Palladium-Catalyzed Asymmetric C(sp3)?H Allylation of 2-Alkylpyridines

Article abstract of DOI:10.1002/anie.201802821

The palladium-catalyzed asymmetric side-chain C(α)-allylation of 2-alkylpyridines, without using an external base, was developed. The high linear selectivities and enantioselectivities were achieved using new chiral diamidophosphite monodentate ligands. G

Full text of DOI:10.1002/anie.201802821

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Palladium-Catalyzed Asymmetric C(sp³)-H Allylation of 2-
Alkylpyridines
Authors: Ryo Murakami, Kentaro Sano, Tomohiro Iwai, Tohru
Taniguchi, Kenji Monde, and Masaya Sawamura
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802821
Angew. Chem. 10.1002/ange.201802821
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10.1002/anie.201802821
Angewandte Chemie International Edition
COMMUNICATION
Palladium-Catalyzed Asymmetric C(sp3)–H Allylation of 2-
Alkylpyridines
Ryo Murakami,+ Kentaro Sano,+ Tomohiro Iwai, Tohru Taniguchi, Kenji Monde, and Masaya
Sawamura*
(Scheme 2). Specifically, P(2-furyl)3 and P(OPh)3 caused
moderate substrate conversion to give the linear allylation
product 3a preferentially over the branched product 3a’ (3a/3a’
93:7 and 97:3, respectively). Xantphos improved linear-
selectivity, albeit with an unsatisfactory yield. Further ligand
screening revealed that Ph-TRAP,[10] featuring a very large bite
angle, induced complete substrate conversion to give 3a
exclusively, but with poor enantioselectivity (with Pd(OAc)2, 3%
ee).
This reaction occurred specifically with allylic substrates
having carbonate leaving groups. Cinnamyl methyl carbonate
(2b) also was a suitable substrate in the reaction with Ph-TRAP
(95%, 3a/3a’ >99:1).[11]
Abstract: Palladium-catalyzed asymmetric side-chain C( )-allylation
a
of 2-alkylpyridines without external base was developed. The high
linear- and enantioselectivities were achieved using new chiral
diamidophosphite monodentate ligands. Due to the no external base
conditions, this catalyst system enabled chemoselective C(
allylation of 2-alkylpyridines containing -carbonyl C–H bonds, which
are more acidic than -pyridyl C–H bonds.
a
)-
a
a
Azaarenes with an
a
-stereogenic alkyl substituent at the C2
position constitute an important structure motif widely found in
biologically active compounds, agrochemicals, and natural
products.[1] Among methods used to access these structures,[2]
asymmetric
alkylazaarenes as pronucleophiles to allow enantioselective
C(sp3)–C(sp3) bond formation at the position
to the azaarene
Tsuji–Trost
allylation
reactions
with
2-
(a) With base and Lewis acid: Trost's work
cat.
a
OC(O)R
ring are promising strategies.[3] However, reported methods
have required the use of stoichiometric or excess amounts of
strong Brønsted bases and/or Lewis acids to activate the
C(sp3)–H bonds of the pronucleophiles (Scheme 1a).[4-6]
R1
O
[Pd-L]
O
*
+
N
R1
N
H
HN
P
LHMDS
n-BuLi
*
N
P
Ph2
n
BF3·OEt2
Ph2
n
Trost ligand (L)
This report describes the Pd-catalyzed asymmetric C(sp3)–H
allylation of 2-alkylpyridines with primary allylic carbonates,
which did not require the use of an external base. With a new
chiral diamidophosphite [P(NR1R2)2(OR3)] monodentate ligand
featuring a D-isomannide framework with a sterically demanding
(b) No added base: This work
cat.
