Palladium-Catalyzed Asymmetric Benzylic Alkylation of Active Methylene Compounds with α-Naphthylbenzyl Carbonates and Pivalates

Article abstract of DOI:10.1002/anie.201602075

A Pd/(R)-H₈-BINAP-catalyzed asymmetric benzylic alkylation of active methylene compounds has been developed. The reaction proceeds without the use of an external base, and the starting racemic diarylmethyl carbonates are converted into the optically active coupling products which contain the benzylic chiral stereocenter by a dynamic kinetic asymmetric transformation (DYKAT). Additionally, with suitable carbonates bases, the same palladium catalysis allows the corresponding pivalates to be adopted in the same DYKAT process. New dynamics: A Pd/(R)-H₈-BINAP-catalyzed asymmetric benzylic alkylation of active methylene compounds has been developed. The reaction proceeds without the use of an external base, and the starting racemic diarylmethyl carbonates are converted into optically active coupling products, containing a benzylic chiral stereocenter, by a dynamic kinetic asymmetric transformation.

Full text of DOI:10.1002/anie.201602075

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International Edition: DOI: 10.1002/anie.201602075
German Edition: DOI: 10.1002/ange.201602075
Asymmetric Catalysis
Palladium-Catalyzed Asymmetric Benzylic Alkylation of Active
Methylene Compounds with a-Naphthylbenzyl Carbonates and
Pivalates
Sho Tabuchi, Koji Hirano,* and Masahiro Miura*
Abstract: A Pd/(R)-H8-BINAP-catalyzed asymmetric ben-
zylic alkylation of active methylene compounds has been
developed. The reaction proceeds without the use of an
external base, and the starting racemic diarylmethyl carbonates
are converted into the optically active coupling products which
contain the benzylic chiral stereocenter by a dynamic kinetic
asymmetric transformation (DYKAT). Additionally, with
suitable carbonates bases, the same palladium catalysis
allows the corresponding pivalates to be adopted in the same
DYKAT process.
Fu.[8] Thus, further development of DYKAT with racemic
benzyl electrophiles is strongly desired. Herein, we report
a Pd/(R)-H8-BINAP catalyst system for the asymmetric
benzylic alkylation of active methylene compounds: the
DYKAT process proceeds and the starting racemic diary-
lmethyl carbonates are converted into the substitution
products with high yields and high enantiomeric ratios. To
the best of our knowledge, this reaction is the first successful
À
example of a C C bond-forming DYKATwith racemic benzyl
electrophiles via a p-benzylpalladium intermediate.
During our recent studies on the base-free, palladium-
À
P
alladium-catalyzed cross-coupling reactions are one of the
catalyzed enantiospecific C C cross-coupling reaction of
most powerful and reliable synthetic tools for the construc-
tion of versatile carbon frameworks in modern organic
chemistry. Among them, the asymmetric allylic alkylation
with allylic electrophiles via p-allylpalladium intermediates
(Tsuji–Trost reaction) has been extensively studied and
applied to the synthesis of various complex natural products
and bioactive molecules.[1] In contrast, the asymmetric
benzylic alkylation with benzylic electrophiles via p-benzyl-
palladium intermediates has been less developed despite its
isoelectronic character to the p-allylpalladium.[2] Although
related asymmetric palladium catalysis with prochiral nucleo-
philes and achiral primary benzylic carbonates or phosphates
were recently reported by Trost and Czabaniuk,[3] a dynamic
kinetic asymmetric transformation (DYKAT)[4] with racemic
secondary benzyl electrophiles still remains largely elusive.
Fiaud, Legros, and co-workers reported the seminal work on
the palladium-catalyzed asymmetric nucleophilic substitution
of racemic 1-(2-naphthyl)ethyl acetate with malonate anions.
