Ruthenium-catalyzed stereospecific benzylic alkylation of optically active benzyl esters with malonate nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2021.152947

The transition metal-catalyzed stereospecific benzylic alkylation of optically active benzyl esters with active methylene compounds remains extremely rare. Herein, we describe the study for the ruthenium-catalyzed benzylic alkylation of chiral benzyl este

Full text of DOI:10.1016/j.tetlet.2021.152947

Tetrahedron Letters 69 (2021) 152947
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ruthenium-catalyzed stereospecific benzylic alkylation of optically
active benzyl esters with malonate nucleophiles
⇑
⇑
Hiroaki Tsuji , Koki Suzuki, Motoi Kawatsura
Department of Chemistry, College of Humanities & Sciences, Nihon University, Sakurajosui, Setagaya-ku, Tokyo 156-8550, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The transition metal-catalyzed stereospecific benzylic alkylation of optically active benzyl esters with
active methylene compounds remains extremely rare. Herein, we describe the study for the ruthe-
nium-catalyzed benzylic alkylation of chiral benzyl esters with malonates as a carbon nucleophile. A
combination of [Cp*RuCl2]2 and picolinic acid found to be effective for the title reaction, providing the
chiral benzylic alkylation products with retention of stereochemistry of the starting material. We pro-
posed that the ruthenium catalysis would proceed via a double inversion mechanism.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 20 January 2021
Revised 11 February 2021
Accepted 18 February 2021
Available online 23 February 2021
Keywords:
Asymmetric synthesis
Ruthenium catalysis
Benzylic alkylation
Benzyl esters
Malonates
Introduction
alkylation products (Scheme 1a). [11] However, only a limited
number of examples for chiral secondary benzyl carbonates and
The transition metal-catalyzed benzylic substitution of benzyl
alcohol derivatives with carbon nucleophiles via a -benzylmetal
malonates were demonstrated in this study.
p
We recently disclosed the ruthenium-catalyzed benzylic substi-
tution of 2-naphthylmethyl-2,3,4,5,6-pentafluorobenzoates with
stabilized carbon nucleophiles, such as malonates, b-ketoester,
and diketones, furnishing the corresponding benzylic alkylation
products in moderate to high yields (Scheme 1b). [12] In the previ-
ous work, we showed a single example for the reaction of an opti-
intermediate is a research topic of ongoing interest in organic syn-
thesis. [1,2] Developing its asymmetric variant is among the most
significant and challenging research subjects that lead to provide
an useful tool for the construction of a carbon stereogenic center
at a benzylic position. [3,4] Stereospecific benzylic substitution of
optically active benzyl esters and benzyl ethers with carbon nucle-
ophiles is one of the method of choice for achieving the goal. [5]
Jarvo and Watson have independently contributed to the develop-
ment of the nickel-catalyzed stereospecific benzylic substitution of
optically active benzyl ethers and benzyl esters with organometal-
lic compounds, such as Grignard reagents and aryl boronate esters,
providing elegant synthetic tools that enable the construction of a
tertiary carbon stereogenic center. [6,7] Although the other types
of the CAC bond-forming reactions such as alkynylation [8] and
intramolecular Mizoroki-Heck type reaction [3f,9] have been also
reported, stereospecific benzylic substitution using a malonate
nucleophile is extremely rare despite its high utility in organic
synthesis. [10] Legros and co-workers reported the palladium-cat-
alyzed stereospecific benzylic substitution of optically active ben-
zyl carbonates with malonates, providing the chiral benzylic
cally active secondary benzyl ester with
a malonate as a
mechanistic experiment, giving the benzylic alkylation product
with perfect stereochemical fidelity. Based on this result, we
decided to investigate the ruthenium-catalyzed stereospecific ben-
zylic substitution of optically active benzyl esters with active
methylene compounds for the construction of a chiral benzylic car-
bon center (Scheme 1c). Herein, we report the ruthenium-cat-
alyzed benzylic substitution of optically active benzyl esters with
malonates as a stabilized carbon nucleophile.