F
OCO2R3
[Pd-L*]
R1
+
R2
N
O
H
N
O
Ph
P
O
R1
*
N
group at
occurred cleanly with exclusive regioselectivity with respect to
the allylic portion to give enantio-enriched -stereogenic 2-
a
distal position, C(sp3)–C(sp3) bond formation
H
O
N
Ph
R2
D
-Isomannide-based
a
F
diamidophosphite (L*)
alkylpyridines with no constitutional isomers (Scheme 1b). The
mildness of the conditions allowed compatibility of the reaction
with various functional groups,[7–9] which was site-selective
a
to the pyridine ring in the
presence of more acidic C(sp3)–H bonds adjacent to carbonyl
groups.
Scheme 1. Asymmetric side-chain C( )-allylation of 2-alkylpyridines
a
[Pd(dba)2] (5 mol%)
ligand (5 or 10 mol%)
toward a C(sp3)–H bond located
OCO2tBu
Me
Me
+
N
N
Me
+
Ph
N
MeCN (1 mL)
25 °C, 6 h
Ph
Ph
1a
(0.2 mmol)
2a
(1.2 equiv)
3a (linear)
3a' (branched)
A preliminary screening of achiral ligands for the reaction
between 2-ethylpyridine (1a) and cinnamyl t-butyl carbonate (2a)
with 5 mol% [Pd(dba)2] as a Pd source in MeCN at 25 °C for 6 h
revealed that electron-deficient monophosphines and large bite-
Ligand, 1H NMR yield, l/b
Me Me
PPh2
Ph2P
H
Me
O
Fe
Me
H
OPh
O
P
P
Fe
O
PhO
OPh
PPh2
PPh2
angle bisphosphines promoted side-chain C( )-allylation
a
O
Xantphos
5 mol%
(S,S)-(R,R)-Ph-TRAP
5 mol%, with Pd(OAc)2
10 mol%
(1.5 equiv of 2a)
10 mol%
Dr. R. Murakami,[+] K. Sano,[+] Dr. T. Iwai, Prof. Dr. M. Sawamura
41% (93:7)
39% (97:3)
57% (98:2)
94% (>99:1)
[*]
Department of Chemistry, Faculty of Science, Hokkaido University
Sapporo 060-0810 (Japan)
Scheme 2. Pd-catalyzed C(
a
)-allylation of 1a with 2a
E-mail: sawamura@sci.hokudai.ac.jp
Homepage:
Next, various chiral ligands were used to achieve better
enantioselectivity in reaction between 5,6,7,8-
tetrahydroquinoline (1b) and 2b (1.3–1.5 equiv) with [Pd(dba)2]
(5 mol%, Pd/ligand 1:1) in MeCN at 25 °C (12 h). The results are
summarized in Scheme 3.
Chiral monodentate phosphoramidite ligands and a Trost’s
bisphosphine ligand (L in Scheme 1)[4] induced no reaction. The
Ph-TRAP again gave complete substrate conversion, albeit with
poor enantioselectivity (19% ee). A change in the P-substituents
http://wwwchem.sci.hokudai.ac.jp/~orgmet/index.php?id=25
Prof. Dr. T. Taniguchi, Prof. Dr. K. Monde
Frontier Research Center for Advanced Material and Life Science,
Faculty of Advanced Life Science, Hokkaido University
Sapporo, 001-0021 (Japan)
[+]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201802821
Angewandte Chemie International Edition
COMMUNICATION
of TRAP from Ph to m-terphenyl (TerPh-TRAP)[10c] improved
enantioselectivity to 45%.
Further ligand screening revealed bis(diamidophosphite)-
type ligands as promising candidates.[12] The 1,3-, 1,4-, and 1,5-
[Pd(dba)2] (5 mol%)
ligand (5 mol%)
OCO2Me
Ph
+
N
N
MeCN (1 mL)
25 °C, 12 h
(R)-3b
Ph
1b (0.2 mmol) 2b (1.3–1.5 equiv)
(l/b >99:1, based on 1H NMR)
TerPh-TRAP; 99%, 45% ee
Ph
alkanediol-based
ligands
(L1–L3)
induced
moderate
Large-bite-angle bisphosphines
enantioselectivity (58–60% ee) with high substrate conversion.
