Pd/PC-Phos-Catalyzed Enantioselective Intermolecular Denitrogenative Cyclization of Benzotriazoles with Allenes and N-Allenamides

Article abstract of DOI:10.1002/anie.201904805

Reported herein is an asymmetric Pd/PC-Phos-catalyzed denitrogenative cyclization of benzotriazoles with allenes and N-allenamides, representing the first example of enantioselective denitrogenative cyclizations of benzotriazoles. A series of optically active 3-methyleneindolines were obtained in good yields with high ee values. The use of inexpensive and readily available starting materials, high regio- and enantioselectivity, a broad substrate scope, mild reaction conditions, no need for base, as well as versatile functionalization of the 3-methyleneindolines make this approach attractive.

Full text of DOI:10.1002/anie.201904805

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Accepted Article
Title: Pd/PC-Phos-Catalyzed Enantioselective Intermolecular
Denitrogenative Cyclization of Benzotriazoles with Allenes or N-
allenamides
Authors: Junliang Zhang, Pei-Chao Zhang, and Jie Han
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201904805
Angew. Chem. 10.1002/ange.201904805
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10.1002/anie.201904805
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Pd/PC-Phos-Catalyzed Enantioselective Intermolecular Denitrogenative
Cyclization of Benzotriazoles with Allenes or N-allenamides
Pei-Chao Zhang,[a] Jie Han[a] and Junliang Zhang*[a] [b]
Abstract: Herein we reported an asymmetric Pd/PC-Phos-catalyzed
denitrogenative cyclization of benzotriazoles with allennes and N-
allenamides, which represents the first example of enantioselective
denitrogenative cyclization of benzotriazoles. A series of optically
active 3-methyleneindolines were obtained in good yields with high
ees. The use of inexpensive and readily available starting materials,
high regio- and enantioselectivity, a broad substrate scope, mild
reaction conditions, base free, as well as versatile functionalization of
the 3-methyleneindoline make this approach quite attractive.
eight isomers (er, rr, Z/E) might be obtained in theory, how to
control over the product distribution, 2) how to avoid the
dimerization of allene, especially the allenamides,[15] 3) potential
compatibility issue between phosphine ligands and diazonium
salts intermediate,[16] 4) how to achieve high enantioselectivity.
Benzotriazoles can undergo ring-chain isomerization to form
the corresponding diazonium or diazo species via a Dimroth-type
equilibrium. Over past years, many methodologies have been
developed by the use of this unique chemical property of
benzotriazoles via denitrogenation.[1-3] In this context, the
development of new denitrogenative reactions of benzotriazoles
with readily accessible unsaturated hydrocarbons have received
much attention, which provide rapid access to various synthetic
valuable compounds (Scheme 1). For example, Nakamura
group[1c] demonstrated a Pd-catalyzed denitrogenative cyclization
of benzotriazoles with internal alkynes. Glorius group[2b] then took
the use of iridium-photocatalysis to achieve the denitrogenation of
benzotriazoles and reacting with terminal alkynes. Recently, Tang
and co-workers[3] developed an alternative seminal synergistic
activating–stabilizing strategy to realize the denitrogenative
reaction of benzotriazoles with alkyne[3a] and 1,3-diene[3b]
.
Allenes and N-allenamides, readily available unsaturated
hydrodcarbons, bearing two cumulative unsaturation have
emerged as highly important building blocks in organic
synthesis.[4] However, to the best of our knowledge, allenes have
not been applied to the denitrogenative cyclization of
benzotriazoles so far.[5] As a part of our continual program in the
discovery of new asymmetric cyclization reactions of allenes and
N-allenamides,[6] we became interest in the enantioselective
Scheme 1. Denitrogenative reactions of benzotriazoles with unsaturated
hydrocarbon.
intermolecular
denitrogenative
cyclization
reaction
of
benzotriazoles with allenes and N-allenamides. If success, 3-
methyleneindolines and related skeleton which are ubiquitous
structural motifs found in an array of biologically active natural
products and pharmaceuticals, would become easily accessible
(Figure 1).[7-14] However, the development of denitrogenative
cyclization of benzotriazoles with allenes, especially in
enantioselective manner, poses considerable challenge: 1) up to
Figure 1. Biologically active natural products featuring functionalized indolines.