We initially assessed the influence of the picolinic acid deriva-
tives in the ruthenium-catalyzed stereospecific benzylic alkylation
of optically active benzyl esters with malonates as the ligand
(Table 1). The reaction of optically pure benzyl ester (S)-1a with
diethyl methylmalonate was performed in the presence of
2.5 mol% [Cp*RuCl2]2, 5 mol% picolinic acid (L1), [13] and 1.1
equivalent of Cs2CO3 in CH3CN at 60ꢀC to give the chiral benzylic
alkylation product (S)-3aa in 77% yield with 99% ee (99% es)
(Table 1, entry 1). The use of picolinic acid ethyl ester L2 as the
ligand led to deterioration of the catalytic performance, lowering
⇑
Corresponding authors.
E-mail addresses: tsuji@chs.nihon-u.ac.jp (H. Tsuji), kawatsur@chs.nihon-u.ac.jp
(M. Kawatsura).
https://doi.org/10.1016/j.tetlet.2021.152947
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

H. Tsuji, K. Suzuki and M. Kawatsura
Tetrahedron Letters 69 (2021) 152947
reaction (Entry 3). Although 2-vinylnaphthalene was formed in
20% NMR yield as a side product, picolinamide (L4) was also effec-
tive ligand in this transformation, furnishing (S)-3aa in 64% yield
with 99% ee (99% es) (Entry 4). No desired product was obtained,
when quinaldic acid (L5) [14] was used as the ligand (Entry 5).
The ruthenium/thiopicolinamide (L6) system failed to give (S)-
3aa, indicating that a carboxylic acid group on picolinic acid (L1)
is critical for the catalytic performance (Entry 6). Furthermore, 8-
quinolinecarboxylic acid (L7) was ineffective as the ligand (Entry
7). [14b,15] This result indicates that five-membered chelation
system is necessary for the present ruthenium catalysis.
We investigated the reaction of chiral 2-naphthylethyl
2,3,4,5,6-pentafluorobenzoate derivatives 1a and 1b with diethyl
methylmalonate (2a) using [Cp*RuCl2]2 and picolinic acid (L1) as
the catalyst (Table 2). Not only (S)-1a but also (S)-1b bearing a 6-
methoxy-naphthalene ring was employed in the ruthenium cata-
lyst system. As a result, the reaction of (S)-1b with 2a gave the
desired alkylation product (S)-3ba in lower yield and stereospeci-
ficity (68% yield, 87% es). [16] Legros et al. reported the similar
influence of the methoxy group at the 6 position on the naph-
thalene ring to the yield and stereospecificity during their study
for the palladium-catalyzed benzylic alkylation of optically active
benzyl carbonates with dimethyl malonate. [11] R-Configured ben-
zyl esters (R)-1a and (R)-1b can be easily prepared by means of the
enzymatic resolution of the corresponding secondary benzyl alco-
hols. Thus, chiral benzylic alkylation products (R)-3aa and (R)-3ba
were also obtained in 80% and 65% yield with 97% ee (>99% es) and
80% ee (86% es), respectively, using the ruthenium-catalyzed stere-
ospecific benzylic alkylation.
Scheme 1. Transition metal-catalyzed stereospecific benzylic substitution of
optically active benzyl esters with malonate nucleophiles.
Table 1
Evaluation of picolinic acid derivatives in the stereospecific benzylic alkylation.a
We next turned our attention to examine the ruthenium-cat-
alyzed benzylic alkylation with a series of malonates (Table 3).
The reaction of (S)-1a with malonate 2b bearing a n-butyl sub-
stituent on the active methylene carbon took place to afford the
desired product (S)-3ab in 66% yield without significant loss of
Table 2
Entry
L
Yieldb (%)
eec (%)
esd (%)
Reaction of chiral 2-naphthylethyl 2,3,4,5,6-pentafluorobenzoate derivatives and
diethyl methylmalonate.a.