Among bis(diamidophosphite) ligands derived from chiral 1,4-
butanediols (L4–L6), the D-isomannide derivative (L6) with a
rigid bicyclic backbone was the most favorable for both product
yield and enantioselectivity (91% yield, 60% ee).[13]
An exploration of N-substituents on the 1,2-diamine moiety
of L6 led to further improvement in enantioselectivity (69% ee)
with L7 containing N-4-fluorophenyl groups. Introduction of the
Me group instead of the F group decreased enantioselectivity
significantly (L8, 49% ee).
The effectiveness of the electron-poor monophosphines in
the reaction of 2-ethylpyridine (1a) (Scheme 2) led to an
exploration of monodentate diamidophosphites containing a
N,N-(4-fluorophenyl)-1,2-diphenylethylenediamino moiety for
enantioselective reaction of the tetrahydroquinoline 1b (Scheme
3). Although primary (L9) and tertiary (L11) alcohol-based
ligands induced only trace or no reaction (<6%), the ligand L10
derived from cyclopentanol gave a high yield of 3b with
moderate enantioselectivity (94% yield, 59% ee). These results
indicated that the second P-center was unnecessary and
promoted further screening of monophosphines with mono-O-
protected isomannide substituents.
Ph-TRAP; 97%, 19% ee
Bis(diamidophosphites)
Ph
Ph
Ph
Ph
Me
N
O
O
n
N
N
Ph
Ph
P
N
P
N
N
P
O
Ph
Ph
P
O
N
Ph
Ph
Ph
N
Me
Ph
Ph
Ph
Ph
L1 (n = 1); 87%, 60% ee
L2 (n = 2); 97%, 58% ee
L3 (n = 3); 93%, 60% ee
L4; 10%, 64% ee
R
R
Ph
Ph
Ph
O
H
N
Ph
Ph
Ph
Ph
N
N
N
O
Ph
P
P
N
Ph
O
N
N
N
P
P
H
Ph
O
Ph
O
O
Ph
O
O
R
R
Me Me
L5; 96%, 53% ee
L6 (R = H);
L7 (R = F);
91%, 60% ee
99%, 69% ee
L8 (R = Me); 91%, 49% ee
Monodentate diamidophosphites
F
F
F
Ph
Ph
O
3
Me
Me
Ph
O
O
O
P
N
N
P
N
P
Me
N
N
N
Ph
Ph
Ph
A
catalyst system prepared from [Pd(dba)2] and
diamidophosphite (L12) having an O-benzoyl group (Pd/P 1:1)
allowed quantitative C( )-allylation with moderate
a
F
F
F
Ph
Ph
L10; 94%, 59% ee
Ph
L11; 0%
L9; 6%, 56% ee
a
F
L12 (R = C(O)Ph); 99%, 62% ee
L13 (R = CH2Ph); 99%, 76% ee
O
H
enantioselectivity (62% ee). Interestingly, the O-substituent had
OR
H
F
a significant impact on the enantioselectivity regardless of its
L14 (R = SiiPr3);
L15 (R = SiPh3):
L16 (R = CPh3):
L16 (R = CPh3):
98%, 76% ee
96%, 75% ee
95%, 84% ee
O
O
N
P
long spatial distance from the
enantioselectivity increased to 76% ee by changing the O-
protecting group to benzyl group (L13). While O-silyl
derivatives, such as L14 and L15, gave nearly the same results
as the benzyl derivative L13, significant increase in
P
atom. Thus, the
N
Ph
94%, 90% ee (–15 °C, 36 h)
Ph
a
Scheme 3. Ligand effects in asymmetric C(a)-allylation. Conditions: 1b (0.2
mmol), 2b (0.26–0.30 mmol), [Pd(dba)2] (5 mol%), ligand (5 mol%), MeCN (1
mL), 25 °C, for 12 h. Yields of isolated product. Ee values determined by
HPLC.