However, the yield and enantiomeric ratio were moderate,
and a partial kinetic resolution was finally proposed.[5] The
groups of Jarvo[6] and Watson[7] independently developed the
nickel-catalyzed, condition-controlled enantiodivergent
cross-coupling of secondary benzyl alcohol derivatives, but
enantioenriched starting substrates are still required for the
synthesis of optically active coupling products. Only limited
successful examples include the nickel-catalyzed DYKAT of
the secondary benzylic (pseudo)halides with organozinc
reagents via radical intermediates, which is reported by
terminal alkynes with diarylmethyl carbonates, we found
that a Pd/(S,S)-BDPP (for structure, see Scheme 1) catalyst
induced small but significant stereoinduction with a racemic
secondary benzyl carbonate in a DYKAT manner.[9] While
preliminary, this intriguing result prompted us to investigate
the asymmetric benzylic alkylation of dimethyl malonate
(2a), the representative soft carbon nucleophile in the Tsuji–
Trost allylic alkylation, with racemic methyl (2-naphthyl)-
(phenyl)methyl carbonate (1a’) in the presence of various
chiral bisphosphine ligands combined with [CpPd(h3-C3H5)]
(Scheme 1). Similar to the original work by Fiaud, Legros, and
co-workers,[5] as well as our previous finding,[9a] (S,S)-BDPP
showed high performance (89% of 3aa) but relatively low
enantioselectivity (63:37 e.r.). In the presence of well-known
[*] S. Tabuchi, Prof. Dr. K. Hirano, Prof. Dr. M. Miura
Department of Applied Chemistry, Graduate School of Engineering,
Osaka University
Suita, Osaka 565-0871 (Japan)
E-mail: k_hirano@chem.eng.osaka-u.ac.jp
miura@chem.eng.osaka-u.ac.jp
Scheme 1. Optimization studies for the palladium-catalyzed asymmet-
ric benzylic alkylation of dimethyl malonate (2a) with diarylmethyl
carbonates 1. [a] With 5 mol% of [CpPd(h3-C3H5)]/ligand in DMSO.
Cp=cyclopentadiene, DMSO=dimethylsulfoxide.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201602075.
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(R,R)-Chiraphos and (R,R)-DPPBA, which is a promising
class of chiral ligands in related asymmetric allylic[1b] and
benzylic[3] alkylations, the reaction was sluggish. In contrast,
common chiral biaryl bis(phosphine) ligands promoted the
reaction with better efficiency and enantioselectivity. Partic-
ularly, (R)-SEGPHOS and (R)-H8-BINAP were good candi-
dates, and the desired 3aa was obtained with 82:18 e.r. The
replacement of 1a’ with the Boc carbonate 1a allowed the
reaction to proceed at lower temperature (808C), and the
enantiomeric ratio slightly increased to 87:13 (with (R)-
SEGPHOS) and 85:15 e.r. (with (R)-H8-BINAP). Subsequent
solvent screening revealed that a combination of 5 mol% of
[CpPd(h3-C3H5)] and (R)-H8-BINAP in DMSO at 608C was
optimal, and 3aa was formed in 97% yield with 95:5 e.r.
Notably, substituents bulkier than Ph on phosphorous gave
negative impact on the enantioselectivity.[10]
slightly modified reaction conditions (3ja; 69%, 84:16 e.r.). In
contrast, the (2-naphthyl)ethyl carbonate gave the racemate
of 3ka (50:50 e.r.).[11,12]
In addition to 2a, some representative symmetrical active
methylene compounds coupled with 1a to furnish the
corresponding benzylic alkylation products enantioselec-
tively: diethyl malonate (2b), acetylacetone (2c), and malo-
nonitrile (2d) gave 3ab, 3ac, and 3ad, respectively, with 93:7–
95:5 e.r. (Table 1, entries 1–3). The unsymmetrical b-
Table 1: Palladium-catalyzed asymmetric benzylic alkylation of various
active methylene and methine compounds (2) with 1a.[a]
With the optimized reaction conditions in hand, we
conducted the asymmetric benzylic alkylation of 2a with
various secondary benzyl carbonates 1 (Scheme 2). The
Entry
1
2
3, Yield [%][b], e.r.[c]
3ab, 87, 95:5
3ac, 71, 93:7
2[d]
3[e,f]
4
3ad, 79, 94:6
3ae, 76, 91:9[g]
5[e]
6[d,h,i]
3af, 88, 94:6[g]
3ag, 61, 94:6[g]
7[j]
3ah, 70, 89:11
3ai, 83, 93:7
8[d,i]
[a] Reaction conditions: [CpPd(h3-C3H5)] (0.013 mmol), (R)-H8-BINAP
(0.013 mmol), 1a (0.25 mmol), 2 (0.30 mmol), DMSO (3.0 mL), 608C,
3 h, N2. [b] Yield of isolated product. [c] Determined by HPLC analysis on
a chiral stationary phase. [d] At 808C. [e] At 1008C. [f] For 6 h.
[g] Obtained as nearly 1:1 mixture of diastereomers. The enantiomeric
ratio (e.r.) was determined after derivatization into the corresponding 4.