1
picolinic acid (L1)
L2
L3
picolinamide (L4)
quinaldic acid (L5)
thiopicolinamide (L6)
L7
77
99
91
–
99
–
99
92
–
99
–
2e
3
25f
<1f
64
4e
5
<1f
<1f
<1f
6
7
–
–
–
–
a
Reaction conditions: (S)-1a (0.25 mmol), 2a (0.275 mmol), [Cp*RuCl2]2
(0.00625 mmol)), L (0.0125 mmol), and Cs2CO3 (0.275 mmol) in CH3CN at 60ꢀC for
18 h. bIsolated yield. cDetermined by chiral HPLC analysis. des = (ee of product)/(ee
of starting material). e2-Vynylnaphthalene was formed in 4% NMR yield for entry 2
and 20% NMR yield for entry 4, respectively. fStarting material (S)-1a and a possible
byproduct generated from the nucleophilic aromatic substitution between the
pentafluorophenyl group of (S)-1a and 2a were observed in the 1H NMR analysis of
the crude reaction mixture.
the yield and stereochemical fidelity of (S)-3aa along with a small
amount of formation of 2-vinylnaphthalene (Entry 2). The ruthe-
nium catalyst system consisting of electron-rich picolinic acid ester
L3 did not exhibit the catalytic activity in the benzylic alkylation
aReaction conditions: Chiral 1a or 1b (0.25 mmol), 2a (0.275 mmol), [Cp*RuCl2]2
(0.00625 mmol), picolinic acid (L1) (0.0125 mmol), and Cs2CO3 (0.275 mmol) in
CH3CN at 60ꢀC for 18 h. Isolated yields were shown.
2

H. Tsuji, K. Suzuki and M. Kawatsura
Tetrahedron Letters 69 (2021) 152947
Table 3
engaged in the reaction to afford the desired alkylation product
(S)-3an in 94% yield with 99% ee (99% es).
Scope of malonate nucleophiles.a.
The reaction using triethyl methanetricarboxylate as a diethyl
malonate analogue was demonstrated as shown in Scheme 2. We
confirmed that the [Cp*RuCl2]2/picolinic acid catalyst did not work
well in the stereospecific benzylic alkylation using a simple dialkyl
malonate as a carbon nucleophile. [17] To overcome this drawback,
we attempted to use triethyl methanetricarboxylate, which is one
of the useful surrogate of diethyl malonte. [18] As a result, the
reaction of (R)-1a (96% ee) with triethyl methanetricarboxylate
(2o) smoothly proceeded under the optimal reaction conditions
to give the desired alkylation product (R)-3ao in 86% with 94% ee
(98% es). The resulting alkylation product (R)-3ao was amenable
to the decarboxylation reaction, leading to the desired product
(S)-4 in 95% yield with 94% ee.
We attempted to determine the stereochemical course of the
ruthenium-catalyzed stereospecific benzylic alkylation and out-
lined the reaction mechanism (Scheme 3). When chiral alkylation
product (S)-4 (94% ee), which was prepared by the ruthenium-cat-
alyzed stereospecific benzylic alkylation of (R)-1a with triethyl
aReaction conditions: (S)-1a (0.25 mmol),
2
(0.275 mmol), [Cp*RuCl2]2
(0.00625 mmol), picolinic acid (L1) (0.0125 mmol), and Cs2CO3 (0.275 mmol) in
CH3CN at 60ꢀC for 18 h. Isolated yields were shown. bCombined isolated yield as a
95:5 mixture of (S)-3am and dearomatized product (See supporting information for
details).