Our investigation began with the cyclization of N1-Tf
benzotriazole 1a and allene 2a with the use of Pd2(dba)3 as a
precatalyst. A series of commercially or readily available chiral
ligands were systematically investigated, and our developed
chiral sulfinamidephosphine type ligands [17-19] delivered 3a in up
to 90% yield and up to 75% ee (see Supporting Information (SI),
Figure S1). Further screening showed that PC-Phos[6a,20] could
give relatively higher ees (Table 1). For example, (Sc, Rs)-PC3
could give 3a in 91% yield with 92% ee (Table 1, entry 3).
Moreover, (Sc, Rs)-N-Me-PC3 lacking the hydrogen-bonding site
delivered 31% ee (Table 1, entry 4). However, (Rs)-PC7 with
chirality only at the sulfur atom give a racemic product, indicating
that carbon chirality is quite important for obtaining high enantio-
[a]
[b]
P.-C Zhang, J. Han and Prof. Dr. J. Zhang*
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, School of Chemistry and Molecular Engineering,
East China Normal University
Shanghai, 200062 (P. R. China)
Prof. Dr. J. Zhang
Department of Chemistry, Fudan University, 2005 Songhu Road,
Shanghai, 200438 (P. R. China)
E-mail: junliangzhang@fudan.edu.cn
Supporting information for this article is given via a link at the end
of the document. ((Please delete this text if not appropriate))
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Table 1. Optimization of the reaction conditions. [a]
deliver the desired 3s–3u in high yields with 90–95% ees.
Gratifyingly, 2-naphthyl and 3-thienyl derived allenes delivered
the cyclization products 3v–3w in 90−91% yields with 91–95%
ees. The structure and absolute configuration of 3x were
determined by single-crystal X-ray diffraction analysis.[21]
Yield (Ee)
Entry
EWGb
[M]
L
Solvent
[%]c,d
1
2
3
4
5
6
7
8
9
Tf (1a)
Tf (1a)
Tf (1a)
Tf (1a)
Tf (1a)
Tf (1a)
Tf (1a)
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(dba)2
PC1
PC2
PC3
DMSO
DMSO
DMSO
90(82)
89(86)
91(92)
87(31)
88(37)
85(0)
89(91)
90(91)
-
N-Me-PC3 DMSO
PC4
PC7
PC3
PC3
PC3
PC3
PC3
PC3
PC3
PC3
PC3
PC3
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Tf (1a) Pd2(dba)3•CHCl3
Tf (1a)
Tf (1a)
Tf (1a)
Tf (1a)
Tf (1a)
Ts (1b)
Bz (1c)
Tfb (1d)
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
10
85(73)
86(78)
-
11
12
13e
14
15
16
MeOH
CH3CN
DMSO
DMSO
DMSO
DMSO
90(89)
-
-
-
[a] Unless otherwise noted, all reactions were carried out with 0.1 mmol of 1 and
0.12 mmol of 2a, 10 mol% of catalyst ([Pd] to PC-Phos = 1:1.1) in 1.0 mL of
solvent at 40 ºC for 24 h; [b] Tf: trifluoromethylsulfonyl; Ts: p-tolylsulfonyl; Bz:
benzoyl; Tfb: 4-(trifluoromethyl)phenylsulfonyl. [c] Isolated yield. [d] Determined
by chiral HPLC. [e] At 30 oC.
selectivity (Table 1, entry 6). Other palladium salts such as
Pd(dba)2, Pd2(dba)3•CHCl3 and Pd(OAc)2 were then examined as
precatalysts under the identical reaction conditions (Table 1,
entries 7–9), among which Pd2(dab)3 exhibited the best
enantioselectivity. Subsequently, other polar solvents such as
DMF, MeOH and CH3CN were then examined but faild to give
better result (Table 1, entries 10–12). Lowering the temperature
to 30 ºC slightly decreased the ee to 89% (Table 1, entry 13).
Finally, the adjustment of the N1-electron-withdrawing group of
benzotriazole (1b, 1c and 1d) from Tf to Ts, Bz and Tfb could not
deliver the corresponding products 3b-3d, indicating that the
electron-withdarwing group also plays crucial role for this
denitrogentive cyclization (Table 1, entries 14–16).[3c]
With the optimized reaction conditions in hand, the scope of this
asymmetric denitrogenative cyclization reaction was then
investigated, and the results are shown in Scheme 2. In general,
high yields (88-97%) with 89–98%ees were exclusively obtained
for the new aza-quaternary stereogenic center. For example, the
benzotriazoles bearing one or two electron-donating groups (Me,
OMe) at the para-positions of N1 or N3, generally react well to
furnish the desired products 3f–3j in 88-90% yields with 91–97%
ees. Notably, naphthotriazole worked also well, furnishing the
corresponding product 3k in 89% yield with 91% ee. Next, the
scope of 1,1-disubstituted allene 2 was further investigated. A
tolerance towards both electron-donating and electron-
withdrawing aryl group of allene was observed, furnishing 3l–3r
in excellent yields (89–97%) with 89-98% ee. Especially, the
halogens (F, Cl, Br) of the phenyl ring are also compatible to
Scheme 2. Cyclization reaction of benzotriazoles with allenes.