See the Supporting Information for details. [h] With [CpPd(h3-C3H5)]
(0.025 mmol) and (R)-H8-BINAP (0.025 mmol). [i] In MeCN (3.0 mL).
[j] For 9 h. EWG=electron-withdrawing group.
Scheme 2. Palladium-catalyzed asymmetric benzylic alkylation of
dimethyl malonate (2a) with various secondary benzyl carbonates (1).
Boc=tert-butoxycarbonyl.
ketoester 2e, cyanoacetate 2 f, and b-sulfonylester 2g were
also suitable coupling partners (entries 4–6). In these cases,
the products 3ae–ag were obtained as nearly a 1:1 mixture of
diastereomers, but the stereochemistry of their benzylic
positions was well controlled (91:9–94:6 e.r.), which are
confirmed after derivatization into 4 by deesterification under
appropriate reaction conditions.[13] Moreover, the Pd/(R)-H8-
BINAP catalyst system was tolerated with relatively sterically
hindered active methine compounds 2h and 2i, and we
obtained 3ah (70%, 89:11 e.r.) and 3ai (83%, 93:7 e.r.),
respectively (entries 7 and 8).
Our proposed mechanism for the formation of (R)-3aa
could involve the racemization process analogous to that of p-
allylpalladium intermediates[14] (Scheme 3). Initial SN2-type
substitution[15] of the secondary benzyl carbonates (R)-1a and
(S)-1a with [Pd0Ln] [L = (R)-H8-BINAP] is followed by
decarboxylation and s-to-p isomerization to form the corre-
enantioselective palladium catalysis was compatible with
electron-donating methoxy as well as electron-withdrawing
trifluoromethyl and chloro groups at the para-position of the
benzene ring of 1, and the corresponding 3ba, 3ca, and 3da
were formed in good yields (86–99%) with high enantiose-
lectivity (91:9–93:7 e.r.). The meta- and ortho-substituted
carbonates also underwent the DYKAT smoothly to deliver
3ea (96:4 e.r.) and 3 fa (95:5 e.r.), respectively. The replace-
ment of the 2-naphthyl group with 6-methoxy-2-naphthyl, 1-
naphthyl, and higher fused phenanthryl substituents was
possible, and the optically active 3ga, 3ha, and 3ia were
obtained in 90:10–94:6 e.r. Additionally, the heterocyclic
dibenzothiophene substrate could also be employed under
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moderate 79:21 e.r., but the enantioselectivity of the coupling
product 3aa was identical to that of the optimized reaction
conditions [Eq. (2)]. This result indicates that the substrate-
dependent partial kinetic resolution occurs in the substitution
step, but the subsequent racemization of p-benzyl palladium
intermediates proceeds much more readily and overall
stereochemistry is thus controlled by the catalyst in the final
À
C C forming event. Actually, the room-temperature reac-
tions of (S)-1a under (R)- and (S)-H8-BINAP-ligated palla-
dium catalysis gave different product yields, but (R)-3aa and
(S)-3aa, respectively, were obtained with the same e.r. value
(96:4) [Eqs. (3) and (4)].
Some (heteroaryl)methyl tert-butyl carbonates are rela-
tively unstable and often difficult to prepare in a pure form.
We thus tested the more stable (heteroaryl)methyl pivalates
(Scheme 4). With Cs2CO3 as an external base, (3-
benzothiophenyl)(phenyl)methyl pivalate (6a) reacted with
Scheme 3. Plausible mechanism. L=(R)-H8-BINAP. The descriptor RL
means the absolute configuration of the ligand L.
sponding diastereomeric cationic p-benzyl intermediates
(S,RL)-5 and (R,RL)-5, respectively (RL means the absolute
configuration of the ligand L). They then undergo the rapid
interconversion, which is racemization at the benzylic chiral
center, probably by the attack of additional [Pd0Ln] spe-
cies.[5b, 6f,14] The asymmetric induction arises from a selective
backside attack of the active methylene compound 2a, which
can be deprotonated by tBuOÀ, with one (S,RL)-5 isomer to
produce the observed major enantiomer (R)-3aa.