a
enantioselectivity was observed with the tritylated ligand L16,
which afforded 3b with 84% ee in 95% yield. The
enantioselectivity with L16 increased to 90% ee by conducting
the reaction at –15 °C.[14,15] Thus, L16 was identified as the
optimal chiral ligand. The effects of the O-protecting groups may
be due to dispersive ligand–substrate attractions.[16,17]
[Pd(dba)2] (5 mol%)
O
L16 (5 mol%)
O
OCO2Me
+
N
R
N
R
Ph
2b (1.3 equiv)
MeCN (1 mL)
–10 °C, 36 h
Ph
(0.2 mmol)
The synthetic utility of the present catalyst system was
1c (R = Me)
1d (R = OBn)
3c (R = Me); 92%, 82% ee
3d (R = OBn); 88%, 83% ee
demonstrated in the chemoselective C(
alkylpyridines containing -carbonyl C–H bonds, which are more
acidic than -pyridyl C–H bonds (Scheme 4). Specifically, allylic
a
)-allylation of 2-
Not Detected
a
O
O
a
alkylation of 1c bearing a ketone moiety with 2b in the presence
of the Pd-L16 system occurred cleanly to afford the side-chain
N
R
N
4c (R = Me)
4d (R = OBn)
5
Ph
Ph
C(
formation of carbonyl C(
a
)-allylation product 3c with 82% ee in 92% yield.[18] No
a
)-allylation products 4 and 5 was
Scheme 4. Side-chain C(a)-allylation of 2-alkylpyridines containing a-carbonyl
observed by 1H NMR analysis. In contrast, the reaction between
1c and 2b catalyzed by the [PdCl(p-allyl)]2/dppf system in the
presence of LiHMDS (1.2 equiv) as a base in THF at rt did not
produce 3c at all but gave a complex mixture.[19] With the Pd-
L16 system, 1d containing an ester moiety was also suitable.
C–H bonds
Reactions with various combinations of 2-alkylpyridines 1
and allylic carbonate 2 catalyzed by Pd-L16 system is shown in
Scheme 5. The reactions occurred in the temperature range of –
20 to +10 °C with exceptional linear selectivity (l/b >99:1) and
good-to-high enantioselectivities (63–93% ee). The allylation of
2,3-cyclopentenopyridine
with
2b
occurred
with
an
enantioselectivity comparable to that of 1b (3e, 96% yield, 87%
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10.1002/anie.201802821
Angewandte Chemie International Edition
COMMUNICATION
ee).
A
piperazine-fuzed substrate underwent regioselective
Reaction between 1b with methyl (1-phenylallyl) carbonate
catalyzed by the Pd-L16 system provided the linear product 3b
with the identical absolute configuration (R) and enantiomeric
purity as that of 2b, but with slightly lower reaction efficiency
(68% yield, 91% ee). This result strongly suggests that both
reactions proceeded through a (p-allyl)palladium(II) species as a
common intermediate.
The P/Pd ratio had a significant impact on the efficiency of
the reaction between 1b and 2b catalyzed by the Pd-L16 system
(Figure 1). The reaction was conducted at –15 °C for 36 h with
varying amounts of L16 relative to Pd in the range of 0.2 to 4.0
equivalents. While no reaction occurred with 0.2 to 0.9
equivalents of L16, a P/Pd ratio of 0.95 gave the moderate yield
(57%) and enantiomeric excess (89% ee) of product (R)-3b. The
maximum yield (99%) was obtained from a P/Pd ratio of 1.0.
Product yield gradually decreased to 92% as the loading of L16
allylation at the position b to the pyridine N atom with a high level
of enantioselectivity (3f, 95% yield, 84% ee).
Acyclic alkyl substituents of pyridine substrates were also
allylated with the Pd-L16 system albeit with slightly lower
enantioselectivities compared to the annulated substituent in 1b.
