 – 1566.
[14] For alternative routes to phenylalanine homologues involving
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1998, 63, 7875 – 7884; b) A. D. Campbell, T. M. Raynham,
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[18] Similarly, the reaction of amino esters bearing branched alkyl
chains failed or gave mixtures of arylated products.
À
À
Keywords: arylation · C C coupling · C H functionalization ·
palladium · synthetic methods
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