To get more insight into the reaction mechanism, we
performed the following control experiments. When the
enantioenriched substrate (S)-1a’ was subjected to reaction
conditions with an achiral dppf or DPEphos ligand, the
expected 3aa was obtained in good yield essentially as
a
racemate [Eq. (1)]. Thus, the racemization proceeds
smoothly, and no enantiospecific reaction occurs. In contrast,
at an early stage of the enantioselective reaction (15 min), the
starting carbonate 1a was recovered in 47% yield with
Scheme 4. Palladium-catalyzed asymmetric benzylic alkylation of
dimethyl malonate (2a) with secondary (heteroaryl)methyl pivalates
(6).
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[5] a) J.-Y. Legros, A. Boutros, J.-C. Fiaud, M. Toffano, J. Mol. Catal.
A 2003, 196, 21; b) J.-Y. Legros, M. Toffano, J.-C. Fiaud,
Tetrahedron 1995, 51, 3235.
2a under otherwise identical reaction conditions to form the
expected product 7aa in 31% with moderate 75:25 e.r.
Notably, the constitutional isomer 7aa’ was also isolated, and
strongly supports the intermediacy of the p-benzylic palla-
dium species: the outer-sphere attack of 2a at the C2-position
of the benzothiophene ring in the p-benzylpalladium (path b)
is followed by rearomatization to furnish 7aa’, while the
reaction course as shown in Scheme 3 (path a) leads to the
usual product 7aa. The 2-benzothienylmethyl and 2-benzo-
furanylmethyl pivalates (6b and 6c) also gave a mixture of
isomers with 75:25 e.r. for 7ba and 94:6 e.r. for 7ca,
respectively, but in the latter case the dearomatized 7ca’
was detected as the byproduct, probably because of the
weaker aromaticity of the furan than that of the thio-
phene.[16,17]
In conclusion, we have developed a Pd/(R)-H8-BINAP-
catalyzed asymmetric benzylic alkylation of active methylene
compounds with racemic diarylmethyl carbonates and piv-
alates. To the best of our knowledge, this is the first successful
example of the dynamic kinetic asymmetric transformation
(DYKAT) of secondary benzylic electrophiles via p-benzyl-
palladium intermediates. The present results provide an
enantioconvergent approach to optically active benzylic
alkylation products from racemic benzyl alcohol derivatives
and prompt further development of related asymmetric
catalysis based on the DYKAT process of secondary benzyl
electrophiles. Expansion of the scope of nucleophiles and
overcoming the “naphthalene limitation”[12] are currently
underway in our laboratory.
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[10] See the Supporting Information for more detailed optimization
studies.
[11] The exact reason in not clear yet, but the diarylmethyl system
can be essential for the rapid interconversion of two diastereo-
meric p-benzylpalladium intermediates or their sufficient kinetic
difference in the backside attack reaction with the malonate
anion (see Scheme 3).
[12] As far as we tested, the present catalyst system did not address
the “naphthalene problem”: (phenyl)(2-thienyl)methyl, (4-
methoxyphenyl)(phenyl)methyl,
and
(4-biphenylyl)-
(phenyl)methyl carbonates gave no desired products. Homo-
coupling byproducts of carbonates were detected even under
more forcing conditions. This homocoupling is probably because
of easy accessibility of naphthalene and related fused aromatics
to the p-benzyl intermediates, which is associated with their
weaker aromaticity. Similar trends are often observed in metal-
Acknowledgements
This work was supported by JSPS KAKENHI Grant Nos.
15K13696 (Grant-in-Aid for Exploratory Research) and
15H05485 (Grant-in-Aid for Young Scientists (A)) to K.H.
and 24225002 (Grant-in-Aid for Scientific Research (S)) to
M.M.
À
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169; d) S. N. Mendis, J. A. Tunge, Org. Lett. 2015, 17, 5164. And
Refs. [2], [6], and [7].
Keywords: asymmetric catalysis · kinetic resolution ·
ligand effects · palladium · synthetic methods
[13] The absolute configuration at the benzylic position of 3af was
determined to be
compound 4af, and others are tentatively assigned by analogy.
See the Supporting Information for details.
R after derivatization into the known
How to cite: Angew. Chem. Int. Ed. 2016, 55, 6973–6977
Angew. Chem. 2016, 128, 7087–7091
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[17] The corresponding naphthalene-derived pivalate gave the usual
benzylic substitution product with the comparable enantiose-
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lectivity (see the scheme below). Thus, the observed unique
reactivity of 6a–c can be associated with the weaker aromaticity
of the benzothiophene and benzofuran but not with the nature of
the leaving group.
Received: February 29, 2016
Published online: April 27, 2016
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