For instance, 2-ethylpyridine (1a) and 2-(3-phenylpropyl)pyridine
afforded 3a in 78% ee and 3g in 76% ee, respectively (Scheme
5). Functional groups such as alkyne (3h), acetal (3i),
methoxymethyl (3j), or carbamate (3k) with an N–H bond in the
acyclic alkyl substituents did not hamper the allylation.[20,21]
Cinnamyl carbonates 2 with electron-rich or electron-neutral
aromatic rings participated in asymmetric reaction of 1b to give
the corresponding C(a)-allylated products (3l–o) in high yields
with enantioselectivities ranging from 90% to 93% ee. However,
cinnamyl carbonates with ester- or CF3-substituted electron-
deficient aromatic rings were less reactive, and reaction at 10 °C
occurred with somewhat lower enantioselectivities (3p and 3q).
Indole-, furan-, and thiophene-based carbonates reacted with 1b
to afford 3r–t in enantioselectivities ranging from 87% to 92%
ee.[22]
increased
from
1.0
to
4.0
equivalents;
however,
enantioselectivity was maintained at 91% ee. These results
suggest that the active species is Pd-L16 in a 1:1 ratio (P/Pd
1:1).[23] For reactions with large-bite-angle bisphosphine ligands
such as TRAPs and Xantphos, one of the two P atoms might
dissociate from Pd during catalysis while bidentate coordination
in the resting state may stabilize the catalytic system.
[Pd(dba)2] (5 mol%)
L16 (5 mol%)
X
OCO2Me
X
+
R1
N
R2
2 (1.5 equiv)
R1
1 (0.2 mmol)
N
MeCN (1 mL)
–20 °C, 36 h
R2
(l/b >99:1, based on 1H NMR)
3
2-Alkylpyridines [with 2b (1.3 equiv)]
N
Ph
N
N
Ph
3e
3f
Ph
Me
96%, 87% ee
95%, 84% ee
Ph
Figure 1. Effect of L16/Pd molar ratio in reaction between 1b and 2b (5 mol%
Me
N
N
N
Pd, in MeCN, at –15 °C, 36 h)
3a
3g
3h
Ph
Ph
Ph
56%, 78% ee
(–10 °C, 48 h, 1.5 equiv of 2b)
82%, 76% ee
77%, 63% ee
(–10 °C)
To have a mechanistic insight, preliminary 1H NMR kinetic
studies were conducted for the reaction between 1a and 2b with
the Pd-L16 (1:1) system in CD3CN at rt. Thus, the rate was
pseudo-first order for the Pd-L16 catalyst, while reaction orders
of 0 and 0.7 were indicated for carbonate 2b and 2-ethylpyridine
1a, respectively.[24] This result suggests the following
mechanistic conclusions: the Pd catalyst participates in the
reaction in a monomeric form; the allylic carbonate 2b has a
high affinity for the Pd catalyst; and an off-cycle species is
formed upon coordination of the alkylpyridine 1a to a catalytically
active species.
(–10 °C, 48 h)
O
O
O
O
OMe
HN
O
Ph
N
N
N
3i
3j
3k
Ph
Ph
Ph
99%, 69% ee
(–10 °C)
83%, 76% ee
(–10 °C)
83%, 79% ee
(–10 °C)
Allyllic Carbonates (with 1b)
3l (R = 4-OMe)
3m (R = 3,5-diOMe)
93%, 93% ee
79%, 93% ee
89%, 91% ee
92%, 90% ee
3n (R = 3,4-(OCH2O))
3o (R = 3-Br)
N
R
3p (R = 4-CO2Me, 10 °C, 12 h) 75%, 84% ee
Kinetic analysis of reactions using 1a or 1a-d5 with 2b
catalyzed by the Pd-L16 system in MeCN at 20–22 °C gave a
significant kinetic isotope effect value [kH/kD = 4.0; Eq. (1)],
which indicates that a turnover-limiting step of Pd catalysis
involved the dissociation of a C(a)–H bond.