Scheme 2. The use of triethyl methanetricarboxylate as
surrogate.
a diethyl malonate
the optical purity of the starting material. Diethyl malonate deriva-
tives 2c–f that bear various functional groups, such as terminal
alkene, chlorine atom, ketone, and nitrile, were successfully
applied to the optimal reaction conditions, providing the corre-
sponding alkylation products (S)-3ac–af in 57–79% yields with
excellent stereochemical fidelity. Diethyl benzylmalonate (2g)
and diethyl isobutylmalonate (2h) also participated in the reaction
to give the desired product (S)-3ag and (S)-3ah in 73% yield and
54% yield with > 99% ee and 99% ee, respectively. Replacing the
alkyl substituents on the active methylene carbon of malonates
to phenyl and N-acetylamino groups (2i and 2j) was tolerated, pro-
ducing the alkylation products (S)-3ai and (S)-3aj in high yields as
an optically pure form. Other dialkyl methylmalonates instead of
diethyl methylmalonate (2a) were also tested. When dimethyl
methylmalonate (2k), dibenzyl methylmalonate (2l), and diiso-
propyl methylmalonate (2m) were used as the malonate nucle-
ophiles, the desired alkylation products (S)-3ak–am in
satisfactory yields and stereospecificity. In the reaction with 2m,
the benzylic alkylation product (S)-3am was obtained as a mixture
of a small amount of dearomatized product, which was estimated
by the 1H NMR analysis (See supporting information for details).
These results indicate the involvement of (p- or r-benzyl)ruthe-
nium species in this catalytic transformation (See Scheme 3 for
Scheme 3. (a) Determination of the stereochemical course of the ruthenium-
the mechanistic details). Meldrum’s acid derivative 2n was also
catalyzed benzylic alkylation. (b) Proposed reaction mechanism.
3

H. Tsuji, K. Suzuki and M. Kawatsura
Tetrahedron Letters 69 (2021) 152947
(d) H.-Q. Do, E.R.R. Chandrashekar, G.C. Fu, J. Am. Chem. Soc. 135 (2013)
16288–16291;
(e) S. Tabuchi, K. Hirano, M. Miura, Angew. Chem. Int. Ed. 55 (2016) 6973–
6977;
methanetricarboxylate (2o) followed by decarboxylation of the
resulting alkylation product as shown in Scheme 2, was subjected
to the transesterification conditions, (S)-5 was obtained in 73%
yield with 94% ee (Scheme 3a). The absolute stereochemistry of
this product was determined to be S by the comparison of the opti-
cal rotation value with the reported one.[11] This result indicates
that the configuration of the starting material retains during the
ruthenium catalysis. Based on this result and our previous report,
[12] we speculate that the ruthenium-catalyzed stereospecific ben-
zylic alkylation might proceed via a double inversion mechanism
as shown in Scheme 3b. [19] Initially, optically active benzyl ester
(S)-1a would react with the Ru/picolinic acid catalyst ([Ru/L1]) via
(f) A. Matsude, K. Hirano, M. Miura, Adv. Synth. Catal. 362 (2020) 518–522;
(g) X. Shen, L. Qian, S. Yu, Sci China Chem 63 (2020) 687–691.
[4] (a)Palladium-catalyzed asymmetric benzylation using prochiral carbon
nucleophiles has been reported. B. M. Trost, L. C. Czabaniuk, J. Am. Chem.
Soc. 2010, 132, 15534–15536;
(b) B. M. Trost, L. C. Czabaniuk, J. Am. Chem. Soc. 2012, 134, 5778–5781.;
(c) K. J. Schwarz, C. Yang, J. W. B. Fyfe, T. N. Snaddon, Angew. Chem. Int. Ed.
2018, 57, 12102–12105.
[5] (a) B.L.H. Taylor, E.R. Jarvo, Synlett (2011) 2761–2765;
(b) E.J. Tollefson, L.E. Hanna, E.R. Jarvo, Acc. Chem. Res. 48 (2015) 2344–2353;
(c) S.M. Pound, M.P. Watson, Chem. Commun. 54 (2018) 12286–12301.