We next turned to examine whether N-allenamides[22] 4 were
applicable to the present reaction. We found that only trace
amount of the corresponding cyclization product 5a was detected
under the above conditions. After many attempts (see SI, Figure
S2 and Table S1), we finally identified the following reaction
conditions : Pd(dba)2 (5 mol%), PC4 (7.5 mol%), 1a, and 1.2 equiv
o
of 4a in toluene at 40 C for 48 h, could well deliver 5a in 91%
yield and 92% ee. The structure and absolute configuration of 5a
were determined by single-crystal X-ray diffraction analysis.[21]
The scope of this reaction was then examined (Scheme 3).
Notably, those benzotriazoles bearing diverse functional groups
(R), such as the halogens (F, Cl, Br), and electron-donating
groups (Me, OMe, SPh) at the various positions of the phenyl ring
were compatible to deliver the desired 5a-5o in high yields with
84–95% ees. Naphthotriazole worked also well, furnishing the
corresponding product 5p in 91% yield with 90% ee. Then, by
changing the substitution on the sulfonyl group (PG), the reaction
could proceed 5q in 91% yield with 91% ee. Next, variation of R3
on the N-allenamides from phenyl to PMP and Bn did not led big
difference and the desired products 5r-5t were produced in high
yields with good ees. Interestingly, the R4 group of attached
indoles of N-allenamide,[6a] which is several bonds away, still
affect the enantioselectivity in some sense (5u-5v).
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10.1002/anie.201904805
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for this palladium-catalyzed denitrogenative cyclization reaction
(Scheme 5). Benzotriazoles 1 would undergo a ring-chain
isomerization to form the corresponding diazonium l-A via a
Dimroth-type equilibrium.[3c,25] Oxidative addition of l-A with
palladium complex and extrusion of nitrogen gas would generate
the intermedaite I-B. The insertion of allene or allenamide into the
C-Pd bond would deliver a π-allylpalladium complex l-C, which
unpon allylic substitution would produce the cyclization product 3
or 5 and regenerate the palladium catalyst.
Scheme 5. Proposed mechanism.
In summary, we have developed the first highly chemo-, regio-,
and enantioselective palladium-catalyzed denitrogenative
cyclization reaction of benzotriazoles with allenes or N-
allenamines with the use of chiral sulfinamidephosphine type
ligand PC-Phos. A series of optically active 3-methyleneindolines
were obtained in high yields and with excellent ees. This method
can be expected to find wide synthetic applications, in view of the
high efficiency, simple operation, mild reaction conditions, base
free, high chemo- and enantioselectivity. Inspired by this work, we
anticipate that more catalytic asymmetric and synthetically
valuable transformations of benzotriazoles will be developed in
near future.
Scheme 3. Cyclization reaction of benzotriazoles with N-allenamides.
To demonstrate the practical utility of our protocol, gram-scale
reactions were carried out under standard conditions,
furnishing1.1 g of 3j in 89% yield with 97% ee and 1.1 g of 3x in Acknowledgements
90% yield with 94% ee, respectively (Scheme 4). Treatment of
compounds 3j and 3x with RuCl3/NaIO4 gave good yields of the
chiral ketones 6, which are common skeleton in biologically
relevant products. [23]
We gratefully acknowledge the funding support of NSFC
(21425205, 21672067), 973 Program (2015CB-856600)
Keywords: Denitrogenative cyclization • Allene • Allenamide•
Palladium•Benzotriazole
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Pd/PC-Phos-Catalyzed Enantioselective
Intermolecular Denitrogenative Cyclization of
Benzotriazoles with Allenes or N-allenamides
The first example of enantioselective denitrogenative cyclization of benzotriazoles with allennes
and N-allenamides was enabled by Pd/PC-Phos catalysis, which provides a rapid access to
optically active 3-methyleneindolines in good yields with high ees.
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