3q (R = 4-CF3, 10 °C, 12 h)
84%, 74% ee
N
N
N
3r
3s
3t
O
S
Me
77%, 87% ee
94%, 91% ee
96%, 92% ee
N
(–10 °C)
Ts
[Pd(dba)2] (5 mol%)
OCO2Me
L16 (5 mol%)
CH(D)3
CH(D)3
Scheme 5. Scope of asymmetric C(a)-allylation. Conditions: 1 (0.2 mmol), 2
(0.26–0.3 mmol), [Pd(dba)2] (5 mol%), L16 (5 mol%), MeCN (1 mL) at –20 °C
for 36 h. Yields of isolated products are shown. Absolute configurations of 3e,
3f, and 3l–t were assigned by analogy to (R)-3b. Absolute configurations of 3a
and 3g–k were assigned by analogy to (R)-3c.
*
H(D)
N
N
(1)
+
Ph
(D)H H(D)
MeCN, 20–22 °C
Ph
1a or 1a-d5
2b (1.5 equiv)
kH/kD = 4.0
Based on these experimental results, a reaction pathway is
proposed in Figure 2. Thus, a mono-P-ligated Pd(0) complex A
undergoes rapid decarboxylative oxidative addition with allylic
This article is protected by copyright. All rights reserved.

10.1002/anie.201802821
Angewandte Chemie International Edition
COMMUNICATION
[3]
[4]
Reviews on Tsuji–Trost allylation reactions: a) B. M. Trost, Tetrahedron
2015, 71, 5708–5733; b) J. Tsuji, Tetrahedron 2015, 71, 6330–6348.
a) B. M. Trost, D. A. Thaisrivongs, J. Am. Chem. Soc. 2009, 131,
12056–12057; b) B. M. Trost, D. A. Thaisrivongs, J. Hartwig, J. Am.
Chem. Soc. 2011, 133, 12439–12441; Synthesis of enantioenriched b-
stereogenic 2-alkylpyridines: c) B. M. Trost, D. A. Thaisrivongs, J. Am.
Chem. Soc. 2008, 130, 14092–14093.
carbonate 2, to produce a neutral alkoxo(p-allyl)palladium(II)
complex (B). Coordination of a 2-alkylpyridine (1) to B forms a
cationic complex with an alkoxide counter anion (C). Further
coordination of 1 to C forms an off-cycle species (D, [Pd(R1-
allyl)(P*)(1)2]+(OR2)–). Next, cleavage of a side chain C(a)–H
bond produces the (h1-enamido)(h3-allyl)palladium(II) complex
(E). This catalyst-turnover-limiting step should be promoted by
effective acid–base cooperation between the cationic Pd(II)
center bound to the N atom and the alkoxide ion interacting with
one of the C(a)–H protons. Finally, diastereoselective reductive
elimination of the h1-enamido ligand and the h3-allyl ligand,
either in a direct manner or through a multi-step pathway
involving h3-to-h1 hapticity change in the allylic ligand, furnishes
the enantio-enriched C(a)-allylation product 3.
[5]
Pd- or Ni-catalyzed allylic substitution reactions with diarylmethane
pronucleophiles containing azaarene units in the presence of strong
bases: a) S.-C. Sha, J. Zhang, P. J. Carroll, P. J. Walsh, J. Am. Chem.
Soc. 2013, 135, 17602–17609; b) S.-C. Sha, H. Jiang, J. Mao, A.
Bellomo, S. A. Jeong, P. J. Walsh, Angew. Chem. 2016, 128, 1082–
1086; Angew. Chem. Int. Ed. 2016, 55, 1070–1074. Pd-catalyzed
benzylic C–H benzylation of 2-benzylazoles without an external base:
c) T. Mukai, K. Hirano, T. Satoh, M. Miura, Org. Lett. 2010, 12, 1360–
1363.
[6]
[7]
a-Deprotonation of alkylazaarenes with bases: a) S. Mangelinckx, N.
Giubellina, N. De Kimpe, Chem. Rev. 2004, 104, 2353–2400; b) R. D.