[6] (a) A. He, J.R. Falck, J. Am. Chem. Soc. 132 (2010) 2524–2525;
(b) B.L.H. Taylor, E.C. Swift, J.D. Waetzig, E.R. Jarvo, J. Am. Chem. Soc. 133
(2011) 389–391;
inversion of configuration to generate a chiral (p-benzyl)ruthe-
nium intermediate. [20] During the study of this transformation,
we observed the formation of small amount of b-elimination prod-
ucts, such as 2-vinylnaphthalene and 2-methoxy-6-vinylnaph-
(c) B.L.H. Taylor, M.R. Harris, E.R. Jarvo, Angew. Chem. Int. Ed. 51 (2012) 7790–
7793;
(d) M.A. Greene, I.M. Yonova, F.J. Williams, E.R. Jarvo, Org. Lett. 14 (2012)
4293–4296;
(e) M.R. Harris, L.E. Hanna, M.A. Greene, C.E. Moore, E.R. Jarvo, J. Am. Chem.
Soc. 135 (2013) 3303–3306;
(f) Q. Zhou, H.D. Srinivas, S. Dasgupta, M.P. Watson, J. Am. Chem. Soc. 135
(2013) 3307–3310;
(g) H.M. Wisniewska, E.C. Swift, E.R. Jarvo, J. Am. Chem. Soc. 135 (2013) 9083–
9090;
(h) I.M. Yonova, A.G. Johnson, C.A. Osborne, C.E. Moore, N.S. Morrissette, E.R.
Jarvo, Angew. Chem. Int. Ed. 53 (2014) 2422–2427;
(i) E.J. Tollefson, D.D. Dawson, C.A. Osborne, E.J. Jarvo, J. Am. Chem. Soc. 136
(2014) 14951–14958;
(j) D.D. Dawson, E.R. Jarvo, Org. Process Res. Dev. 19 (2015) 1356–1359;
(k) Q. Zhou, K.M. Cobb, T. Tan, M.P. Watson, J. Am. Chem. Soc. 138 (2016)
12057–12060.
thalene, in some cases. Therefore, the involvement of a chiral (r-
benzyl)ruthenium species cannot be ruled out at this stage and it
seems to be a possible intermediate in this catalysis. The chiral
alkylation product (S)-3aa is formed via a nucleophilic addition
of the malonate anion to the chiral benzylruthenium intermediates
via inversion of configuration.
In conclusion, we have developed the ruthenium-catalyzed
stereospecific benzylic alkylation of optically active benzyl esters
with malonates as the carbon nucleophile. The Ru/picolinic acid
catalyst system promoted the reaction of chiral 2-naphthylethyl
2,3,4,5,6-pentafluorobenzoate derivatives with a series of malo-
nate nucleophiles to give the corresponding chiral benzylic alkyla-
tion products without significant loss of the stereochemical
fidelity. The retention of stereochemistry during the ruthenium
catalysis would be attributed to the double inversion mechanism
[7] Other examples, see, M. Brambilla, M. Tredwell, Angew.Chem. Int. Ed. 56
(2017) 11981–11985.
[8] (a) S. Tabuchi, K. Hirano, M. Miura, Chem. Eur. J. 21 (2015) 16823–16827;
(b) S.N. Mendis, J.A. Tunge, Org. Lett. 17 (2015) 5164–5167.
[9] M.R. Harris, M.O. Konev, E.R. Jarvo, J. Am. Chem. Soc. 136 (2014) 7825–7828.
[10] L.Kürti, B. Czakó, Strategic Applications of Named Reactions in Organic
Synthesis, Elsevier, 2005, pp 2–3, pp 242–243, pp 272–273, pp 286–287, pp
458–459, and references cited therein.
[11] J.-Y. Legros, M. Toffano, J.-C. Fiaud, Tetrahedron 51 (1995) 3235–3246.
[12] K. Suzuki, H. Tsuji, M. Kawatsura, Chem. Commun. 56 (2020) 3273–3276.
[13] S. Tanaka, Y. Suzuki, T. Kimura, M. Kitamura, Bull. Chem. Soc. Jpn. 92 (2019)
1707–1720.
via the formation of chiral
intermediates.