Clark, A. Jahangir, Org. React. 1995, 47, 1–314.
R1
OCO2R2
R3
*
N
2
P* Pd(solv)n
Breinbauer and co-workers reported the non-enantioselective additive-
free Pd-catalyzed side-chain C(a)-allylation of imine-containing
heterocycles. However, 2-alkylpyridines were out of scope: M. Kljajic, J.
G. Puschnig, H. Weber, R. Breinbauer, Org. Lett. 2017, 19, 126–129.
Pd-catalyzed allylation with allylic carbonates without external bases: J.
Tsuji, I. Shimizu, I. Minami, Y. Ohashi, T. Sugiura, K. Takahashi, J. Org.
Chem. 1985, 50, 1523–1529.
3
A
R1
fast
R1
CO2
Enantioselection step
R1
[8]
[9]
Pd
P* Pd
OR2
P*
–OR2
R1
B
N
R3
E
Pd-catalyzed intramolecular decarboxylative side-chain C(a)-allylation
of 2-alkylazaarenes: a) S. R. Waetzig, J. A. Tunge, J. Am. Chem. Soc.
2007, 129, 4138–4139; b) J. D. Weaver, A. Recio, A. J. Grenning, J. A.
Tunge, Chem. Rev. 2011, 111, 1846–1913.
– 1
P* Pd+
N
1
R2OH
R3
R3
Turnover-limiting step
N
C
[10] a) M. Sawamura, H. Hamashima, Y. Ito, Tetrahedron: Asymmetry 1991,
2, 593–596; b) M. Sawamura, H. Hamashima, M. Sugawara, R.
Kuwano, Y. Ito, Organometallics 1995, 14, 4549–4558; c) Y. Asano, H.
Ito, K. Hara, M. Sawamura, Organometallics 2008, 27, 5984–5996.
[11] The use of allylic substrates containing acetate, phosphate, or chloride
as a leaving group did not provide 3. See Supporting Information.
[12] a) I. Ayora, R. M. Ceder, M. Espinel, G. Muller, M. Rocamora, M.
Serrano, Organometallics 2011, 30, 115–128; b) B. M. Trost, T. M. Lam,
J. Am. Chem. Soc. 2012, 134, 11319–11321; c) B. M. Trost, T. M. Lam,
M. A. Herbage, J. Am. Chem. Soc. 2013, 135, 2459–2461.
– 1
+ 1
[Pd(R1-allyl)(P*)(1)2]+(OR2)–
D Off-cycle species
Figure 2. A possible reaction pathway
In conclusion, a Pd-catalyzed asymmetric side-chain C(a)-
allylation of 2-alkylpyridines without an external base was
developed.
Newly
synthesized
D-isomannide-based
monodentate diamidophosphite ligands enabled the highly
linear- and enantioselective allylation with good functional group
compatibility. The reaction pathway is proposed to involve
formation of a (p-allyl)palladium(II) complex coordinated with a
single molecule of the phosphine ligand and the 2-alkylpyridine
substrate followed by side-chain C(a)-deprotonation by an
alkoxide anion. Studies on extending this strategy to other alkyl
azaarenes for catalytic asymmetric C–H functionalization
reactions are ongoing.
[13] Asymmetric catalysis with D-isomannide-based diamidophosphites: K.
N. Gavrilov, S. V. Zheglov, P. A. Vologzhanin, E. A. Rastorguev, A. A.
Shiryaev, M. G. Maksimova, S. E. Lyubimov, E. B. Benetsky, A. S.
Safronov, P. V. Petrovskii, V. A. Davankov, B. Schäffner, A. Börner,
Russ. Chem. Bull. 2008, 57, 2311–2319.
[14] The absolute configuration of 3b was determined to be R by a chemical
transformation to a known compound. See Supporting Information.
[15] The ee value of 3a remained almost unchanged at shorter and longer
reaction time (12–48 h), indicating no racemization during the catalysis.