(
p-
or
r-benzyl)ruthenium
Declaration of Competing Interest
[14] (a) S. Tanaka, H. Saburi, Y. Ishibashi, M. Kitamura, Org. Lett. 6 (2004) 1873–
1875;
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
(b) H. Saburi, S. Tanaka, M. Kitamura, Angew. Chem. Int. Ed. 44 (2005) 1730–
1732;
(c) S. Tanaka, H. Saburi, M. Kitamura, Adv. Synth. Catal. 348 (2006) 375–378;
(d) H.-J. Zhang, B. Demerseman, L. Toupet, Z. Xi, C. Bruneau, Adv. Synth. Catal.
350 (2008) 1601–1609.
Acknowledgement
[15] We speculate that the steric repulsion between the methyl substituent and the
fused aromatic ring of quinaldic acid on the corresponding
p-benzylruthenium
This work was supported by a Grant-in-Aid for Scientific
Research (C) from the Japan Society for the Promotion of Science
(17K05794 and 20K05500).
intermediate would be cause of the loss of the catalytic activity. We
a
previously showed that the ruthenium/picolinic acid catalyst system is very
sensitive to the substituent on the benzylic position of the substrate (See ref.
12).
[16] We speculate that the mesomeric effect of the methoxy group on the
Appendix A. Supplementary data
naphthalene ring would facilitate racemization of the chiral
p- or r-
benzylruthenium intermediate via reversible ruthenium dissociation,
resulting in the loss of the optical purity of the benzylic alkylation product.
Supplementary data (1H and 13C NMR spectra of all new com-
pounds and HPLC chromatograms for chiral compounds) to this
article can be found online at https://doi.org/10.1016/j.tetlet.
2021.152947.
[17] We
examined
the
reaction
of
secondary
2-naphthylmethyl
pentafluorobenzoate 1a with dimethyl malonate and diethyl malonate,
giving the desired benzylic alkylation products in 40% and 45% NMR yields,
respectively, with concomitant formation of inseparable byproducts probably
assigned to the nucleophilic aromatic substitution product and the
dearomatized product.
References
[18] G. Huang, C. Cheng, L. Ge, B. Guo, L. Zhao, X. Wu, Org. Lett. 17 (2015) 4894–
4897.
[19] (a)
A double inversion mechanism was proposed as a possible reaction
[1] B.M. Trost, L.C. Czabaniuk, Angew. Chem. Int. Ed. 53 (2014) 2826–2851.
[2] (a) B. Liegault, J.-L. Renaud, C. Bruneau, Chem. Soc. Rev. 37 (2008) 290–299;
(b) R. Kuwano, Synthesis (2009) 1049–1061;
(c) J.L. Bras, J. Muzart, Eur. J. Org. Chem. (2016) 2565–2593.
[3] (a) J.-Y. Legros, M. Toffano, J.-C. Fiaud, Tetrahedron: Asymmetry 6 (1995)
1899–1902;
pathway in the ruthenium-catalyzed allylic substitution of optically active
allyl esters with carbon nucleophiles. A. Bayer, U. Kazmaier, Org. Lett. 2010, 12,
4960–4963.;
(b) M. Kawatsura, M. Sato, H. Tsuji, F. Ata, T. Itoh, J. Org. Chem. 2011, 76, 5485–
5488.
[20] (a) M.A. Bennett, I.J. McMahon, T.W. Turney, Angew. Chem., Int. Ed. Engl. 21
(1982) 379;
(b) M. Assié, J.-Y. Legros, J.-C. Fiaud, Tetrahedron: Asymmetry 16 (2005) 1183–
1187;
(c) M. Assié, A. Meddour, J.-C. Fiaud, J.-Y. Legros, Tetrahedron: Asymmetry 21
(2010) 1701–1708;
(b) M.A. Bennett, L.Y. Goh, I.J. McMahon, T.R.B. Mitchell, G.B. Robertson, T.W.
Turney, W.A. Wickramaslnghe, Organometallics 11 (1992) 3069–3085.
4