[16] A review for dispersive interactions: J. P. Wagner, P. R. Schreiner,
Angew. Chem. 2015, 127, 12446–12471; Angew. Chem. Int. Ed. 2015,
54, 12274–12296.
Acknowledgements
This work was supported by JST ACT-C Grant Number
JPMJCR12YN and JSPS KAKENHI Grant Number JP15H05801
in Precisely Designed Catalysts with Customized Scaffolding to
M.S. R.M. thanks JSPS for scholarship support.
[17] For dispersive ligand–substrate attractions in asymmetric metal
catalysis, see: a) M. C. Schwarzer, A. Fujioka, T. Ishii, H. Ohmiya, S.
Mori, M. Sawamura, Chem. Sci. 2018, 9, 3484–3493. b) T. Ishii, R.
Watanabe, T. Moriya, H. Ohmiya, S. Mori, M. Sawamura, Chem. Eur. J.
2013, 19, 13547–13553.
[18] The absolute configuration of 3c was determined to be R by vibrational
circular dichroism. See: T. Taniguchi, K. Monde, J. Am. Chem. Soc.
2012, 134, 3695–3698. See Supporting Information.
Keywords: Asymmetric catalysis
· C–H functionalization ·
Allylation · 2-Alkylpyridines · Palladium
[19] Related works on the Pd-catalyzed allylic alkylation with ketone
enolates: a) M. Braun, F. Laicher, T. Meier, Angew. Chem. 2000, 112,
3637–3640; Angew. Chem. Int. Ed. 2000, 39, 3494–3497; b) W.-H.
Zheng, B.-H. Zheng, Y. Zhang, X.-L. Hou, J. Am. Chem. Soc. 2007,
129, 7718–7719.
[1]
[2]
a) J. A. Joule, K. Mills, Heterocyclic chemistry, 5th ed.; John Wiley &
Sons: Chichester, U.K. 2010; b) S. D. Roughley, A. M. Jordan, J. Med.
Chem. 2011, 54, 3451–3479; c) E. Vitaku, D. T. Smith, J. T. Njardarson,
J. Med. Chem. 2014, 57, 10257–10274.
D. Best, H. M. Lam, J. Org. Chem. 2014, 79, 831–845.
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[20] The reaction of papaverine, an isoquinoline alkaloid used as
vasodilators, with the Pd-L16 system gave the corresponding C(a)-
allylation product with 82% ee in 18% yield (25 °C, 12 h). 1-Methyl-2-
phenethyl-1H-benzo[d]imidazole did not participate in the reaction.
[21] The reaction of 2-methylpyridine and 2b with the Pd-L16 system at
25 °C for 12 h gave a mixture of C(a)-monoallytion (22%) and a,a-
diallylation products (39%). A related work on the enantioselective Ir-
catalyzed allylic substitution with 2-methylpyridines: X.-J. Liu, S.-L, You.
Angew. Chem. 2017, 129, 4060–4063; Angew. Chem. Int. Ed. 2017, 56,
4002–4005.
[22] The C(a)-allylation with allyl methyl carbonate (60% yield, 67% ee; –
20 °C, 36 h) or 3-cyclohexyl-2-propenyl methyl carbonate (63% yield,
39% ee; 0 °C, 12 h) were less enantioselective as compared to the
reaction with aryl-substituted allylic carbonates.
[23] The non-linear dependence of the product yields on the P/Pd ratios
suggests that P-uncoordinated Pd species may become a seed to
induce rapid catalyst decomposition leading to total catalyst
deactivation.
[24] See the Supporting Information for details of the kinetic studies.
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Entry for the Table of Contents (Please choose one layout)
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Ryo
Murakami,+
Kentaro
Sano,+
Tomohiro Iwai, Tohru Taniguchi, Kenji
Monde, and Masaya Sawamura *
Page No. – Page No.
Palladium-Catalyzed
Asymmetric
of 2-
C(sp3)–H
Allylation
Alkylpyridines
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